Objective: To analyze synovial tissue obtained at surgery of patients with hemochchromatosis arthropathy and compare them with rheumatoid arthritis (RA) and osteoarthritis (OA) specimens qualitatively and quantitatively.

Methods: Synovial tissues of 15 HH patients, 20 RA patients and 39 OA patients were obtained during surgery. A synovitis grading system was used to determine the severity of synovial inflammation. Using immunohistochemistry, synovial neovascularization and infiltration of macrophages, neutrophils and lymphocytes was quantitatively assessed.

Results: Synovitis in hemochromatosis arthropathy largely resembles OA with mild infiltration of mononuclear cells and lymphocytes, decent formation of synovial microvessels and low degree of synovial hyperplasia. While many features of hemochromatosis arthropathy are reminiscent of OA, macrophage and especially neutrophil invasion is clearly more prominent in hemochromatosis arthropathy than in primary OA and mimics features of RA. This finding was especially observed in synovial tissue of hemochromatosis samples with marked haemosiderin deposition.

Discussion: The histological picture of the synovium in hemochromatosis arthropathy largely resembles a process reminiscent of osteoarthritis. Neutrophil invasion is however markedly increased in hemochromatosis arthropathy especially in joints with iron deposition. Accumulation of neutrophils may be crucial for production of matrix enzymes, which enables cartilage degradation and more rapidly progressing articular damage.

Methods: In this double-blind, Phase II, placebo-controlled 2-year study, anti-CCP2-positive patients with UA (not fulfilling the ACR criteria for RA) and clinical synovitis of ≥2 joints were randomized to abatacept (~10 mg/kg) or placebo for 6 months, then study drug was terminated. The primary endpoint was development of RA (by ACR criteria) at Year 1. Patients were monitored by radiography, MRI, CCP2, RF, DAS28 and 28-joint count over 2 years.

Results: At Year 1, 12/26 (46%) abatacept-treated versus 16/24 (67%) placebo-treated patients developed RA (difference [95% CI] –20.5% [–47.4, 7.8]). Adjusted mean changes from baseline to Year 1 in Genant-modified Sharp radiographic scores for abatacept- versus placebo-treated patients, respectively, were: 0 versus 1.1 for TS, and 0 versus 0.9 for ES. Mean changes from baseline to Year 1 in MRI erosion, osteitis and synovitis scores were 0, 0.2 and 0.2, respectively, versus 5.0, 6.7 and 2.3 in the abatacept versus placebo groups. Safety was comparable between groups; serious AEs occurred in one patient (3.6%) in each group.

Conclusion: Abatacept delayed progression of UA/very early RA in some patients. An impact on radiographic and MRI inhibition was observed, which was maintained for 6 months after therapy cessation. This suggests that it is possible to alter the progression of RA by modulating T-cell responses at a very early stage of disease.

Objectives: To investigate the role of ASIC3 in joint tissue, specifically the relationship between ASIC3 and hyaluronan, and the response to decreased pH.Methods: We utilized histochemical methods to compare morphology, hyaluronan expression and ASIC3 expression in ASIC3+/+ and ASIC3-/- mouse knee joints. We used isolated fibroblast-like synoviocytes (FLS) to examine hyaluronan release and intracellular calcium in response to decreases in pH.

Results: In tissue sections from ASIC3+/+ mice, ASIC3 localized to articular cartilage, growth plate, meniscus, and Type B synoviocytes. In cultured FLS, ASIC3 mRNA and protein was also expressed. In FLS cultures, pH 5.5 increased hyaluronan release in ASIC3+/+ FLS, but not ASIC3-/- FLS. In FLS from ASIC3+/+ mice, approximately 50% of cells (25/53) increased intracellular calcium while only 24% (14/59) showed an increase in ASIC3-/- FLS. Of the cells that responded to pH 5.5, there was significantly less intracellular calcium increases in ASIC3-/- FLS compared to ASIC3+/+ FLS.

Conclusion: ASIC3 may serve as a pH sensor in synoviocytes, and be important for modulation of expression of hyaluronan within joint tissue.

Methods: RA patients (n=24) and controls (n=15) were included. Nine RA patients were re-evaluated after 8 weeks of intensive treatment with a combination of drugs (COBRA-scheme). Disease activity was measured by ESR, C-reactive protein (CRP) and disease activity score of 28 joints (DAS28). Flow cytometry was used to study MP and exposure of complement activator molecules and complement components.

Results: At baseline, concentrations of MP exposing C1q, CRP or SAP were all significantly elevated in early RA patients compared to controls (p=0.003, p=0.002, and p=0.003, respectively). Upon treatment, DAS28, ESR and CRP significantly decreased (P=0.008, P=0.008 and P=0.012), but the concentrations of circulating MP and MP exposing complement components or activator molecules were unaffected.

Conclusion: Circulating MP exposing complement components or activator molecules are elevated in early RA. Since a strong anti-inflammatory therapy suppressed inflammation in early RA patients but not levels of circulating MP, it is unlikely that inflammation is the main underlying cause of MP release in these patients.

Methods: Five tag single-nucleotide polymorphisms (SNPs) and eight variations in all known regulatory sequences affecting IFNG expression within and around IFNG were genotyped in 1759 unrelated Korean subjects. SLE susceptibility association was assessed by comparing 742 SLE patients and 1017 unaffected controls using multivariate logistic regression analysis with adjustment for age and gender.

Results: SLE susceptibility association was significant with rs2069705 in the promoter (adjusted OR 2.27, p = 0.0024) and marginal with rs3181032 in the promoter (p = 0.037), rs2430561 in intron 1 (p = 0.022) and rs2069718 in intron 3 (p = 0.026) in a recessive genetic model. Five other SNPs showed no association and four other variations were not polymorphic.

Conclusion: Several SNPs in IFNG are associated with SLE susceptibility, and the risk allele of an associated SNP (rs2430561) located in an NF-B binding site has elevated IFNG expression versus the non-risk allele, supporting that elevated IFNG expression is associated with increased SLE susceptibility.

Methods: Mouse articular chondrocytes in primary culture were challenged with IL-1β, alone or combined with Notch1 and IL-β pathways inhibitors. Notch1 and Hes1 expressions were investigated by immunocytochemistry, western blot and real-time qPCR. IL-β-responsive genes were assessed by real-time qPCR and a specific siRNA against Hes1 was used to identify Hes1 target genes.

Results: Notch1 labeling remained nuclear and stable in intensity irrespective of treatment, suggesting a steady-state activation of this pathway in our model. IL-1β transiently increased Hes1 mRNA (2.5-fold) and protein expression in treated versus naive chondrocytes. Hes1 mRNA level then decreased below control and its cyclic pattern of expression was lost. This was associated with nuclear translocation of the cytoplasmic Hes1 protein. IL-1β induced increase in Hes1 mRNA was transcriptional, occurred through NF-B activation and appeared to be associated with down-regulation by its own protein. Hes1 induction was insensitive to the -secretase inhibitor DAPT which suggested its independence from novel Notch1 activation. Hes1 expression was efficiently silenced by a specific siRNA. This experiment revealed that Hes1 did not mediate IL-1β-induced down-regulation of Sox9, type II collagen and aggrecan transcription but mediated IL-1β induction of MMP-13 and ADAMTS-5. The Hes1-related repressor Hey1 was expressed at a very low level and was not inducible by IL-1β.

Conclusion: Hes1 is a novel IL-1β target gene in chondrocytes which influences a discrete subset of genes linked to cartilage matrix remodeling and/or degradation.

Whole body magnetic resonance imaging (MRI) has recently been introduced for the assessment of various skeletal pathologies including malignancy, myositis and arthritis [8-12]. MRI in inflammatory disorders has the capacity to show both soft tissue inflammatory changes and osteitis. We hypothesised that patients with TRAPS without obvious clinical manifestations and the absence of fevers have subclincal disease affecting the anatomical territories that are prone to inflammation during acute attacks. Herein, we confirm that some cases of TRAPS do indeed have ongoing soft tissue and joint inflammation between attacks. Given that autoinflammatory disorders, like TRAPS, are diseases of the innate immune system, these findings support the concept of persistent innate immune activation between attacks.

The Galway (Ireland) TRAPS cohort consists of 15 affected family members, 2 of whom have amyloidosis and all having the T50M mutation in the TNFRSF1A gene [13]. A total of 9 members of this family attend the clinic regularly. Persistently raised inflammatory markers were found in 7 of these patients, 2 members did not give consent for MRI due to claustrophobia. A total of 5 members participated in the study, however during the course of the study; one of these patients had normal inflammatory markers in spite of having persistently raised markers before screening. Interview and clinical examination were performed to document symptoms, frequency of flares, inflammatory markers and medications (Table 1).

All cases described classical attacks of fever, sweats, abdominal pain and serositis. They also had symptoms between attacks including prominent myalgia, arthralgia, malaise and fatigue, with persistently elevated inflammatory markers in 4 out of 5 patients confirming ongoing disease activity between attacks. After obtaining informed consent, all 5 cases had whole body scanning on a Siemens 1.5 T MRI (Siemens-AG, Symphony). Images were reviewed on Agfa PACS High resolution workstation by two fellowship trained musculoskeletal radiologists. One patient had a flare during the MRI and was rescanned between flares. MRI results are shown in Table 1.

Bilateral knee and hip effusions and bone oedema of left tibia were found in one patient, who was asymptomatic at the time of his scan and did not have osteoarthritis clinically or radiologically in this knee. Repeat MRI of the left knee was done. It is possible that the knee changes could have been contributed to by ligament injury and joint degeneration that was asymptomatic. Only one MRI of 5 was completely normal with corresponding normal inflammatory markers (Figure 1).

In conclusion, we provide MRI evidence for persistent subclinical tissue inflammation in an identical pattern to that seen during classical attacks of TRAPS. This suggests that the innate immune driven pathology is actually chronic and most likely represents recurrent acute attacks of subclinical tissue inflammation. Unlike some other conditions of chronic innate immune activation including Blau syndrome, the inflammation in TRAPS does not appear to lead to target organ destruction [14]. The utility of whole body MRI for exploring febrile illness with a TRAPS phenotype without TNFRS1A mutations is also worthy of consideration.

Method: Blood samples from 31 pSS patients and 28 gender- and age-matched healthy controls were analyzed by flow cytometry using the Miltenyi Blood DC Enumeration kit. The presence of pDC in salivary glands (SG) from pSS patients was analyzed by immunohistochemistry.

Results: Patients with pSS had significantly less pDC and mDC2 in peripheral blood compared to healthy controls. Moreover, pDC are present in SG from patients with pSS.

Conclusion: Alterations among DC populations have been considered to play a role in other autoimmune diseases. Here we show that patients with pSS have decreased levels of pDC and mDC2 in peripheral blood and pDC are present in the SG, suggesting a potential role of these cells in SS.

Vaspin, a member of the serine protease inhibitor family, and omentin (also known as intelectin) were recently identified in adipose tissue (7, 8). Vaspin is an adipokine with insulin-sensitizing effects that has been suggested to be a compensatory mediator for abrogating obesity and its inflammatory complications (7). Expression of the omentin gene was demonstrated in omental adipose tissue of patients with Crohn’s disease, suggesting that it may be implicated in chronic inflammatory diseases (8). The aim of the present report was to compare local concentrations of vaspin and omentin in synovial fluid of RA patients with those in osteoarthritis (OA) patients and to characterize their potential association with the severity of the disease.

Synovial fluid was obtained during therapeutic arthrocentesis from 33 patients with RA and 33 patients with knee OA. The disease activity of RA patients was assessed by DAS28. C-reactive protein (CRP), IgM-rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) were routinely analyzed from peripheral blood obtained at the time of arthrocentesis. Characteristics of the patients are given in Table 1. Vaspin (AdipoGen Inc. Korea) and omentin (Apotech Corporation) were analyzed in synovial fluid by ELISA assays. Ethical approval was obtained from the local Ethics Committee and all patients provided informed consent. Statistical analysis was performed using GraphPad Prism 5.0 software. To meet a normal distribution, vaspin and omentin concentrations were naturaly logarithmically (log)-transformed. Differences between two independent parameters were determined by Kruskal-Wallis or T-test. The Spearman test was used for correlation of parameters.

As shown in figure 1, the mean (SD) levels of vaspin were significantly higher in the synovial fluid of RA patients than in OA patients (-2.439±1.226 vs. -3.366±1.318 (log) pg/ml; p=0.003), but interestingly the levels of omentin were significantly lower in the synovial fluid of RA patients compared to OA patients (1.491±0.948 vs. 1.964±0.902 (log) ng/ml; p=0.045). After log-transformation, synovial fluid vaspin, but not omentin, had a tendency to correlate with DAS28 (r=0.320, p=0.070) in RA patients. However, neither vaspin nor omentin correlated with serum CRP or leukocyte counts in synovial fluid. In addition, levels of synovial fluid omentin, but not vaspin, significantly correlated with serum ACPA (r=0.398, p=0.029) and IgM-RF (r=0.592, p<0.001). The levels of synovial fluid vaspin and omentin were not affected by body mass index (BMI) or age of the patients. The mean concentration of synovial fluid vaspin, but not omentin, was twice as high in female as in male patients, but possibly due to the low number of male patients in this study, it failed to reach statistical significance.

Our data shows different levels of the new adipokines vaspin and omentin at the site of local inflammation. We demonstrate here for the first time elevated levels of vaspin and reduced levels of omentin in synovial fluid of patients with RA compared with those with OA.

Two SNPs, rs1887346 and rs9565072 mapping to the KLF12 gene, were tested. The former was selected because it showed weak evidence for association in the UK GWAS, whilst the latter is perfectly correlated (r2=1, HapMap CEU population) with rs1324913, the SNP reported to be most associated with RA in independent Spanish cohorts but which failed assay design. The SNPs were genotyped using the Sequenom platform after imposing quality control thresholds of >90% SNP and sample success rates and no significant deviation from Hardy-Weinberg expectations (p>0.05). However, in an available cohort of 3962 cases and 3531 controls recruited from throughout the UK as reported previously (5;6), no evidence for association with either SNP was detected at a significance threshold of p < 0.025, corrected for multiple testing (Table 1). Similarly, stratification analysis by gender and autoantibody status revealed no evidence for association (data not shown).

It is well-recognised that individual GWA studies have limited power to replicate association at all truly associated loci meaning that failure to detect association in independent cohorts does not necessarily mean that the association is not real. However, the sample size used in the current study had >95% power to detect an effect size of 0.77 reported for rs1324913 intron 1 KLF12 SNP in the Spanish cohort at the 1% significance level. Effect sizes can be over-estimated in the first study to report an association (winner’s curse); hence power calculations were made based on the Spanish validation cohort effect size.

The KLF12 gene is large (~448Kb) and contains several linkage disequilibrium (LD) blocks. Although meta-analysis incorporating data from UK, US and Swedish populations did not highlight this locus as showing evidence for association (7), different SNPs showed weak association in the UK and US GWA series raising the possibility that the true effect may be due to a SNP not directly genotyped by any of these studies but in LD with the genotyped variants. if the extent of the LD varied between populations, this may explain the different associations reported. However, imputed data for all HapMap phase 2 SNPs across this locus from the UK GWAS (433 SNPs, 81% coverage at r2 > 0.8) does not reveal increased evidence for association with any other SNP in the region (data not shown).

In summary, in a large UK RA cohort, we have failed to add to the evidence for association at the KLF12 locus, reported to be associated with RA in independent Spanish cohorts. Analysis in other large cohorts and subsequent meta-analysis will be required before association at this locus can be confidently excluded.

Methods: Peak KAM and KAM impulse were measured during walking and BMLs were assessed from knee MRI in 91 individuals with medial knee OA. Logistic regression analyses were performed with presence/absence of medial tibial or medial femoral BMLs as the outcome and either peak KAM or KAM impulse as the independent variable. Analyses were also adjusted for age, gender, BMI, alignment and walking speed.

Results: Medial tibial BMLs were found in 64% of knees and medial femoral BMLs in 60%. In adjusted analyses, peak KAM was significantly related to medial tibial (OR 2.3; 95%CI 1.07-4.7), but not medial femoral BMLs (OR 1.85; 95%CI 0.93-3.7). KAM impulse was significantly related to both medial tibial (OR 9.4; 95%CI 1.53-57.2) and medial femoral (OR 14.4; 95%CI 2.3-89.8) BMLs.

Conclusions: The findings support the hypothesis that greater mechanical loading of the medial compartment plays a role in the pathogenesis of BMLs in medial tibiofemoral OA.

Methods: 19 systemic sclerosis (SSc) patients were treated with maximally tolerated sildenafil doses up to 6 months. Primary outcome was the healing of DU. Furthermore, changes in other clinical symptoms were evaluated.

Results: 49 DU were present at baseline that decreased to 17 ulcers (p < 0.001) at the end of sildenafil therapy. Furthermore, the visual analogue scale score for Raynaud’s phenomenon (RP), pain, and activity improved (p = 0.003, p = 0.002, and p = 0.05, respectively). Nine patients developed 12 new DU during sildenafil therapy.

Conclusions: This study indicates an effect of sildenafil on DU healing in SSc patients, improvement of RP and associated symptoms that should be validated in controlled studies.

Methods: Patients with very early IP (4-10 weeks duration) were randomised to receive 3 injections of either 80 mg IM methylprednisolone-acetate or placebo, given at weekly intervals. Assessments were monthly until six months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the six month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months.

Results: Patients in the placebo group (76%) were more likely to need DMARDs during the first six months of the trial than patients in the glucocorticoid group (61%) (adjusted OR: 2.11, 95%CI 1.16 to 3.85, p=0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid treated group (adjusted OR: 0.42, 95%CI 0.18 to 0.99, p=0.048).

Conclusion: Treatment of patients with very early IP with IM methylprednisolone-acetate appears to postpone the prescription of DMARDs and prevent one in ten patients from progressing into RA.

Methods: We followed the EULAR standardised procedures for guideline development. The following techniques were applied: nominal group, Delphi surveys for priorisation, small group discussion, systematic literature review, and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine.

Results: Ten recommendations have been developed, including the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment.

A "core set" of minimal variables for the assessment and monitoring of SLE patients in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart.

Conclusions: A set of recommendations for monitoring SLE patients in routine clinical practice has been developed. The use of a standardized core set to monitor SLE patients should facilitate clinical practice, as well as the quality control of care for SLE patients, and the collection and comparison of data in observational studies.

Methods: 642 subjects from a primary-care registry of patients with new onset IP, recruited 1990-1994, were followed for 10 years. Mean change in HAQ scores between baseline and 10 years were compared by time to and time on first DMARD treatment and total time on treatment, using linear regression. Adjustment for time dependent confounders and censoring was performed using marginal structural weights.

Results: When adjusted for baseline and subsequent disease severity, those treated early (<6 months from symptom onset) experienced a non-significant improvement in function compared to those never treated (adjusted mean difference in change (adj_MDIC) in HAQ -0.24; 95% CI -0.58, 0.09); and a significant benefit for each additional month of treatment within 6 months of the onset of symptoms (adj_MDIC -0.10 95% CI; -0.19, -0.02). Patients who discontinued their first DMARD within 6 months experienced a significant deterioration in long-term function (adj_MDIC in HAQ 0.28 95% CI; 0.04, 0.52), while those who continued their first therapy for greater than 3 years experienced an improvement (adj_MDIC in HAQ -0.37; 95% CI -0.77, 0.04).

Conclusions: We have demonstrated the importance of time to and response to first DMARD treatment and total duration of DMARD treatment in modifying the 10 year function in patients with IP.

To compare lipid profiles in patients with rheumatoid arthritis (RA) and non-RA subjects during the 5 years before and 5 years after RA incidence/index date.

Cardiovascular disease (CVD) is partially attributed to traditional cardiovascular risk factors, which can be identified and managed based on risk stratification algorithms (Framingham Risk Score, National Cholesterol Education Program, Systematic Cardiovascular Risk Evaluation and Reynolds risk score). We aimed to: (a) identify the proportion of at risk RA patients requiring statin therapy identified by conventional risk calculators, and (b) assess whether patients at risk were receiving statins.

Genetic association of Interferon Regulatory Factor 5 (IRF5) with SLE susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, we examined whether such genetic variation predisposes to activation of the Interferon-) (IFN-) pathway.

Dehydroepiandrosterone (DHEA) has been reported to improve fatigue and reduced well-being. Both are major problems in patients with systemic lupus erythematosus (SLE), even with quiescent disease. Low serum DHEA levels are common in SLE. We investigated the effects of DHEA administration on fatigue, well-being, and functioning in women with inactive SLE.

The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-TNF therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). We aimed to compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity.

Patients with rheumatoid arthritis (RA) complain about fatigue. Aim of this study was to gain further insight into the experience of fatigue in RA.

To replicate and refine the reported association of ankylosing spondylitis (AS) with 2 non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1.

To identify a novel serum biomarker of disease activity in inflammatory autoimmune disorders using a quantitative proteomic approach.

To evaluate the impact of TNF blockers on the presence of liver fibrosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with methotrexate (MTX).

Dendritic cells (DCs) play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Reduced numbers of blood DCs and the accumulation of DCs at inflammatory sites have been observed in SLE. One crucial feature of DCs is their ability to migrate. We analyzed thematuration/activation state and the migratory capacity of different DC precursor subsets in SLE to further elucidate their role in autoimmunity.

Negative radiographic change scores obtained under blinded time-sequence conditions suggest that repair of joints may indeed occur. It is likely that - C if it truly exists - C repair would be preferentially seen in clinically inactive joints from patients treated with drugs with well known structural efficacy.

To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare risks for different anti-TNF agents.

Physical disability is a main outcome in rheumatoid arthritis which tends to increase with comorbidities. Nevertheless it is not yet investigated to which extent comorbidities contribute to the multifactorial process of disability.

To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its sub-phenotypes.

To optimize a strategy for identifying gene expression signatures differentiating SLE and anti-neutrophil cytoplasmic antibody-associated vasculitis that provide insight into the pathogenesis and identify biomarkers.

We evaluated the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identified predictors of good clinical responses for joint and skin lesions.

To investigate if the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of pro-thrombotic antiphospholipid antibodies (aPL) in SLE patients.

Currently, the assessment of dermal thickness in Systemic Sclerosis (SSc) is performed by palpation with the modified Rodnan Skin Score (mRSS).

Background: Early endothelial cell (EC) activation/damage and pro-fibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin (IL)-33 is a novel IL-1 family member that promotes Th2-responses and inflammation through the ST2 receptor. IL-33 is also a chromatin-associated transcriptional regulator in ECs.

Objective: To investigate the role of IL-33/ST2 axis in SSc.

Methods: Skin biopsies were obtained from 30 SSc patients (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, esophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from SSc patients and controls were also analysed. IL-33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, Western blotting and RT-PCR.

Results: In control skin, constitutive nuclear IL-33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In early SSc skin, IL-33 protein was down-regulated or absent in ECs and epidermis, while IL-33 mRNA was normally expressed or even up-regulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells, and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In late SSc skin, IL-33 was constitutively found in most ECs, while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL-33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL-33 expression in SSc.

Conclusion: IL-33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage, IL-33 may be mobilised from ECs to signal through ST2 in key pro-fibrotic players, such as inflammatory/immune cells and fibroblasts/myofibroblasts.

Objective: Autoantigen-specific immunotherapy by means of mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human Cartilage glycoprotein-39 (HC gp-39) has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesized to induce immunological tolerance in RA patients and to ameliorate disease activity. In a Phase I/IIA clinical trial in RA patients, intranasal application of HC gp-39 was safe and well tolerated. The current paper describes the first large clinical study investigating the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141).

Methods: In a 13-wk multicenter, double-blind, randomized, placebo-controlled, parallel group, dose-finding, Proof-of-Concept trial, patients with RA (DMARD naïve or following wash-out of DMARD therapy) were randomized to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 micrograms, once per week. The primary efficacy variable was the DAS28.

Results: During the treatment period the DAS28 decreased similarly for all treatment groups - including placebo - indicating lack of efficacy of intranasal HC gp-39 therapy in the current setting. Safety variables were similar for all study groups.

Conclusion: It was concluded that, with the use of the chosen treatment protocol (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in clinical improvement different from that seen in placebo-treated patients.

Objectives: TNF blockade is an effective therapy for rheumatoid arthritis (RA). Immunomodulatory effects of TNF antagonists are thought to contribute to their therapeutic action. Here, we investigated whether anti-TNF therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function.

Methods: Two complementary approaches were taken: In the first 'in vitro' approach monocyte-derived DC from healthy donors were matured with LPS and treated with TNF antagonists in vitro for 48 hours. In the second 'ex vivo' approach monocyte-derived DC were generated from RA patients before and 8-12 weeks into anti-TNF treatment. DC were analysed for survival, phenotype, cytokine production and T cell stimulatory capacity.

Results: TNF blockade during DC maturation in vitro induced approximately 40 % of DC to undergo apoptosis. Importantly, the surviving DC displayed a semi-mature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced as compared to DC matured without TNFfnantagonists. Furthermore, anti-TNF-treated DC were poor stimulators of T cell proliferation and polarised T-cell development towards a higher IL-10/lower IFN- cytokine profile. Similarly, DC derived from RA patients after anti-TNF treatment showed impaired upregulation of CD80 and CD86 upon LPS activation and displayed poor T cell stimulatory activity.

Conclusions: Our data show that TNF blockade has profound effects on DC function with downstream, potentially immunoregulatory, effects on T-cells. These data provide an interesting new insight into the potential mechanism by which anti-TNF drugs contribute to the restoration of immunoregulation in RA patients.

Objective: It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. TNFSF4, which encodes for the T-cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.

Methods: We tested 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, for association with SSc in a collection of 1059 SSc cases and 698 controls.

Results: Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95%CI 1.04-1.4, P_FDR=0.019), rs2205960 (OR 1.24, 95%CI 1.10-1.50, P_FDR=0.019), and rs844648 (OR 1.16, 95%CI 1.01-1.30, P_FDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95%CI 0.70-0.97, P_FDR=0.038). Analysis of subsets of SSc patients demonstrated significant associations of the TNFSF4 SNPs with both limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.

Conclusions: Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

Background: Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings.

Purpose: To study whether a 3-month placebo period is sufficient to prove efficacy.

Methods: Meta-analysis of placebo- or active control trials of biologic agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months.

Results: Twenty trials yielded 15 placebo and 18 active control contrasts (> 10.000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and -50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months due to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and-70 these decreased somewhat due to 'catch-up' responses in the control groups.

Conclusion: The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes to then switch placebo patients to standard of care, allowing a more valid and comprehensive assessment including safety.

Objective: To assess the responsiveness of ultrasound (US) inflammatory findings in the shoulder and hip of patients with polymyalgia rheumatica (PMR) who began treatment with corticosteroids (CST).

Methods: 53 patients with active PMR who started treatment with prednisone from 6 Spanish centres were prospectively studied. The patients underwent clinical, laboratory, and US assessment at baseline, 4 weeks, and 12 weeks. The US investigation consisted of detection and quantification of inflammatory findings in the shoulder and the hip. Responsiveness of clinical, laboratory and US parameters was tested by the standardized response mean (SRM). Intraobserver and interobserver reliability between US investigators were assessed.

Results: At baseline, 34 (69%) patients presented inflammation in at least a bilateral site. During the follow-up, clinical, laboratory, and US variables showed a parallel decrease. A significant decrease in US inflammatory parameters was found at week 4 (p<0.001). After 4 weeks and 12 weeks of CST therapy, US inflammatory findings showed similar or better sensitivity to change than clinical and laboratory markers of PMR activity. Intraobserver and interobserver intraclass correlation coefficients were 0.96 and 0.99, respectively (p<0.05).

Conclusion: US may be a responsive additional tool in monitoring CST response in PMR patients in daily practice and multicentre trials.

Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA).

Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing 9 European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's 'standardised operating procedures', the multidisciplinary steering committee formulated evidence-based and expert opinion based recommendations for CV risk screening and management in patients with inflammatory arthritis.

Results: Annual CV risk assessment using National Guidelines is recommended for all RA patients and should be considered for all AS and PsA patients. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk.

Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA on the other hand, as evidence for an increased CV risk is most compelling for RA.

Objective: To explore perspectives among patients and rheumatologists on glucocorticoid (GC) therapy and EULAR recommendations on the management of systemic GC therapy in order to enhance implementation of the recommendations.

Methods: Rheumatologists (from eight countries) and patients (from five countries) acquainted with GCs participated in separate meetings, during which positive and negative aspects of GC therapy were discussed and possible adverse events (AEs) were ranked for importance; in addition participants were asked to evaluate the published EULAR recommendations. The reports from these meetings and themes related to implementation of the recommendations were discussed during an international forum of the experts who had formulated the recommendations and patient participants.

Results: 140 patients (78% female; mean age 53 years; 61% rheumatoid arthritis patients) and 110 rheumatologists (mean work experience 15 years) participated in the meetings. Osteoporosis, diabetes and cardiovascular diseases were ranked among the five most worrisome AEs by patients and rheumatologists. In both groups, there was agreement with most of the recommendations; the recommendations on GC information cards and GC use during pregnancy scored lowest. Ideas to improve implementation of the recommendations and a research agenda were generated.

Conclusion: The patients' and rheumatologists' views on GCs correspond to a large extent, reflected by concerns in both groups about osteoporosis, diabetes and cardiovascular diseases. Specific problems with the EULAR recommendations were identified and addressed to improve their implementation. This exercise shows that patients’ and rheumatologists’ perspectives should be included early in the process of formulating recommendations.

Objectives: To develop evidence based recommendations for the diagnosis of knee osteoarthritis (OA).

Methods: The multidisciplinary guideline development group, representing 12 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the sensitivity, specificity and likelihood ratio were calculated for individual diagnostic indicators and a diagnostic ladder was developed using Bayes' method. Secondary analyses were undertaken to directly test the recommendations using multiple predictive models in two populations from the UK and the Netherlands. Strength of recommendation was assessed by the EULAR visual analogue scale.

Results: Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests, and differential diagnosis. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged 45 years and older, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all 6 symptoms and signs were present. The performance of the recommendations in the study populations varied according to the definition of knee OA, background risk and number of tests applied.

Conclusion: 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus. Although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.

Gout is characterised by monosodium urate crystals in hyperuricemic individuals.[1, 2] Impaired excretion of urate exacerbates this condition.[1] Urate transporter 1 (encoded by SLC22A12) is an urate-anion exchanger in the kidneys mediating urate transportation across the proximal tubules' apical membrane.[3, 4] SLC22A12 has been reported to influence urate homeostasis in Caucasian and Japanese[5-8] but SNPs' genotype effect on gout is unclear. We studied four SLC22A12 single-nucleotide polymorphisms' (SNPs) associations with gout and urate levels in male Han Chinese of Taiwan and Solomon Islanders.

Objective: Specific composite indices assessing disease activity in psoriatic arthritis (PsA) have not yet been sufficiently validated. The objective of this study was to identify instruments best reflecting disease activity in PsA.

Methods: Measures for inclusion in clinical trials, as recommended by the OMERACT-7/8 PsA workshops, were assessed. A principal component analysis (PCA) was performed with cross-sectional data of 105 PsA patients to identify a minimal set of important dimensions for a disease activity assessment tool for PsA. This was compared with components contained in existing composite indices.

Results: The PCA revealed four principal components best reflecting disease activity. The first contained patient global and pain assessment. The second contained 66/68 swollen and tender joint counts as main variables. C-reactive protein (CRP) best loaded to the third component. The fourth was loaded by skin assessment but did not reach significance. When comparing the three significant principal components with items of established composite measures, they were best covered by the Disease Activity Index for Reactive Arthritis (DAREA), which comprises patient pain and global assessments, 66/68 joint counts, and CRP.

Conclusion: Among the currently available indices used in arthritic conditions, the DAREA best reflects the domains found to be important in PsA.

Objective: Familial Mediterranean Fever (FMF) is characterized by recurrent periodic febrile attacks and persistent subclinical inflammation. The Damage Associated Molecular Pattern (DAMP) protein S100A12 has proven to be a sensitive marker for disease activity and inflammation in numerous inflammatory disorders. The aim of this study was to analyse the role of S100A12 in the detection of inflammation in patients with FMF.

Methods: 52 children and adolescents with the clinical and/or genetic diagnosis of FMF were prospectively followed up over 18 months (in total 196 visits). During clinical visits, erythrocyte sedimentation rate, C-reactive protein, serum amyloid A, and S100A12 serum concentrations were determined. Patients were categorized into four groups according to the clinical activity of FMF.

Results: Serum concentrations of S100A12 were excessively increased in patients with a mean increase of about 290-fold in active FMF above normal controls. S100A12 decreased significantly after introduction of colchicine therapy. Serum concentrations of S100A12 were significantly higher in colchicine treated patients with persistent symptoms (mean "b SEM, 6260 "b 2120 ng/ml) than in those with clinically controlled disease (440 "b 80 ng/ml, p < 0.001). In contrast to classical markers of inflammation, S100A12 was significantly elevated in clinically unaffected homozygous MEFV mutation carriers, indicating subclinical inflammation.

Conclusions: S100A12 is a valuable biomarker for monitoring disease activity, inflammation and response to colchicine treatment in patients with FMF. It might even be more sensitive in detecting subclinical inflammation than other available indicators.

Introduction: Subchondral bone attrition (SBA), a feature of OA, may be caused by excess focal load to bone, and/or inadequate bone quality to withstand loads through the joint. We evaluated the effects of malalignment, which can cause focal excessive load, and systemic bone density on the presence and incidence of SBA.

Methods: The Multicenter Osteoarthritis (MOST) Study is a cohort of individuals who have or are at high risk for knee OA. Baseline alignment and BMD measures were assessed. Baseline and 30-month knee MRIs were graded for SBA (grade 0-3) using WORMS. We evaluated the association of alignment in medial and lateral compartments, respectively, and systemic BMD with baseline presence of SBA and incident SBA using logistic regression and adjusting for age, sex, and BMI.

Results: There were 1253 participants with mean age 62, mean BMI 30 and 61% were female. 33% had baseline SBA and 44% had knee OA. Associations between presence of and incident SBA with malalignment in both compartments were noted (ORs (95% CI) 2.9 (2.1-4.0) and 1.9 (1.2-2.9), respectively, for varus knees in the medial compartment; 4.5 (2.8-7.1) and 2.1 (1.1-4.1), respectively, for valgus knees in the lateral compartment). Low BMD was not associated with SBA.

Conclusions: Presence and incidence of SBA are associated with malalignment in a compartment-specific manner, but not with low BMD. SBA may be a marker of increased load experienced by overlying cartilage, which may in turn contribute to increased forces transmitted to the cartilage due to alteration in subchondral bone.

Polymorphisms in the genomic region encoding B lymphoid tyrosine kinase (BLK) and family with sequence similarity 167, member A (FAM167A, also referred to as C8orf13) at 8p23.1 have been associated with systemic lupus erythematosus (SLE) in Caucasian[1,2] and Asian[3,4] populations. A recent genome-wide study in a north-American population demonstrated new associations with rheumatoid arthritis (RA), among which was a single nucleotide polymorphism (SNP) rs2736340 in the intergenic region of BLK and FAM167A.[5] In the HapMap Japanese samples (http://www.hapmap.org/index.html.ja), this SNP is in absolute linkage disequilibrium (r²=1) with rs13277113, previously associated with SLE.[1-4] We demonstrated that both the population frequency of the risk genotype, rs13277113A/A, and the odds ratio (OR) for SLE were substantially higher in the Japanese compared with the Caucasian populations.[3]

Objective: To assess the effect of reproductive factors, especially hormonal replacement therapy (HRT) and its interaction with HLA-DRB1 *01 and/or *04 alleles on the diagnosis of RA and the presence of anti-CCP in women included in the ESPOIR cohort (early arthritis cohort).

Methods: 568 patients were included in the analyses. Analyses were performed using logistic regression.

Results: HRT would reduce the risk for RA due to the HLA-DRB1 *01 and/or *04 alleles: from OR=1.88 (95%CI 1.32-2.68, p<0.000) for HLA-DRB1 *01 and/or *04 alleles alone to OR=1.07 (0.51-2.26, p=0.85) in women who carry HLA-DRB1 *01 and/or *04 alleles and who received a HRT. One explanation would be the protective effect of HRT on the presence of anti-CCP (OR=0.43, 95%CI 0.24-0.77, p<0.006). Other reproductive factors such as the number of pregnancies, menopause, and age of the menopause, age of the menarche and a history of pregnancy with poor outcome were not associated with the diagnosis of RA and the presence of anti-CCP.

Conclusion: HRT may reduce the risk of RA due to HLA-DRB1 *01 and/or *04 alleles by protecting against the production of anti-CCP.

Objective: To study the associations of gout, tophi, and uric acid levels with the gout-related SLC2A9 (solute carrier family 2, member 9) single-nucleotide polymorphisms (SNPs) between two different racial groups.

Methods: We genotyped eight SLC2A9 SNPs in 109 gout and 191 control subjects from male Han Chinese in Taiwan, and 69 gout and 168 control subjects from Solomon Islands.

Results: Nonsynonymous SLC2A9 rs3733591 Arg265His was associated with risk for gout and tophaceous gout in Han Chinese (p=0.0012 and p=0.0044). Genetic effect of this SNP on tophaceous gout was replicated in Solomon Islanders (p=0.0184). Patients with SLC2A9 Arg265His risk C-allele consistently had higher risk for tophi (OR=2.05-2.15) than non-tophi (OR=0.91-1.62). SNP rs3733591 described 3.68% and 5.98% of the total variability in uric acid levels for Chinese and Solomon Islands peoples, respectively.

Conclusion: Nonsynonymous SNP rs3733591 variant within SLC2A9 gene from two geographically diverse populations served as an important genetic checkpoint for tophaceous gout and increased uric acid levels.

Objective: To examine effectiveness and 2-year retention rates of methotrexate (MTX) in MTX naïve patients with psoriatic arthritis (PsA).

Methods: We analyzed data on 430 PsA patients participating in an ongoing longitudinal observational multicenter study in Norway. 1218 MTX naïve rheumatoid arthritis (RA) patients from the same study served as a reference population. Assessments included measures of disease activity (28-joint counts, acute phase reactants), health status and utility scores. Six-month effectiveness data were compared both by crude analyses and with adjustments for age, sex and the respective baseline values. Two-year drug survival was compared by Kaplan-Meier and Cox regression analyses.

Results After 6 months of MTX treatment, both PsA and RA patients improved in most disease activity measures and patient reported outcomes. In the adjusted analysis PsA patients tended to have less improvement, but changes were in the same range as in RA patients. Two-year retention rates of MTX therapy in PsA and RA patients were 65% and 66%, respectively, with only minor differences in reported reasons for discontinuation. Lower age, longer disease duration, and higher MHAQ score and patient global assessment were independent predictors of MTX termination within the first two years of treatment.

Conclusion In this real life study, MTX treatment was associated with improvement of disease activity and health related quality of life in PsA patients after 6 months of therapy. Retention rates of MTX were similar in PsA and RA.

Objectives: To evaluate different global ultrasonographic (US) synovitis scoring systems as potential outcome measures of Rheumatoid Arthritis (RA) according to the OMERACT filter.

Patients-Methods: 1. Selected global scoring systems: for both the clinical, B-mode and Power Doppler techniques, the following joints were evaluated: 28 joints (DAS28), 20 joints (MCPs+MTPs) and 38 joints (28+MTPs) using either a binary (yes/no) or a 0-3 grade. 2. Study design: Prospective, 4 months follow-up of 76 RA patients requiring anti-TNF therapy (complete follow-up data: 66 patients) 3. Analysis: 3.a. intra-observer reliability was evaluated using the intra-class coefficient of correlation (ICC), 3.b. validity, 3.b.1. construct validity using the Cronbach’s alpha test and 3.b.2. external validity using level of correlation between scoring system and CRP; 3.c. sensitivity to change was evaluated using the Standardized Response Mean; 3.d. discriminating capacity was evaluated using the Standardized Mean Differences in patients considered by the physician as significantly improved or not at the end of the study.

Results: Different clinimetric properties of various US scoring systems were at least as good as the clinical scores with as examples intra-observer reliability ranging from 0.61 to 0.97 versus from 0.53 to 0.82, construct validity ranging from 0.76 to 0.89 versus from 0.76 to 0.88, correlation with CRP ranging from 0.28 to 0.34 versus from 0.28 to 0.35, sensitivity to change ranging from 0.60 to 1.21 versus from 0.96 to 1.36 for US versus clinical scoring systems respectively.

Conclusion: This study suggests that US evaluation of synovitis is an outcome measure at least as relevant as physical examination. Other studies are required in order to achieve optimal US scoring systems for monitoring RA patients both in clinical trials and in clinical practice.

Objectives: To investigate construct validity and responsiveness of the novel ankylosing spondylitis disease activity score (ASDAS) in patients with spondyloarthritis (SpA).

Methods: In a 46 weeks prospective, longitudinal multi-center study of 60 SpA patients (80% men, median age 40 years (range 21-62)) treated with tumor-necrosis-factor-alpha (TNF-) inhibitors (infliximab (n=41), etanercept (n=13), adalimumab (n=6)) responsiveness of ASDAS, conventional clinical measures of disease activity and treatment response, and the Berlin magnetic resonance imaging (MRI) sacroiliac joint (SIJ) and lumbar spine inflammation scores were compared.

Results: After 22 weeks, 58.3% of the patients were clinical responders (50% or 20mm reduction in BASDAI). At baseline, clinical responders had significantly higher ASDAS (median 4.15 (range 1.98-6.04), p=0.008) compared with non-responders (2.99, 2.05-6.19). Changes in ASDAS correlated with changes in clinical measures of disease activity (incl. BASDAI (rho=0.76) and CRP (0.79)), MRI SIJ inflammation (0.46) and MRI total inflammation scores (0.34). Patients with higher BASDAI or ASAS responses obtained more profound reductions in ASDAS. ASDAS demonstrated the highest responsiveness with an effect size of 2.04 and a standardized response mean of 1.45, whereas BASDAI (1.86; 1.36) and CRP (0.63; 0.70) were less responsive. Linear regression demonstrated that a change in BASDAI of 20mm or 50% corresponded to change in ASDAS of 1.38 and 1.95, respectively.

Conclusion: ASDAS demonstrated construct validity and high responsiveness during treatment with TNF- inhibitors in SpA patients. The proposed thresholds for disease activity and treatment response need further validation.

Churg-Strauss-Syndrom (CSS) is a disorder characterized by pulmonary and systemic small-vessel vasculitis, extravascular granuloma and hypereosinophilia that occurs in patients with asthma and allergic rhinitis. The involvement of the central nervous system (CNS) is less common than peripheral neuropathy, but causes significant morbidity and mortality in affected patients.

Systemic glucocorticoids in combination with cyclophosphamide represent the treatment of choice in patients with systemic involvement of heart, nervous system or kidney. In case of intolerance or failure to cyclophosphamide, plasma exchange, interferon alpha, or other immunosuppressants such as mycophenolat mofetil have been suggested as alternative treatment options.

Recently, the successful use of rituximab (RTX) in patients with ANCA-associated vasculitis as an anti-CD20 directed B-cell depleting antibody was reported. However, only few case reports on the use of RTX in CSS are available, none of them including patients with CNS.

Objective: To determine the incremental cost-effectiveness ratios (ICERs) of 2 therapeutic regimens of infliximab for ankylosing spondylitis (AS).

Methods: 230 patients with active AS who were participating in a randomized controlled trial comparing 2 infliximab infusion modalities – every 6 weeks (Q6) and on demand (DEM) – were included in an economic evaluation within the trial. Data were collected by phone every 3 months for 1 year. Direct and indirect costs were calculated from a payer perspective. Health-related quality of life was assessed with a general health rating scale. ICERs were calculated for one 20% improvement (ASAS20), for one partial remission and for one quality-adjusted life year (QALY) gained.

Results: The Q6 regimen was significantly more efficacious than the DEM regimen but also more costly (22,388 vs 17,596 ; p<0.0001), because it required significantly more infliximab infusions per patient (8.4 vs 6.2). The ICERs of the Q6 to DEM regimen were 15,841 for one ASAS20 response, 23,296 for one partial remission and 50,760 for one QALY gained.

Conclusion: The administration of infliximab every 6 weeks is cost-effective as compared with a DEM regimen; however, the ICER is close to the acceptability threshold of 50,000 for one QALY gained.

Objectives: We report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomized, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids.

Methods: Patients received subcutaneous placebo (n=75), denosumab 60mg (n=71), or denosumab 180mg (n=72) at baseline and 6 months. Assessments included dual X-ray absorptiometry scans of the lumbar spine and hip, serum type I C-telopeptide (sCTx-I), and serum procollagen 1N terminal peptide (P1NP).

Results: Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP versus placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use.

Conclusions: This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.

Objective: Variants in CLEC16A have conferred susceptibility to autoimmune diseases in genome-wide association studies. We aimed to investigate the locus’ involvement in juvenile idiopathic arthritis (JIA), and further explore the association with rheumatoid arthritis (RA), type 1 diabetes (T1D) and Addison’s disease (AD) in the Norwegian population.

Methods: Three SNPs were genotyped in patients with RA (n=809), JIA (n=509), T1D (n=1211) and AD (n=414), and in healthy controls (n=2149).

Results: All diseases were associated with CLEC16A, but with different SNPs. The intron 22 SNP, rs6498169, was associated with RA (p=0.006) and JIA (p=0.016), and the intron 19 SNPs, rs12708716/rs12917716, with T1D (p=1x10-5) and AD (p=2x10-4). The RA association was confined to the anti-CCP negative subgroup (p=2x10-4).

Conclusion: This is the first report of a CLEC16A association with JIA, and a split of the RA association according to anti-CCP status. Different causative variants underlie the rheumatic versus the organ specific diseases.

Objective: To determine whether spa therapy, plus home exercises and usual medical treatment provides any benefit over exercises and usual treatment, in the management of knee osteoarthritis.

Methods: Large multicentre randomised prospective clinical trial of patients with knee osteoarthritis according to the American College of Rheumatology criteria, attending French spa resorts as outpatients between June 2006 and April 2007.

Zelen randomisation was used so patients were ignorant of the other group and spa personnel were not told which patients were participating. The main endpoint criteria were patient self-assessed. All patients continued usual treatments and performed daily standardised home exercises. The spa therapy group received in addition 18 days of spa therapy (massages, showers, mud and pool sessions).

Main endpoint: The number of patients achieving Minimal Clinically Important Improvement at six months, defined as ≥19.9 mm on the VAS pain scale and/or ≥9.1 points in a normalised WOMAC function score and no knee surgery.

Results: The intention to treat analysis included 187 controls and 195 spa therapy patients. At 6 months, 99/195 (50.8%) spa group patients had Minimal Clinically Important Improvement and 68/187 (36.4%) of controls (chi2=8.05; df =1; p=0.005). However, no improvement in quality of life (SF36) or Patient Acceptable Symptom State was observed at 6 months.

Conclusion: For patients with knee OA a 3 week course of spa therapy together with home exercises and usual pharmacological treatments offers benefit after 6 months compared to exercises and usual treatment alone, and is well tolerated.

Objectives: To assess levels of oxidative DNA damage (8-oxo-dG) and lipid peroxidation (4-HNE) in serum, synovial fluid and tissue of inflammatory arthritis patients in relation to in vivo hypoxia levels, disease activity and angiogenic markers.

Methods: Oxygen levels in synovial tissue were assessed using an oxygen/temperature probe. Nuclear and cytoplasmic 8-oxo-dG and 4-HNE were assessed in synovial tissue from 23 patients using immunohistochemistry. 8-oxo-dG and 4-HNE levels in serum and synovial fluid were determined using 8-oxo-dG and Hexanoyl-Lys (HEL) adduct ELISA’s respectively. Serum VEGF and Ang2 were also measured by ELISA.

Results: The median pO2 level in synovial tissue was profoundly hypoxic at 19.35mmHg (2.5%). Nuclear 8-oxo-dG was significantly higher than nuclear 4-HNE levels in lining and sublining layers (all p values<0.001). In contrast, cytoplasmic 4-HNE levels were higher than cytoplasmic 8-oxo-dG in both cell layers (all p values <0.001). Reduced in vivo oxygen tension correlated with high lipid peroxidation in synovial fluid (p=0.027; r=0.54) and tissue (p=0.004; r=0.58). Serum VEGF positively correlated with cytoplasmic 4-HNE expression (p=0.05; r=0.43) and intensity (p=0.006; r=0.59) in the lining layer. Serum Ang2 positively correlated with nuclear 4-HNE expression and intensity in both cell layers (all p values<0.05). DAS28-CRP correlated with nuclear 4-HNE expression in sublining layer (p=0.02; r=0.48) and DAS28-ESR correlated with nuclear 4-HNE expression in both cell layers (p values<0.03).

Conclusions: Lipid peroxidation is associated with low oxygen tension in vivo, with disease activity and angiogenic marker expression in inflammatory arthritis.

Objectives: To determine if genetic variation in genes in the Hypothalamic-Pituitary-Adrenal (HPA) axis, the primary stress-response system, influences susceptibility to developing musculoskeletal pain.

Methods: Pain and co-morbidity data was collected at 3 time-points in a prospective population-based cohort study. Pair-wise tagging SNPs were selected and genotyped for 7 genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the 3 time-points in subjects reporting pain, reported as proportional change with 95% confidence intervals (95%CI). SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting Odds Ratios and 95%CI.

Results: Seventy-five SNPs were successfully genotyped in 994 subjects including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites e.g. each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16 (1.04, 1.28) p=0.006) more pain sites compared to subjects with the CC genotype. SERPINA6 SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in CRHBP and POMC were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and co-morbidity of poor sleep quality and depression explained some of the associations observed.

Conclusions: Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by co-morbidities. Replication of these findings is required in independent cohorts.

Background: Antimalarial drugs (AM), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in lupus patients with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. Our aim was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in SLE.

Methods: Systematic review of the English literature between 1982-2007 using MEDLINE and EMBASE. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence.

Results: 95 articles were included in the systematic review. We have found high evidence that AM prevent lupus flares and increase long-term survival of SLE patients; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss .Toxicity related to AM is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, we have found high evidence that AM, particularly HCQ, decrease lupus activity without harming the baby. On the other hand, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting lupus patients against cancer.

Conclusion: Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.

Objectives: To investigate if 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with SLE in a Swedish case-control cohort, also are associated with SLE risk in a Finnish SLE family cohort.

Method: Genotyping was performed in 192 Finnish families, with 237 affected individuals and their healthy relatives, using the SNPstream genotyping system.

Results: TDT analysis provided the strongest signal of association for two linked SNPs; rs7582694 (P-value = 0.002, OR = 2.57) and rs10181656 (P-value = 0.001, OR = 2.53). We further performed haplotype association analysis using a sliding window approach which showed that the strongest association signal originates from SNPs in intron 3 of STAT4.

Conclusion: Our results provide evidence that the main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.

Background: Joint damage is an important outcome in trials of RA, usually assessed by Total Sharp Score (TSS). It is currently unknown how it translates numerically into disability by the health assessment questionnaire (HAQ).

Objective: To determine the units of HAQ score corresponding to one TSS unit.

Methods: We evaluated a short-term observational trial of glucocorticoids in RA (BELIRA), and used randomized controlled clinical trial (RCT) data for confirmation. For each trial arm we assessed HAQ, TSS, and the simplified disease activity index (SDAI). Based on the hypothesis that short term HAQ changes will mostly be due to changes of disease activity, we determined activity-HAQ (ACT-HAQ) at endpoint (EP), and defined remaining disability as damage-related (DAM-HAQ). Using TSS at EP, we estimated the HAQ units corresponding to a TSS unit.

Results: In BELIRA, one TSS unit corresponded to a mean of 0.017 HAQ units; to account for other causes of irreversible disability, we used the 25th percentile: 0.011 HAQ units/TSS unit. In RCT trial arms, the HAQ/TSS were similar (0.013 and 0.015 in established and early RA, respectively; 25th percentile: 0.010). The correlation between DAM-HAQEP and TSS was r=0.829. Over 5 years, damage would amount to an increase of irreversible HAQ of 0.33 on placebo, 0.13 on DMARDs and 0.03 on TNF-inhibitors+MTX.

Conclusion: We presented an approach to estimate the numerical relationship between HAQ and damage as 0.01 HAQ points/TSS unit, although linear relationship may not be generally valid. This allows assessing functional correlates of radiographic changes in trials.

Ankylosing spondylitis (AS) is a progressive disease of which spinal fusion is the clinical and pathologic hallmark.

Objective: It is known that onset of rheumatoid arthritis (RA) is increased post partum. We wanted to compare incidence rates between RA and other chronic arthritides (OCA) 0-24 months after delivery, and to compare the incidence rates within each group 0-24 versus 25-48 months post partum.

Methods: Premenopausal women from a Norwegian patient register were linked with the Medical Birth Registry of Norway to study the interval between delivery and time of diagnosis. Cox regression analysis with adjustments for age at delivery and birth order was applied to compare proportions of incident cases of RA and OCA with onset 0-24 months post partum. Poisson regression analysis with adjustment for population at risk was applied to estimate incidence rate ratio (IRR) 0-24 versus 25-48 months post partum.

Results: Out of 183 RA and 110 OCA patients diagnosed after delivery, 69 (37.7 %) had RA and 31 (28.2 %) OCA during the first 24 months post partum (p=0.09). The IRR (95 % CI) for diagnosis during 0-24 months versus 25-48 months was 1.73 (1.11, 2.70) (p=0.01) for RA, 1.05 (0.59, 1.84) (p=0.86) for OCA. The IRR was 2.23 (1.06, 4.70) and 1.87 (0.67, 5.21), respectively, when only considering diagnoses after 1st pregnancy. Clinical characteristics were similar within each diagnostic group.

Conclusion: The proportions of incident cases with onset 0-24 months after delivery were not different between RA and OCA. A peak in incidence during 0-24 months was seen in the RA group, both when considering all pregnancies and only the first pregnancy.

Aims: Large epidemiological studies have identified that low fat dairy intake reduces the risk of developing gout. We hypothesized that factors within dairy inhibit the inflammatory response to monosodium urate monohydrate (MSU) crystals.

Methods: Dairy fractions were tested in MSU crystal stimulated THP-1 cell assays. Fractions with inhibitory effects were then tested in the murine urate peritonitis model.

Results: Two dairy fractions were found to have consistent inhibitory effects. Glycomacropeptide inhibited IL-1â gene and protein expression in the THP-1 cell assay. G600 milk fat extract inhibited IL-8 gene and protein expression in the THP-1 cell assay. Conversely, standard milkfat increased IL-8 protein expression in the THP-1 cell assay. Oral administration of glycomacropeptide and G600 milkfat extract inhibited cellular influx in the urate peritonitis model.

Conclusions: Both protein and lipid fractions within dairy are capable of modulating the inflammatory response to MSU crystals.

Objectives: To investigate the possible role of a functional polymorphism in the interleukin-6 receptor (sIL-6R) gene in the genetic background of rheumatoid arthritis (RA).

Methods: We tested for association between disease status and of the sIL-6R rs8192284 (A358D) variant in 965 RA patients and 988 unrelated healthy controls. Odds ratios (OR) for disease were calculated with asymptotic 95% confidence intervals (95% CI); p-values less than 0.05 were considered statistically significant after adjustment for multiple testing. To determine the relationship between protein levels and IL-6R A358D genotype we measured the protein levels of sIL-6R in 100 plasma samples from healthy controls using an enzyme-linked immunosorbant assay (ELISA) and compared them across the genotype groups.

Results: The allele frequency of the C allele (alanine) was lower in cases compared with controls (38.4% and 41.7% respectively, p=0.04, OR=0.9, CI= 0.8-1.0) as were the CC/AC genotypes compared to AA genotype frequencies(61.0% in RA cases vs 67.5% in controls, p=0.004, OR=0.8, 95% CI=0.6-0.9). Plasma levels of sIL-6R differed significantly according to genotype in the controls: 17.00 ± 2.03 ng/ml for A/A, 20.08 ± 1.83 for A/C and 21.57 ± 2.10 for C/C (p = 0.0001).

Conclusion: These data suggest a role for genetically determined lower sIL-6R levels as being a risk factor for RA. The pro-inflammatory role of the IL-6 system in established RA has been highlighted by the used of anti-sIL-6R antibodies. Our data, however, suggest a protective effect of IL-6 on the risk of developing RA.

Objectives: Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A-158V allele and RA and then sought to estimate specific subgroup effects.

Methods: FCGR3A-158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 RA patients and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (RF and CCP) status were undertaken in a pooled cohort of 2963 RA patients and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles.

Results: In the combined RA cohort, we demonstrated borderline association with homozygosity for the FCGR3A-158V allele (OR 1.2, P=0.05), which was stronger in men (OR 1.7, P=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction.

Conclusions: FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.

T-cells and proinflammatory cytokines seem to play important roles in the pathogenesis of psoriatic arthritis (PsA). TNF- antagonists have shown remarkable therapeutic efficacy, reducing the progression of bone damage and improving the quality of life of PsA patients. A significant number of PsA patients do not respond or are intolerant to these therapies and require alternatives. Drugs interfering with T cell activation have shown variable effects in PsA. We describe a PsA patient with moderate-to-severe skin and nail disease, and severe polyarthritis refractory to anti-TNF therapy, which were successfully treated with abatacept. Synovial tissue cellular changes and changes in synovial fluid cytokines after 24 weeks of abatacept therapy are described. The excellent clinical response in our patient was paralleled by a reduction in synovial neutrophils, macrophages, and T-cells, and a substantial reduction in interferon-gamma and pro-inflammatory cytokine levels

Objectives: To assess the changes in carotid intima-media thickness (IMT) and the associated risks factors in patients with low severity Systemic Lupus Erythematosus.

Methods: Common carotid IMT measurements were obtained by ultrasound from 101 patients with SLE at an interval of two years. Cardiovascular risk factors, disease activity, accumulated damage, severity (Katz’s index) and biochemical parameters (including high sensitive CRP, IL6, C3a, C4a, C5a and homocysteine) were also assessed. Multiple linear regression was used to assess the effect of these variables on the end IMT measurement (eIMT) adjusted to the baseline (bIMT).

Results: The cohort was 94.1% female, with a mean age at entry of 41.5 years and a mean disease duration of 12.1 years. An increase of 0.078 mm in IMT was detected over two years, from the mean bIMT (0.37 mm) to the mean eIMT (0.44 mm, P < 0.001). When adjusted for the bIMT, multiple linear regression identified bIMT, age at diagnosis, homocysteine, C3 and C5a as risk factors for IMT progression.

Conclusions: IMT significantly increases over two years in patients with SLE. Age, baseline IMT, C3, C5a anaphylatoxin and homocysteine are all associated risk factors, supporting a role for complement and homocysteine in the early stages of premature SLE associated atherosclerosis.

Objective To investigate how antibodies against anti-TNF agents influence response after switching from infliximab to adalimumab in rheumatoid arthritis (RA).

Methods: This cohort study consisted of 235 RA patients, all treated with adalimumab. At baseline fifty-two patients (22%) were previously treated with infliximab ("switchers"), and 183(78%) were anti-TNF naive. Disease activity (using the DAS28score) and presence of antibodies against infliximab and adalimumab was assessed. Clinical response to adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-adalimumab antibody status.

Results After 28 weeks of adalimumab therapy the decrease in DAS28 (DAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-adalimumab antibodies were detected in 46 patients (20%). DAS28 was 1.8±1.4 in patients without anti-adalimumab and 0.6±1.3 in patients with anti-adalimumab (P<0.0001). Thirty-three out of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-adalimumab than anti-TNF naive patients, (11(33%) versus 32(18%);(P=0.039)). DAS28 was greater for anti-TNF naive patients (1.7±1.5) compared to switchers without anti-infliximab antibodies (DAS28=0.9±1.4) (P=0.009). DAS28 for switchers with anti-infliximab was 1.2±1.3 and did not differ significantly from anti-TNF naive patients (P=0.262).

Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against adalimumab than anti-TNF naive patients. Response to adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF therapy should be offered to RA-patients who fail on initial treatment with anti-TNF, in the absence of anti-biological antibodies.

Objectives: Behçet's disease (BD) is a rare, chronic, systemic, inflammatory disorder characterized by recurrent ocular, genital and skin lesions. Although its etiology is still uncertain, an intricate interplay between the environment (e.g. viruses) and the host seem to initiate and/or perpetuate the disease, although its mechanistics remains presently speculative. Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled. We hereby present the results of a first genomewide association study (GWAS) of BD.

Methods: 300 Japanese patients with BD and an equal number of controls were recruited. The samples were screened using a dense panel of 23,465 microsatellites (MS) covering the entire genome.

Results: We identified the six best (of a total of 147) positively associated MS with BD. Of these six, two were located within the HLA class I region itself. Although one of these was clearly reminiscent of the association with HLA-B, the second, not in linkage disequilibrium with the former was in the telomeric side of the class I region and remained to be formally identified. In fine, HLA genotyping and haplotype analysis conclusively led to the deciphering of a dual, independent, contribution of two HLA alleles to BD’s pathogenesis: HLA-B*5101 and HLA-A*26.

Conclusions: This GWAS highlights the premier genetic susceptibility locus for BD as the MHC itself, wherein reside two independent loci: HLA-B and HLA-A.

Objectives: Genome wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of utilising information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association to two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features to JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci.

Methods: Fifteen SNPs at nine RA-associated loci were genotyped in Caucasian JIA patients (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK.

Results: We identified two JIA susceptibility loci, one of which is a novel JIA association (STAT4) and the second confirms previously published associations of the TRAF1/C5 locus with JIA. We also present weak evidence of association of JIA to three additional loci (Chr6q23, KIF5A and PRKCQ) that warrant further investigation.

Conclusion: All of these loci represent good candidates in terms of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T cell receptor signalling or activation pathways.

Objectives: The objectives of this study were to determine whether late apoptotic cell material directly induces autoantibodies characteristic of systemic lupus erythematosus (SLE) and to investigate the innate recognition pathways involved.

Methods: B6, B6.MyD88-/-, B6.TLR7-/- and B6.TLR9-/- mice were subcutaneously injected with B6 syngeneic late apoptotic thymocytes (SLATs) without adjuvant on d0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and dsDNA by ELISA and Crithidia luciliae indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy.

Results: SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88-/- mice. TLR7-/- and TLR9-/- mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7-/- and TLR9-/- mice that were absent in MyD88-/- mice. Unlike B6 and TLR9-/- animals, TLR7-/- mice failed to exhibit IgG co-localized glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype.

Conclusions: Late apoptotic cell-induced anti-histone and anti-dsDNA antibodies require MyD88 but not TLR9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.

Objective: To estimate biologic drug effects on risk of demyelinating events in rheumatoid arthritis (RA).

Methods: Case-control analyses, nested in an administrative database cohort.

Results: Initially, risk of demyelinating events appeared increased after anakinra drug exposure, and decreased after anti-TNF agents. However, this apparent differential risk was due to more anakinra use (and avoidance of anti-TNF agents), in persons at high risk for demyelinating events. In individuals not at high risk, the adjusted rate ratio after anti-TNF exposures was 1.31 (95% CI 0.68, 2.50) and after anakinra, 0.80 (0.29, 2.24).

Conclusions: When accounting for differential prescription patterns, we noted a trend towards more events after anti-TNF exposures. When studying rare but important potential drug associations, pharmacoepidemiologic studies are valuable but must be carefully-done.

Psoriatic arthritis (PsA) is a heterogeneous disease involving the musculoskeletal structures, the skin and nails (1, 2). Traditional DMARDs and TNF antagonists are effective on both cutaneous and articular manifestations of psoriatic disease (3, 4).

Objective: Fatty changes at vertebral corners have been reported on MRI in ankylsoing spondylitis but the distribution or specificity of these lesions to axial-SpA has not been determined. This study assessed the diagnostic utility of Fatty Romanus Lesions (FRLs) for axial-SpA in a chronic back pain population.

Methods: Axial-skeleton TI SE and fat-suppressed MRI were performed on 174-patients with back pain and 11-controls. MRI lesions including FRLs were scored blind. An imaging diagnosis was given on MRI findings alone and compared to the gold-standard treating physician diagnosis.

Results: Twenty-nine patients had FRLs. Thirty-one percent(20/64) of SpA, 13%(6/45) of degenerative arthritis, 4%(2/45) of spinal malignancy, 5%(1/20) of "other" diagnoses and 0/11 normals. The majority of FRLs in SpA 59%(135/226) were present in the thoracic-spine. The diagnostic utility of FRLs for SpA(LR=4.7) was significantly(p<0.05) greater than for other diagnoses and increased further(LR=12.6,p<0.05) when >5 FRLs were present. Of note 5/20(25%), of SpA patients with FRLs had no diagnostic bone-oedema lesions on fat-suppressed MRI suggesting that FRLs may be useful diagnostically in axial-SpA.

Conclusion: This study defines the FRL as a diagnostic imaging feature of axial-SpA which may be useful where inflammatory changes are absent on fat-suppression MRI and where radiography is normal.

Objectives: Anti-citrullinated peptide antibodies (ACPA) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV).

Methods: A cohort of 238 RA patients was followed longitudinally for 10 years; 125 patients with complete X-ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-CCP, and were genotyped for HLA-DRB1 "shared epitope" (SE) and PTPN22 1858T.

Results: Anti-MCV and anti-CCP were strongly associated both regarding status and level. Both antibodies were associated to SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% CI 3.2-16.5) compared to 5.7 (2.6-12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level.

Conclusion: Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a higher association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

Objective: To identify differentially expressed genes in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared to healthy individuals.

Methods: RNA was extracted from PBMCs collected from 18 AS patients with active disease and 18 gender- and age-matched controls. Expression profiles of these cells were determined using microarray. Candidate genes with differential expressions were confirmed in the same samples using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). These genes were then validated in a different sample cohort of 35 AS and 18 patients by qRT-PCR.

Results: Microarray analysis identified 452 genes detected with 485 probes which were expressed at significantly different levels (p<0.006) between AS patients and controls. Under-expression of NR4A2, TNFAIP3, and CD69 was confirmed. These genes were further validated in a different sample group where the AS patients had a wider range of disease activity. Predictive algorithms were also developed from the expression data using Receiver-Operator Characteristic (ROC) curves, which demonstrated that the 3 candidate genes have ~80% power to predict AS according to their expression levels.

Conclusions: Our findings showed differences in global gene expression patterns between AS patients and controls suggesting an immunosuppressive phenotype in AS patients. Furthermore, we confirmed downregulated expression of 3 immune-related genes. These candidate genes were also shown to be strong predictive markers for AS.

Background: Adiponectin is an anti-inflammatory and potentially anti-atherogenic molecule. Some recent reports suggest that TNF blockade therapy increases circulating adiponectin levels but data are sparse and inconsistent.

Methods: Data from a double-blind placebo-controlled study of onercept in 126 psoriatic arthritis patients (PsA) and data from pre- and post adalimumab treatment in 171 rheumatoid arthritis (RA) patients were used to examine the effect of TNF blockade therapy on adiponectin.

Results: Despite expected associations of adiponectin to gender and baseline HDL-cholesterol and triglyceride, adiponectin levels did not change over time with TNF blockade therapy in either group. Absolute change in adiponectin levels were -0.23 ±4.6µg/ml in onercept 50mg and onercept 100mg combined group (versus placebo, p=0.60) in PsA patients and 0.28 ±3.23µg/ml (p=0.66 versus baseline) in RA patients treated with adalimumab.

Discussion: These results go against a significant effect of TNF blockade therapy on circulating adiponectin levels in patients with autoimmune disease.

Background: TNF blockers are known to increase the risk of serious infections in rheumatoid arthritis. Despite a wide use of TNF blockers in ankylosing spondylitis (AS), the infection risk has never been evaluated in this disease.

Objectives: To assess serious infections in AS patients not exposed and exposed to TNF blockers.

Methods: A systematic literature review using Pubmed, Embase and Cochrane Library was performed until May 2008. All randomized controlled trials (RCTs), published between 1995 and 2008, monitoring serious infections, with treatment by Non Steroid Anti-Inflammatory Drugs (NSAIDs) or TNF blockers were included. Infection risks were calculated by naive pooling and for 100 patient-years (pyrs) of exposure. To assess the serious infection risk with TNF blockers, a meta-analysis of RCTs was performed using Mantel-Haenszel’s method with several sensitivity analyses.

Results: Fourteen RCTs were included (N patients=3345). With placebo or NSAIDs (N=2202) 2 serious infections were observed (0.09%, 0.01 to 0.3) i.e., 0.4/100pyrs. In TNF blocker trials, 2 serious infections were observed with placebo (2/500, 0.4% (0.0 to 1.4), i.e., 1.0/100pyrs), versus 14 serious infections with TNF blockers (14/996, 0.7% (0.3 to 1.4), i.e., 1.9/100pyrs). By meta-analysis of RCTs, the increase in serious infections with TNF blockers compared to placebo was not significant: risk difference=0.4% (-8% to 1.6%).

Conclusion: Absolute risks of serious infections in AS patients not exposed to TNF blockers are low. Absolute risks of serious infections in patients receiving TNF blockers are higher, but the difference was not significant, possibly through lack of power. Continued monitoring is necessary.

Objectives: To compare long-term effectiveness of surgical with non surgical treatment in patients with chronic low back pain.

Methods: Two merged randomised clinical trials compared instrumented transpedicular fusion with cognitive intervention and exercises in 124 patients with disc degeneration and at least 1 year of symptoms after or without previous surgery for disc herniation. The main outcome measure was the Oswestry Disability Index.

Results: At 4 years 14 (24%) patients randomly assigned to cognitive intervention and exercises had also undergone surgery. Fifteen (23%) patients assigned fusion had undergone re-surgery. The mean treatment effect for the primary outcome was 1.1; 95% CI: -5.9 to 8.2, according to the intention-to-treat analysis, and -1.6; 95% CI: -8.9 to 5.6 in the as-treated analysis. There was no difference in return to work.

Conclusions: Long-term improvement was not better after instrumented transpedicular fusion compared with cognitive intervention and exercises.

Objective: In persons with rheumatoid arthritis, studies have described an association of rheumatoid factor (RF) with increased mortality. Our objective was to determine the effect of RF on mortality and coronary heart disease (CHD) in the general population.

Methods: Subjects were participants in a population-based study focused on cardiovascular disease who came for study visit during the years 1974-1984. RF was measured and information obtained on cardiovascular risk factors, joint symptoms and erythrocyte sedimentation rate (ESR). Subjects were followed with respect to mortality and incident CHD through 2005. Adjusted comparison of overall survival and CHD-event free survival among the RF-positive vs. RF-negative subjects was performed with Cox proportional hazards regression models.

Results: Of 11,872 subjects, 140 had positive RF. At baseline, RF was associated with diabetes mellitus and smoking and inversely associated with serum cholesterol. RF-positive subjects had increased all-cause mortality (HR=1.47, 95% CI: 1.19-1.80) and cardiovascular mortality (HR=1.57, 95% CI: 1.15-2.14) after adjusting for age and sex. Further adjustment for cardiovascular risk factors and ESR only modestly attenuated this effect. Increase in CHD among the RF-positive subjects did not reach statistical significance. (HR=1.32, 95% CI: 0.96-1.81) adjusted for age and sex. Subjects with RF but without joint symptoms also had increased overall mortality and cardiovascular mortality (after adjustment, HR for overall mortality =1.33, 95% CI 1.01-1.74).

Conclusion: In a general population cohort, RF was associated with increased all-cause mortality and cardiovascular mortality after adjustment for cardiovascular risk factors, even among subjects without joint symptoms.

Objective: A case-control association study was conducted to determine HLA-class II (DRB1, DQB1, DQA1, and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis or SSc) and its sub-phenotypes in a large multi-ethnic US cohort.

Patients and methods: 1300 SSc cases (961 whites, 178 blacks and 161 Hispanics) characterized for clinical skin forms (limited vs diffuse), SSc- specific autoantibodies (anti-centromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 RNP (fibrillarin), and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modeling for dominant (D), additive (A) and recessive (R) effects from HLA.

Results: The strongest positive class II associations with SSc in whites and Hispanics were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype, and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate limited SSc from diffuse SSc. SSc in blacks was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR=14). Moreover, it showed no LD or gene interaction with DR/DQ. ACA was best explainable by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in whites and Hispanics but DRB1*08 in blacks. These data indicate unique and multiple HLA class II effects in SSc, especially on autoantibody markers of different sub-phenotypes.

Objectives: Both antibody and cell-mediated immune responses are involved in the defence against influenza. Although antibody responses are unaltered in Wegener’s granulomatosis (WG), the level of cell-mediated responses to vaccination could be deficient.

Methods: Twenty-five WG patients and healthy controls received subunit influenza vaccine. PBMCs were obtained before and one month after vaccination. Cell-mediated responses to A/H1N1 and A/H3N2 were assessed using interferon- (IFN-) ELISpot and intracellular cytokine staining for IFN-, tumour necrosis factor (TNF) and interleukin-2 (IL-2).

Results: Prior to vaccination, patients and controls showed similar recall responses to A/H1N1 and A/H3N2. Following vaccination, patients and controls showed similar levels of increase in spot-forming cells against A/H1N1 and A/H3N2. By flow cytometry, upon vaccination, proportions of cytokine-producing CD4⁺ T-cells increased in patients and controls for A/H1N1 and A/H3N2.

Conclusions: Cell-mediated responses to influenza vaccination in WG patients are comparable to those in healthy controls. Dutch Trials Register, NTR1130.

Objectives: To analyze whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in rheumatoid arthritis (RA) patients are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation.

Methods: Fifty-eight RA patients were treated with rituximab. The clinical response was determined 24 weeks after each treatment course using the disease activity score evaluated in 28 joints (DAS28) and EULAR response criteria. Rituximab serum levels, ARAs and synovial B lineage cell numbers were determined before and after treatment.

Results: Four weeks after treatment rituximab serum levels were highly variable. Low rituximab levels were associated with ARA formation (in 5 patients [8.6%]) and high baseline erythrocyte sedimentation rate. Interestingly, serum rituximab levels were not related to persistence of synovial B lineage cells or clinical response. Furthermore, response to treatment and re-treatment was similar in ARA positive compared to ARA negative patients.

Conclusion: There is clear variability in serum levels after rituximab treatment, but rituximab levels are not lower in patients with persistence of synovial B lineage cells or lack of clinical response. The current treatment schedule suffices to induce and maintain a clinical response, even when ARAs are formed.

Objective: To prospectively study the relation between menopause, postmenopausal hormone use and risk of gout, since female sex hormones have been postulated to decrease gout risk among women.

Methods: In the Nurses' Health Study, we examined the association between menopause, age at menopause, postmenopausal hormone use and risk of self-reported physician diagnosed incident gout among 92,535 women without gout at baseline. We used multivariate proportional hazards regression analysis to adjust for other risk factors for gout such as age, body mass index, diuretic use, hypertension, alcohol intake and dietary factors.

Results: During 16 years of follow-up (1,240,231 person-years), we documented 1,703 incident gout cases. The incidence rate of gout increased from 0.6 per 1000 person-years in women <45 years of age to 2.5 in women ≥75 years of age (p for trend<0.001). Compared with premenopausal women, postmenopausal women had a higher risk of incident gout (multivariate-adjusted relative risk [RR], 1.26; 95% Confidence Interval [CI], 1.03 to 1.55). Among women with natural menopause, women with age at menopause <45 years had a RR of 1.62 (95% CI, 1.12 to 2.33) of gout compared with women with age at menopause 50 to 54 years. Postmenopausal hormone users had a reduced risk of gout (RR, 0.82; 95% CI, 0.70 to 0.96).

Conclusion: These prospective findings indicate that menopause increases the risk of gout, whereas postmenopausal hormone therapy modestly reduces gout risk.

Objectives: To determine the efficacy of CP-690,550 in improving pain, function, and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a TNF- inhibitor.

Methods: Patients were randomized equally to placebo, CP 690,550 5, 15, or 30 mg BID for 6 weeks, with 6 weeks' follow-up. Patient's Assessment of Arthritis Pain (Pain), Patient's Assessment of Disease Activity, HAQ-DI, and SF-36 were recorded.

Results: At Week 6, significantly more patients in the CP-690,550 5, 15, and 30 mg BID groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78%, and 14%, respectively), clinically meaningful reductions in HAQ-DI (≥0.3 units) [57%, 75%, 76%, and 36%, respectively], and clinically meaningful improvements in SF-36 domains and physical and mental components.

Conclusions: CP-690,550 was efficacious in improving the pain, function, and health status of patients with RA, from Week 1 to Week 6.

Objectives: Treatment of patients with rheumatoid arthritis (RA) has improved markedly over the past 25 years. We investigated if rates of joint surgery, a long-term consequence of poorly-controlled RA, have changed over this period.

Methods: In this population-based, serial cross-sectional study of patients aged ≥ 40 years with RA in California, we examined trends in annual rates of total knee arthroplasty, total hip arthroplasty, total ankle arthroplasty or arthrodesis, and total wrist arthroplasty or arthrodesis from 1983-2007.

Results: Rates of joint surgery peaked in the 1990s and since have decreased. Among patients aged 40-59 years, rates of knee surgery in 2003-2007 were 19% lower than in 1983-1987 (adjusted rate ratio 0.81; 95% confidence interval (CI) 0.74 - 0.87, P < 0.0001), while rates of hip surgery in 2003-2007 were 40% lower (P < 0.0001). Rates of knee and hip surgery did not decrease in patients aged ≥ 60 years but increased as observed in the general population. Compared with rates of ankle and wrist surgery in the mid-1980s, rates in the mid-2000s decreased significantly in both age groups.

Conclusions: Rates of joint surgery in RA peaked in the 1990s and have declined thereafter, suggesting that long-term outcomes of RA are improving.

Objective: To evaluate changes in Health-Related Quality of Life (HRQoL) in patients with refractory Juvenile Idiopathic Arthritis (JIA) while treated with etanercept.

Methods: We included 53 JIA patients from seven Dutch centres. HRQoL was measured by the Childhood Health Assessment Questionnaire (CHAQ), Child Health Questionnaire (CHQ) and Health Utilities Index mark 3 (HUI3) at start and after 3, 15 and 27 months of treatment. At the same time points the following JIA disease activity variables were collected; physician’s global assessment through the Visual Analogue Scale (VAS), number of active and limited joints and erythrocyte sedimentation rate. Statistical method Linear Mixed Models was used to assess outcomes over time.

Results: During etanercept therapy HRQoL improved dramatically on both disease specific and generic HRQoL outcomes. Significant improvements were shown after three months and these improvements continued at least up to 27 months of treatment.

The disease specific CHAQ, including VAS pain and well-being, showed a significant improvement on all domains. The generic health-profile measure CHQ improved on all the health concepts except for "family cohesion", which was normal. The generic preference-based HUI3 showed impairment and subsequently significant improvement on the more specific domains ("pain", "ambulatory", "dexterity").

In accordance also disease activity variables improved significantly over time.

Conclusion: This study shows that HRQoL of patients with refractory JIA can substantially be improved by the use of etanercept on all aspects impaired by JIA. Information on HRQoL is crucial to understand the complete impact of etanercept treatment on JIA patients and their families.

Objective: To evaluate toxicity profiles in patients with rheumatoid arthritis (RA) treated either according to an intensive or a conventional treatment strategy approach with methotrexate (MTX) and to study factors associated with MTX related toxicity.

Methods: Data were used from the CAMERA study in which clinical efficacy of an intensive treatment strategy with MTX was more beneficial compared to a conventional treatment strategy approach. In the present study, data on adverse events were compared between the two treatment groups. Logistic regression analyses were used to identify possible associations between factors assessed at baseline and withdrawal due to MTX related adverse events or liver toxicity at follow-up.

Results: Although significantly more patients in the intensive treatment group experienced MTX related adverse events compared to the conventional treatment group, all recorded adverse events were relatively mild. A higher Body Mass Index (BMI) was significantly associated with withdrawal due to MTX related adverse events in the multiple regression analyses. There was a trend towards an association between diminished creatinine clearance and MTX withdrawal. For liver toxicity, increased serum liver enzymes at baseline were associated with liver toxicity during follow-up.

Conclusion: Although the occurrence of adverse events in the intensive treatment group was higher than in the conventional treatment group, the previously observed clinical efficacy of an intensive treatment strategy seems to outweigh the observed toxicity profiles. When starting MTX, attention should be given to patients with a high BMI and those with increased levels of liver enzymes and decreased renal function.

Objective: To contrast the effect of the burden of vasculitis activity with the burden of adverse events on one-year mortality of patients with ANCA-associated vasculitis (AAV).

Methods: We assessed outcome and adverse events in patients prospectively recruited to 4 European AAV clinical trials. We included data on 524 patients with newly diagnosed AAV. The burden of adverse events was quantified using a severity score for leukopenia, infection and other adverse events, with an additional weighting for follow up duration. A "combined burden of events score (CBOE)" was generated for each patient by summing the individual scores. Vasculitis severity was quantified using BVAS and GFR.

Results: One-year mortality probability was 11.1%; 59% and 14% of deaths were due to therapy associated adverse events and active vasculitis respectively. Using Cox regression analysis, infection score (p<0.001), adverse event score (p<0.001), leukopenia score (p<0.001) and GFR (p=0.002) were independently associated with mortality. The risk of one-year mortality remained low (5%) with CBOE scores <7, but increased dramatically with scores above this. Hazard ratio for death with a CBOE>7 was 14.4 (95% CI 8.4 to 24.8). Age and GFR were independent predictors of CBOE score.

Conclusions: The greatest threat to patients with AAV in the first year of therapy is from adverse events rather than active vasculitis. Accumulation of adverse events, monitored using this scoring method, should prompt increased awareness that the patient is at high risk of death.

Objective: To develop a disease activity index for patients with primary Sjögren’s syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI).

Methods: Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific "domains" contributing to disease activity. For each domain, features of disease activity were classified in 3 or 4 levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0-10 physician global assessment (PhGA) scale, each expert scored the disease activity of 5 patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.

Results: All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.0001). Compared to 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.

Conclusion: The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardized evaluation of primary SS should facilitate clinical research and should be helpful as an outcome measure in clinical trials.

Objectives: Molecular biological approaches recently have identified urate transporters in renal proximal tubular cells. Human sodium-dependent phosphate cotransporter type 1 (NPT1) encoded by SLC17A1 is a urate transporter localized to the renal proximal tubular cells and candidate molecule to secret urate from renal tubular cells to urine. Here, we investigated the roles of SLC17A1 in the development of gout.

Patients and Methods: SNPs in the human SLC17A1 gene (rs1165176, rs1165151, rs1165153, rs1165196, rs1165209, rs1165215, rs1179086, rs3799344, and rs3757131) were selected, and an association study was conducted using male patients with gout (n=175) and male controls (n=595).

Results: There were significant differences between gout and control groups in the distribution of genotypes at rs1165196 (T806C; Ile269Thr, OR = 0.55, p = 0.0035), rs1179086 (OR = 0.57, p = 0.0018), and rs3757131 (OR = 0.54, p = 0.0026). In controls, T806C alone had no effect on serum uric acid (sUA) levels. However, T806C showed significant interaction with reduction of sUA in obese individuals (body mass index ≥25) using multiple regression analysis.

Conclusions: Our data suggest that SLC17A1 polymorphisms are associated with the development of gout.

Objective: Increased expression of insulin-like growth factor 2 (IGF2) by fibroblast-like synoviocytes (FLS) was associated with low inflammatory synovium of patients with rheumatoid arthritis (RA). The aim of this study was to analyze whether the differential expression of IGF2, whose expression is normally restricted to one allele, is due to activation of the normally suppressed allele.

Methods: IGF2 gene expression of RA FLS was quantified by quantitative RT-PCR. FLS heterozygous for a 3’UTR IGF2 polymorphism were selected to measure the relative contribution of the allelic transcripts by allele-specific transcript quantification assay. Proliferation was determined by [3H]-Thymidine incorporation.

Results: IGF2 was shown to contribute to RA FLS proliferation. FLS could be classified in IGF2 high- and IGF2 low-expressing cell lines. Here we report that allelic IGF2 transcript quantification analysis revealed that in part of the RA FLS the normally suppressed allele was activated, resulting in biallelic expression of the IGF2 gene. Biallelic expression was associated with increased levels of IGF2 mRNA production.

Conclusion: Our findings indicate that the imprinting status of IGF2 might underlie increased expression of IGF2 that may contribute to autonomous growth of RA FLS of low inflammatory synovial tissues.

Objectives: Synovial fibroblasts and osteoblasts generate active glucocorticoids (GCs) via the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or GCs. During inflammatory arthritis synovium and bone are exposed to both these factors. We hypothesised that GCs magnify the effects of inflammatory cytokines on local GC production in both synovium and bone.

Methods: We assessed the effects of inflammatory cytokines (IL-1β/TNF) and GCs, alone or combined, on expression and activity of 11β-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA.

Results: In synovial fibroblasts and osteoblasts, treatment with cytokines or GCs in isolation induced 11β-HSD1 expression and activity. However, in combination, 11β-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11β-HSD1 gene. The synergistic induction had functional consequences on IL-6 production.

Conclusions: Combined treatment with inflammatory cytokines and GCs synergistically induces 11β-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localized GC levels. However, synergistic induction of 11β-HSD1 might also cause detrimental GC accumulation in bone or surrounding tissues.

Objective: The aims of this study were to evaluate the effect of oral treatment with a whole plant extract of Brachystemma calycinum D. don (BCD) on the development of osteoarthritic (OA) lesions and symptoms in the experimental dog anterior cruciate ligament (ACL) transection model and to document its mechanism of action.

Methods: OA was induced by sectioning the ACL of the right knee in crossbred dogs. There were two experimental groups (n = 6-7 dogs/group): placebo and BCD extract (200 mg/kg/day) given orally for 8 weeks. Macroscopic and histopathological evaluation of cartilage lesions and immunohistochemical analysis of cartilage to assess levels of iNOS, MMP-13, and protease activated receptor (PAR)-2 were done. A gait analysis of dogs was performed.

Results: Treatment with BCD reduced the severity (depth) (p=0.04) and histopathological score (p<0.02) of OA cartilage lesions. BCD treatment also significantly reduced the OA chondrocyte level of key inflammatory and catabolic factors (iNOS, p=0.009 and MMP-13, p=0.003) as well as the level of PAR-2 (p=0.03). Dogs treated with BCD showed significant improvement in peak vertical force measured at 8 weeks (p<0.05).

Conclusions: Treatment with BCD extract can exert a positive effect on the prevention of cartilage lesions induced by joint instability and improve joint function. This effect was associated with the inhibition of major catabolic and inflammatory mediators. This study is the first to demonstrate that a therapeutic intervention that can inhibit PAR 2 is associated with a disease-modifying OA effect.

Objective: Evaluate the responsiveness of joint counts, patient-reported measures and proposed composite scores in hand osteoarthritis (HOA).

Methods: We used data from a previously reported study in which 83 patients with HOA were randomized to CRx-102 or placebo. CRx-102 consists of prednisolone (3 mg / day) and dipyridamole (400 mg / day), and was shown to be superior to placebo. Assessments were performed at baseline and after 7, 14, 28 and 42 days, and included AUSCAN, VAS pain and patient global, and counts of DIP, PIP, MCP and CMC joints (tenderness, soft tissue swelling, bony enlargement, limited motion). Various combinations of patient-reported outcomes and joint counts were computed as composite scores (similar to clinical disease activity index (CDAI)) and tested for responsiveness. For each measure, we calculated mean change from baseline to Day 42, treatment effect, standardized response mean (SRM) and relative efficiency compared to AUSCAN pain.

Results: The SRMs were largest for VAS patient global (0.92), VAS pain (0.77) and AUSCAN pain (0.68), while the responsiveness of tender (0.46) and swollen joint counts (0.51) (18 joint assessment of DIP, PIP, CMC) was similar to AUSCAN stiffness (0.53) and physical function (0.37). Composite scores showed similar responsiveness as patient-reported pain and global.

Conclusion: Patient-reported pain and patient global assessment were the most responsive outcomes, while joint counts had similar responsiveness as patient-reported stiffness and physical function. Composite scores were as responsive as VAS pain, and these results encourage further elaboration and validation of composite scores in HOA in larger studies.

Objective: In the present study we evaluated the decrease of cartilage destruction by a novel orally active and specific MMP-13 inhibitor in three different animal models of rheumatoid arthritis (RA).

Material and methods: The SCID mouse co-implantation model of RA, collagen-induced arthritis (CIA) model in mice and the antigen induced arthritis model (AIA) in rabbits were used.

Results: In the SCID mouse co-implantation model this inhibitor resulted in reduced cartilage destruction by 75%. In the CIA model of RA, the MMP-13 inhibitor resulted in a significant and dose dependent decrease in clinical symptoms as well as of cartilage erosion by 38% (30 mg/kg), 28% (10 mg/kg) and 21% (3 mg/kg). No significant effects were observed in the AIA model. No toxic effects were observed in all three animal models.

Conclusion: Although several MMPs in concert with other proteinases play a role in the process of cartilage destruction, there is a need for highly selective MMP inhibitors to reduce severe side effects that occur with non-specific inhibitors. Significant inhibition of MMP-13 reduced cartilage erosions in two out of three tested animal models of RA. These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.

Objective: To investigate the association between weight or Body Mass Index (BMI) and the development of hand osteoarthritis (OA).

Methods: Systematic review of observational studies. Medical databases were searched up to April 2008. Articles which presented data on the association between weight and hand OA were selected. The qualities of these studies were then assessed by two independent reviewers using a 19 criteria scoring system. Using the mean scores of all studies as cut-off value, the studies were deemed as high- or low- quality. Study quality and study designs were combined to determine the level of evidence using best-evidence synthesis which consisted of five levels of evidence.

Results: From the 25 studies included, two had cohort, three case-control and 20 cross-sectional study designs. Fifteen studies were considered as high-quality studies. Of these high-quality studies, one cohort, two case-control and seven cross-sectional studies showed a positive association between weight or BMI and hand OA. Based on three high-quality studies with preferred study designs (one cohort and two case-control) with a positive association, the level of evidence of the association between overweight and developing hand OA is moderate. The approximate risk ratio of this association is 1.9.

Conclusion: Weight or BMI is associated with hand OA development. The level of evidence of published studies is moderate according to best-evidence synthesis. Further high-quality cohort or case-control studies are needed to elucidate the role of weight in hand OA.

Objectives: Animal models of arthritis are frequently used to evaluate novel therapeutic agents. However, their ability to predict responses in humans is variable. We examined the time course of signaling molecule and gene expression in two models of arthritis to assist with selection of the model and timing of drug administration.

Methods: The passive K/BxN serum transfer and collagen-induced arthritis (CIA) models were studied. Activation of MAP kinase and IFN-response pathways was evaluated by Q-PCR and Western blot analysis of ankle joints at various time points during the models.

Results: The kinetics of gene expression and kinase phosphorylation were strikingly different in passive K/BxN and CIA. All three MAP kinases (ERK, JNK, and p38) and upstream kinases were activated within days in passive K/BxN and, except for p38, declined as arthritis severity decreased. Surprisingly, IFN-regulated genes, including IRF7, were not induced in the model. In CIA, activation of ERK and JNK was surprisingly low, and p38 phosphorylation mainly peaked late in disease. IFN-response genes were activated during CIA, with especially prominent peaks at the onset of clinical arthritis.

Conclusions: Timing of treatment and selection of CIA or passive K/BxN could have an important impact on therapeutic response. p38, in particular, increases during the late stages of disease. ERK and JNK patterns are similar in passive K/BxN and RA, while IFN-response genes in CIA and RA were similar. The dichotomy between RA and animal models could help explain the poor correlation between efficacy in RA and pre-clinical studies.

Background: Polymorphisms of the peptidylarginine deiminase type 4 (PADI4) gene confer susceptibility to rheumatoid arthritis (RA) in East Asians. However, studies in European populations have produced conflicting results. This study explored the association of PADI4 genotype with RA in a large UK Caucasian population.

Methods: The PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian RA patients (n=3,732) and population controls (n=3,039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was utilised to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1,859) and controls (n=10,599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study.

Results: PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all RA cases (n=5,591) and controls (n=13,638) gave an overall OR of 1.01 (0.96-1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between PADI4_94 genotype and RA in people of European descent (OR 1.06, 0.99-1.13, p=0.12).

Conclusion: In the largest study performed to date, we found that, in contrast to Asian populations, PADI4 genotype is not a significant risk factor for RA in people of European ancestry.

Objective: To investigate the effect of TNF-antagonist treatment on work-force participation in rheumatoid arthritis (RA) patients.

Methods: Data from the Stockholm anti-TNF follow-up registry (STURE) were used in this observational study. RA patients (n=594) aged 18-55y, (mean±SD 40±9) followed for up to five years were included with hours worked/week as the main outcome measure. Analyses were performed unadjusted and adjusted for baseline age, disease duration, HAQ, DAS28 and pain score.

Results: At baseline patients worked a mean 20h/week (SD 18). In unadjusted analyses, significant improvements in hours worked/week were observed in patients already at six months +2.4h (1.3 to 3.5; mean, 95% confidence interval (95%CI)) with further increases compared to baseline at the one-year (+4.0h, 2.4 to 5.6) and two-year follow-up (+6.3h, 4.2 to 8.4). The trajectory appeared to stabilise at the 3year (+6.3h, 3.6 to 8.9), 4year (+5.3h, 2.3 to 8.4) and 5year follow-up (+6.6h, 3.3 to 10.0). In a mixed piecewise linear regression model, adjusted for age, sex, baseline disease activity, function and pain, an improvement of +4.2h/week was estimated for the first year followed by an added improvement of +0.5h/week annually during the years thereafter. Over five years of treatment, the expected indirect cost gain corresponded to 40% of the annual anti-TNF drug cost in patients continuing treatment.

Conclusion: Data from this population-based registry indicate that biologic therapy is associated with increases in work-force participation in a group typically expected to experience progressively deteriorating work ability. This could result in significant indirect cost benefits to society.

Objective: Assess uveitis (including iritis and iridocyclitis) incidence from clinical trials of etanercept in ankylosing spondylitis (AS) subjects.

Methods: Clinical trials of etanercept in AS (4 placebo-controlled; one active-controlled; and three open-label) were examined for reports of uveitis. Between-group differences with confidence intervals (CI) in the uveitis rates were calculated for the double-blind, active-controlled, and long-term studies.

Results: In placebo-controlled trials, the uveitis rate per 100 subject years (95% CI) for etanercept (8.6 [4.5, 14.2]) was lower than that for placebo (19.3 [11.0, 29.8] p=0.03). In the active comparator trial, rates for etanercept and sulphasalazine were similar (10.7 [5.5, 11.6] and 14.7 [6.4, 26.5], respectively; p=0.49). The long-term rate for etanercept, estimated from both placebo-controlled and open-label extension studies was 12.0 (10.0, 14.1).

Conclusions: In subjects with AS, rates of uveitis events with etanercept were lower than with placebo in placebo-controlled trials and similar to sulfasalazine in an active-comparator trial.

Objectives: To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biologic therapy for rheumatoid arthritis (RA).

Methods: Patients with active RA entered a randomized study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800µg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline and 2 further time-points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis (DIA). Selected mediators were also measured in serum.

Results: Twenty-two patients were randomized: 11 received monotherapy and 11 combination therapy. American College of Rheumatology (ACR) 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy, and 36%, 9%, and 0% with monotherapy, respectively.

In synovial tissue, T-cell infiltration, vascularity and transforming growth factor β (TGFβ) expression demonstrated significant utility as biomarkers of disease activity and the therapeutic response. In serum, interleukin-6 (IL-6), matrix metalloproteinase -1 (MMP-1), MMP-3 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pre-treatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor (VEGF) / TGFβ, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII and IL-18 correlated with radiographic progression.

Conclusions: Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.

Background: Joint destruction in rheumatoid arthritis (RA) was until recently seen as an irreversible state. Lately, it was defined that repair of bone erosions occurs; however little is known about its prevalence. This study investigates the frequency of repair and patients characteristics associated with repair in an inception cohort.

Patients and methods: 250 RA-patients, included in the Leiden Early Arthritis Clinic between 1993-2000 and treated with conventional DMARD-therapy, were studied (mean follow-up 10.1 years). Yearly made radiographs were scored using the Sharp–van der Heijde method, initially aware of the chronology. Patients with a negative change in erosion scores on subsequent radiographs were selected and their series of radiographs were rescored with concealed time sequence by three readers. Repair was defined as agreement of two readers in having a negative change in erosion scores that persisted for at least two years.

Results: Repair was identified in 32 joints in 18 patients (7.2%). Patients with repair had more frequent autoantibodies (RF,ACPA) and a higher level of joint destruction. In the joints with repair arthritis was absent in the two years preceding repair.

Conclusions: Repair occurred in 7.2% of the RA-patients, particularly in clinically inactive joints in patients with severe destructive disease.

Objectives: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis. Since genetic risk factors tend to overlap with several autoimmune diseases, we aimed to investigate whether this region is associated with Type I Diabetes (TID), Celiac Disease (CD), Systemic Sclerosis (SSc) and Systemic Lupus Erythematosus (SLE).

Methods: We genotyped the most consistently associated SNP, rs10818488, in a total of 735 T1D, 1049 CD, 367 SSc, 746 SLE and 3494 ethnically and geographically matched healthy individuals. The replication sample set consisted of 99 T1D, 272 SLE patients and 482 healthy individuals from Crete.

Results: We detected significant association of the rs10818488 A allele with T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016) which was replicated in 99 T1D, 272 SLE patients and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002 respectively). Joint analysis of all T1D (N=961) and all SLE (N=1018) patients compared to 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (P=2.6x10-4) respectively. However, combining our dataset with the T1D sample set from the WTCCC results in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study shows significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02x10-6) in a total of 1577 SLE patients and 4215 healthy individuals.

Conclusion: We report significant association of the TRAF1-C5 locus in SLE implying that this region lies in a pathway relevant to multiple autoimmune diseases.

Objectives: This study evaluates the diagnostic performance of the anti-CCP2, anti-CCP3 and anti-MCV tests in differentiating rheumatoid arthritis (RA) from other forms of arthritis in a clinical setting of early arthritis.

Methods: In 917 patients with recent-onset arthritis (566 RA, 351 other diseases) and in 99 healthy-controls the anti-MCV, anti-CCP2 and anti-CCP3.1 tests were performed and the test-characteristics compared.

Results: Comparing RA with other causes of arthritis revealed a lower specificity for anti-MCV (82.9%) than for anti-CCP2 (93.4%) and anti-CCP3.1 (90%). Similarly, the positive likelihood-ratio for anti-MCV was lower as well (3.6, compared to 8.7, 5,8 for anti-CCP2 and anti-CCP3.1). The anti-MCV test had a higher sensitivity (62% versus 56.9% and 58.1% respectively). In psoriatic-arthritis, ankylosing-spondylitis and other arthritis anti-MCV-antibodies had a prevalence of 15.2%, 13.9% and 19.4%.

Conclusion: The diagnostic performance of the anti-MCV test in the differential diagnosis of early arthritis is lower compared to the anti-CCP tests.

Background: COBRA combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort.

Methods: In the COBRA trial, 155 early RA patients were treated with sulfasalazine monotherapy (SSZ-group) or a combination of step-down prednisolone, methotrexate and sulfasalazine (COBRA-group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollized scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests.

Results: 152 out of 155 patients yielded at least partial data. After mean 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, hazard ratio 0.57 (95%CI: 0.21-1.52). Treatment for hypertension was significantly more prevalent in the COBRA-group (P=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, i.e. difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, i.e. difference in yearly progression rates similar to that seen in the first 5 years of follow-up.

Conclusions: After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared to initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

Objectives: Genome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions. We meta-analyzed the available evidence on these proposed associations.

Methods: Data were synthesized for four polymorphisms: rs3761847 (n=12 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. We also performed meta-analyses for subgroups defined by anti-CCP and RF status.

Results: The polymorphism rs6920220 reached genome-wide statistically significance with p=7.9x10^-17 and an allelic odds ratio of 1.24 (95% CI: 1.18-1.30) and no between-study heterogeneity (I² =0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with rheumatoid factor (RF). The other three variants showed large between-study heterogeneity across datasets (I² range 74-82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220).

Conclusions: Genetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and rheumatoid factor profile. With the exception of rs6920220 that shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognized phenotypic or genetic variability (e.g. gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.

Background: Rheumatoid arthritis (RA) patients with an inadequate response to TNF inhibitors (aTNF) may switch to an alternative aTNF or start a treatment from a different class, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit.

Objective: To analyze the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients.

Methods: This is a prospective cohort study of RA patients who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA). The primary outcome, longitudinal improvement in DAS28, was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders.

Results: Of the 318 RA patients included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than alternative aTNF (p = 0.03; at 6 months, –1.34 (95% CI: –1.54; –1.15) versus –0.93 (95% CI: –1.28; –0.59) respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar between RTX and alternative aTNFs (p =0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of DMARD co-therapy.

Conclusion: This observational study suggests that RTX is more effective than switching to an alternative aTNF in RA patients who stopped a previous aTNF treatment because of ineffectiveness.

Objectives: CARD8 and NLRP3 are constituents of the inflammasome, which regulates interleukin 1β production. We evaluated the influence of polymorphisms in CARD8 and NLRP3 on rheumatoid arthritis (RA) susceptibility and severity.

Methods: CARD8 p.C10X and NLRP3 p.Q705K genotypes were assessed in >500 controls and early RA patients from northern Sweden. The patients were monitored regularly during 2 years. The 28 joint disease activity score (DAS28) and its separate components were compared across genotypes.

Results: Patients with ≥1 variant allele in CARD8 (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2 year follow-up, despite receiving disease-modifying anti-rheumatic drugs to a higher extent. CARD8-X was significantly overrepresented among patients who received anti-TNF therapy during the first two years. CARD8 and NLRP3 genotypes did not influence radiological joint damage or associate with an increased susceptibility.

Conclusions: Carriage of CARD8-X associates with a worse disease course in early RA.

Introduction: PSORS4 is a susceptibility locus for psoriasis vulgaris (PsV), a common inflammatory, hyperproliferative skin disorder. Recently, a deletion of two late cornified envelope (LCE) genes within epidermal differentiation complex on chromosome 1 was shown to be enriched in 1,426 PsV patients, suggesting compromised barrier function in deletion carriers. We subsequently confirmed this genetic association in a German cohort.

Methods: In order to investigate whether this variant also predisposes to psoriatic arthritis (PsA), we genotyped this deletion and three SNPs in strong linkage disequilibrium with it in a case-control cohort of 650 patients and 937 control individuals of German origin.

Results: LCE deletion frequency did not significantly differ between PsA patients and controls (65.0% vs. 65.5%). Similarly, no evidence for association to the three SNPs was observed.

Discussion: This is the first non-HLA risk factor predisposing only to skin-type of psoriasis supporting the concept of partially overlapping, but different etiological factors underlying skin and joint manifestations.

Objective: Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, we recently reported that steroid treatment was associated with decreased lymphoma risk. This study sought to further assess the nature of this association.

Methods: In a cohort of 74,651 patients with RA, we identified 378 cases with lymphoma and 378 matched RA controls, and abstracted information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (OR) through conditional logistic regression.

Results: A total duration of oral steroid treatment less than two years was not associated with lymphoma risk (OR=0.87; 95% confidence interval [CI] 0.51-1.5), whereas total treatment longer than two years was associated with a lower lymphoma risk (OR= 0.43; 95% CI 0.26-0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare therapy (OR= 0.22; 95% CI 0.13-0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37-0.94).

Conclusion: In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.

Objective: A recent meta-analysis of published genome wide association studies (GWASs) in populations of European descent reported novel associations of markers mapping to the CD40, CCL21 and CDK6 genes with RA susceptibility whilst a large-scale, case-control association study in a Japanese population identified association with multiple single nucleotide polymorphisms (SNPs) in the CD244 gene. The aim of the current study was to validate these potential RA susceptibility markers in a UK population.

Methods: Four SNPs (rs4810485 in CD40, rs2812378 in CCL21, rs42041 in CDK6 and rs6682654 in CD244) were genotyped in a UK cohort comprising 3,962 UK RA cases and 3,531 healthy controls using the Sequenom iPlex platform. Genotype counts in cases and controls were analysed using the chi squared test using Stata.

Results: Association to the CD40 gene was robustly replicated [P= 2 x 10-4, OR (95% CI) 0.86 (0.79-0.93)] and we found modest evidence for association to the CCL21 locus [P= 0.04, OR (95% CI) 1.08 (1.01-1.16)]. However, we found no evidence for association of rs42041 (CDK6) and rs6682654 (CD244) with RA susceptibility in our UK population. Following a meta-analysis including the original data, association to CD40 was confirmed [P= 7.8 x 10-8, OR (95% CI) 0.87 (0.83-0.92)].

Conclusion: In this large UK cohort, we have found strong association of the CD40 gene with susceptibility to RA, and weaker evidence for association with RA in the CCL21 locus.

Objective: FoxO3a is a transcriptional factor implicated in cell cycle regulation and apoptosis. Since rheumatoid arthritis (RA) is associated with apoptosis defects, we investigated FoxO3a expression level, regulation and phosphorylation status in RA blood and synovium.

Methods: In microarray experiments, an overexpression of FoxO3a mRNA was observed in RA blood compared to healthy controls. FoxO3a mRNA expression was quantified in RA polymorphonuclear (PMN) and peripheral blood mononuclear cells (PBMC) by qRT-PCR. Total FoxO3a and phosphorylated FoxO3a (pFoxO3a) protein expression was analyzed in blood leukocytes from RA vs. controls and in RA vs. OA synovium by immunostaining.

Results: FoxO3a mRNA and protein expression levels were increased in RA blood compared to controls. FoxO3a overexpression was primarily observed in PMNs. In RA synovium, both total and inactive phosphorylated FoxO3a proteins were detected. FoxO3a was detected primarily in the sublining T lymphocytes of RA synovium compared to the lining layer in RA and OA tissue, underlying a role for FoxO3a proteins in RA inflammation.

Conclusion: The overexpression of FoxO3a in RA blood, particularly in PMNs, suggests a potential role for this gene in RA pathogenesis through increased survival of blood PMNs. In RA synovium, FoxO3a mainly detected in inflammatory aggregates may also regulate the chronic survival of T lymphocytes.

Objective: Interleukin-6 (IL-6) blockade raises blood lipid levels in rheumatoid arthritis (RA) patients. In this study, we examined the influence of IL-6 on lipid metabolism.

Methods: Vascular skeletal muscle cells (VSMC) were cultured in the presence of IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R or TNF- for 24 h. After culture, the expression of very-low-density lipoprotein receptor (VLDLR), low-density lipoprotein receptor (LDLR) and low-density lipoprotein-related protein-1 (LRP-1) were measured by real-time PCR. Human IL-6 was injected into mice twice a day for 2 weeks and then VLDLR expression in several tissues and the change of total cholesterol (T-Chol) and triglyceride (TG) levels were investigated. Finally, the effect of anti-IL-6 receptor (IL-6R) antibody injection on blood lipid levels was examined.

Results: IL-6 + sIL-6R significantly induced expression of VLDLR mRNA in VSMC, but IL-6 or sIL-6R alone and TNF- did not do so. None of these cytokines induced LDLR and LRP-1 mRNA expression. IL-6 injection into mice significantly increased the expression of VLDLR in heart, adipose tissue and liver and decreased T-Chol and TG levels. The injection of anti-IL-6R antibody normalized the reduced levels of T-Chol and TG caused by IL-6 injection, whereas it had no influence on the levels of T-Chol and TG in normal mice.

Conclusions: Over-produced IL-6 decreased blood lipid levels by increasing VLDLR expression in several tissues. Therefore, we conclude that IL-6 blockade normalizes reduced lipid levels caused by IL-6, but does not affect normal lipid metabolism.

Objectives: We assessed whether there is excess transmission of alleles from the ERAP1 ERAP2 locus in ankylosing spondylitis (AS) families.

Methods: We genotyped 199 multiplex AS families with four non-synonymous SNPs: three in the ERAP1 gene (endoplasmic reticulum aminopeptidase 1; rs27044, rs10050860 and rs30187) and one in the ERAP2 gene (endoplasmic reticulum aminopeptidase 2; rs2549782) and performed family-based association analyses.

Results: Family-Based Association Testing (FBAT –e; empirical variance option) analysis revealed that ERAP1 rs30187[T] was associated with AS (additive model: P = 0.02; dominant model: P = 0.007). Haplotype permutation tests (HBAT -p) showed that a haplotype in the ERAP1 and ERAP2 loci (rs27044[G] rs30187[T] rs2549782[T]) was significantly associated with AS (2-sided P value by permutation test: 0.009 for additive and 0.008 for dominant model respectively).

Conclusion: We showed that one ERAP1 SNP and a haplotype in the ERAP1 and ERAP2 locus are associated with familial AS.

Objectives: To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee.

Methods: This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multi-center study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan-Meier survival data analyses. Predictive factors for joint replacement were identified by univariate Log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features.

Results: Of the 600 original patients, 531 (88.5%), mean age 67±10 years, mean disease duration 6.1±6.9 years had follow-up data and were analysed. During follow-up (median 3yrs; range 0 to 4yrs), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were: Kellgren & Lawrence radiographic grade (grade ≥ III vs < III, Hazards Ratio (HR) = 4.08 [95% CI = 2.34-7.12], p < 0.0001); ultrasonographic knee effusion (≥ 4 mm versus < 4 mm), HR = 2.63 [95% CI = 1.70-4.06], p < 0.0001); knee pain intensity on a 0-100 mm VAS (≥ 60 versus <60) HR= 1.81 [95% CI=1.15-2.83], p=0.01); and disease duration (≥ 5 years versus <5 yrs), HR= 1.63 [95% CI=1.08-2.47], p=0.02). Clinically detected effusion and US synovitis were not associated with joint replacement in the univariate analysis.

Conclusion: Longitudinal evaluation of this OA cohort demonstrated significant progression to joint replacement. In addition to severity of radiographic damage and pain, US detected effusion was a predictor of subsequent joint replacement. Osteoarthritis (OA) of the knee is a major problem for ageing Western populations (1). A major part of the economic burden is related to joint replacement surgery (2). It would be advantageous to have predictors of subsequent joint replacement in order to prioritise research in these patients, address reversible risk factors and provide cohorts for evaluating putative disease-modifying therapies (3). The limited prospective studies on joint replacement for OA suggest that radiographic severity, pain and global disease assessments, and willingness to consider surgery are the strongest predictors of subsequent joint replacement surgery (4, 5). Such research highlights the complexity of joint replacement as an outcome measure in clinical trials, as patient perceptions of need for surgery and potential side effects affect willingness to undergo a procedure, socio-economic features are important and these factors are reflected in regional and national variations in utilisation of joint replacement (3, 5).

Objective: To evaluate the performance of whole body (WB) MRI versus conventional (CON) MRI in assessing active inflammatory lesions of the entire spine in patients with established and clinically active axial spondyloarthritis (SpA) using the Spondyloarthritis Research Con-sortium of Canada (SPARCC) MRI index.

Methods: 32 consecutive SpA patients fulfilling the modified New York criteria and with clinically active disease (BASDAI score ≥ 4) were scanned by sagittal WB and CON MRI of the spine. The MR images were scored independently in random order by 3 readers blinded to patient identifiers. Active inflammatory lesions of the spine were recorded on a web-based scoring form. Pearson correlation coefficient served to compare scores for WB and CON MRI for each rater whilst intra-class correlation coefficient (ICC) was used to assess inter-observer reliability.

Results: The median percentage of inflammatory lesions recorded concordantly for both WB and CON MRI ranged from 83% to 91% for the 3 readers; 4% to 9% were only recorded by WB MRI, and 4% to 9% were recorded by CON MRI only. The Pearson correlation coeffi-cient between WB and CON MRI per rater was 0.79, 0.89 and 0.81, respectively. The ICC(2, 1) for CON MRI was 0.75, 0.80 and 0.68 and for WB MRI 0.82, 0.83 and 0.93, respectively, for the 3 possible reader pairs.

Conclusion: WB and CON MRI scores showed a high correlation and comparable high reli-ability for the detection of active inflammatory lesions in the spine of patients with clinically active SpA.

Objective: We tested the association between ARTs1 and Koreans with AS.

Methods: All patients and controls were Koreans. 872 AS patients fulfilling the modified New York criteria and 403 healthy controls were genotyped for five single nucleotide polymorphisms (SNPs), rs27044, rs17482078, rs10050860, rs30187, and, rs2287987, known to be associated with AS in Caucasians.

Results: SNPs rs27044 (p = 9.37 X 10-7) and rs30187 (p = 7.16 X 10-6) of ARTS1 were significantly associated with AS in Koreans. There was no significant association for rs17482078, rs10050860, and rs2287987. Two four marker haplotypes were found to be associated with AS (GCCT: p = 4.71 X 10-7, CCCC: p = 8.56 X 10-6).

Conclusions: This is first confirmation in a non-Caucasian population that genetic polymorphisms in ARTS1 are associated with AS, implicating common pathogenetic mechanisms in Korean and Caucasian AS.

Objective: Using a three-year nationwide population-based database (2001-2003), this study aims to examine the relationship between rheumatoid arthritis (RA) and adverse pregnancy outcomes, after adjusting for characteristics of infant, mother and father.

Methods: The study used the Taiwan National Health Insurance Research Dataset and birth certificate registry. In total, 1,912 mothers with RA and 9,560 matched comparison mothers were included for analysis. Separate conditional logistic regression analyses were carried out to explore the risk of low birthweight (LBW), preterm births, small for gestational age (SGA) infants, preeclampsia, and delivery mode (vaginal vs. cesarean section (CS)) for the study and comparison groups, after adjusting for potential confounders.

Results: Regression analyses showed that the adjusted odds of LBW, SGA infants, preeclampsia, and CS for women with RA were 1.47 (95% CI=1.22-1.78), 1.20 (95% CI=1.05-1.38), 2.22 (95% CI=1.59-3.11), and 1.19 (95% CI=1.07-1.31) times, respectively, that of comparison mothers.

Conclusion: After adjusting for potential confounding factors, women with RA had increased risk of LBW, SGA babies, preeclampsia, and CS, compared with unaffected women. Our findings suggest a need for active monitoring and early intervention to counter the increased risk of adverse obstetric outcomes for pregnant women with RA.

Objective: Assess long-term efficacy and safety of infliximab plus methotrexate (MTX) in juvenile rheumatoid arthritis (JRA).

Methods: Patients eligible for the open-label extension (OLE, weeks 52-204) received infliximab 3-6 mg/kg q8wks plus MTX.

Results: Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (8 patients) or patient/physician/sponsor requirement (8 patients). Infliximab (mean dose=4.4 mg/kg/infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24%, and 13%, respectively.

Conclusions: In the limited population of JRA patients remaining in the study through 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.

Objectives: To ascertain the prevalence of myocardial infarction (MI) in ankylosing spondylitis (AS) relative to that in the general population.

Methods: A questionnaire was sent to 593 AS patients, aged between 50 and 75 years and registered at the Jan van Breemen Institute or VU University Medical Centre. A total of 383 (65%) AS patients returned their questionnaire that covered the primary outcome (non-fatal) MI. The prevalence for MI was calculated with data from the general population provided by Netherlands Information Network of General Practice databases as reference.

Results: The overall prevalence for MI was 4.4% in AS patients versus 1.2% in the general population, resulting in an age and gender adjusted odds ratio of 3.1 (95%CI: 1.9-5.1) for AS patients. When non-responders (35%) were considered as non-MI the odds ratio decreased to 1.9 (95%CI: 1.2-3.2).

Conclusions: Our observations indicate that the MI prevalence is increased in AS patients.

Objectives: The aim of this study was to assess the value of power doppler ultrasound (PDUS) in combination with routine management in a very early inflammatory arthritis (IA) cohort.

Methods: 50 patients with ≤12 weeks of inflammatory symptoms +/- signs had clinical, laboratory and imaging assessments. Diagnosis was recorded at 12 months. Assuming a 15% pre-test probability of IA, post-test probabilities for various assessments were calculated and used to develop a diagnostic algorithm.

Results: All RF and/or CCP positive patients developed persistent IA so the added value of PDUS was assessed in the sero-negative (RF and CCP negative) group. The probability of IA in a sero-negative patient was 6%. The addition of clinical and radiographic features raised the probability of IA to 30% and with certain US features this rose to 94%.

Conclusions: In sero-negative early IA patients, combining PDUS with routine assessment can have a major impact on the certainty of diagnosis.

Background: Therapeutic approaches to rheumatoid arthritis have undergone significant changes. The importance of tight control and early therapy, rapidly altered if goals are not achieved, is supported by evidence. However, it is unknown to which extent these insights are accepted by practitioners in clinical practice.

Objective: We intended to learn about standard follow-up and treatment practices, and rheumatologists’ aims in the care of RA patients.

Methods: We conducted a survey at the 2008 EULAR Congress.

Results: Most specialists who were mainly from Europe and Latin America are well informed about recent concepts: Two thirds specified remission as a major goal. The experts attempted to reach treatment aims within 12-14 weeks, altering therapy otherwise. Disease activity assessment by composite measures is performed by a majority, although one third preferentially relied upon their judgement.

Conclusion: These results suggest the acceptance of ambitious treatment concepts in practice. While voluntary surveys have limitations, the answers reflect wide-spread adoption of desirable standards of care.

Objective: Two novel genetic polymorphisms on chromosome 6q23 are associated with sus-ceptibility to rheumatoid arthritis (RA). Both polymorphisms (rs6920220 and rs10499194) reside in a region close to the gene encoding tumor necrosis factor -induced protein 3 (TNFAIP3). TNFAIP3 is a negative regulator of NFB and as such involved in inhibiting TNF-Receptor mediated signalling effects. Interestingly, the initial associations were detected in patients with long-standing RA. However, no association was found for rs10499194 in a Swedish early arthritis cohort. As this could be caused by overrepresentation of patients with severe disease in cohorts with long-standing RA, we analyzed the effect of the 6q23 region on the rate of joint destruction.

Methods: Five single nucleotide polymorphisms (SNPs) in 6q23 were genotyped in 324 Dutch patients with early RA. Genotypes were correlated to progression of radiographic joint damage for a follow-up time of 5 years.

Results: Two polymorphisms (rs675520 and rs9376293) associated with severity of radio-graphic joint damage in ACPA+ patients. Importantly, the effects were present after correc-tion for confounding factors such as secular trends in treatment.

Conclusions: Our data associate the 6q23 region with the rate of joint destruction in ACPA+ RA.

Background: The Raynaud’s Condition Score (RCS) is a validated outcome measure for Raynaud’s phenomenon (RP). Our objective was to assess the minimally important difference (MID) and Patient Acceptable Symptom State (PASS) for RCS in patients with RP.

Subjects and methods: Patients with active RP (N=162) [mean RCS > 25 (0-100 VAS)] participated in a placebo-controlled, cross over randomized clinical trial (RCT). Data from the 2 treatment groups were combined for this analysis. We administered retrospective and prospective anchors during the RCT. MID groups were defined as the group who reported being somewhat better (anchor#1) and a 1-step change from "unbearable" to "very severe" etc. (anchor#2). We considered patients as achieving PASS if they rated their Raynaud’s condition as ‘very mild’ or ‘mild’ at the last study visit.

Results: The mean age of participants was 48.9 years and the mean baseline RCS score was 46.4. The RCS change score for the MID improvement group ranged from –13.9 to -14.3 points and PASS estimate was 34.0 points.

Conclusion: The MID and PASS estimates for RCS are 14-15 points for improvement and 34 points, respectively on a 0-100 scale in a large RCT of patients with active RP. This information can aid in interpreting RCS in future RP trials.

Objectives: Wegener's granulomatosis is a systemic vasculitis of unknown aetiology. Previous studies have presented environmental exposures such as silica and farming as potential risk factors. The aim of this study was to investigate the potential risk for Wegener's granulomatosis associated with occupations involving contact with animals and various airway exposures, using a population-based approach.

Methods: In the Swedish Register of Inpatient care we identified 2,288 cases with Wegener's granulomatosis. Ten matched controls for every case were selected from the Swedish Population Register. By linking the cases and controls to the Swedish Population censuses information on employments before the diagnosis of Wegener's granulomatosis was collected. Relative risks were assessed as odds ratios using conditional logistic regression.

Results: Odds ratios for specific occupations ranged from 0.6-1.9, and centred symmetrically around 1. No statistically significant increased risk was noted for the investigated occupations.

Background: Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration.

Methods: We obtained the number of patients with pain relief over baseline (≥15%, ≥30%, ≥50%, ≥70%) at two, four, eight, and 12 weeks of treatment, using the WOMAC 100 mm visual analogue pain subscale score for each treatment group of seven randomised, placebo-controlled trials of etoricoxib in osteoarthritis lasting six weeks or longer. Dropouts were assigned 0% improvement from baseline from then on. Numbers needed to treat (NNTs) were calculated at each level of response and time point.

Results: 3,554 patients had placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1,000 mg, or ibuprofen 2,400 mg daily. Response rates fell with increasing pain relief; 60-80% experienced minimally important pain relief (≥15%), 50-60% moderate pain relief (≥30%), 40-50% substantial pain relief (≥50%), and 20-30% extensive pain relief (≥70%). NNTs for etoricoxib, celecoxib, and naproxen were stable over 2-12 weeks. Ibuprofen showed lessening of effectiveness with time.

Conclusion: Responder rates and NNTs are reproducible for different levels of response over 12 weeks, and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost 1 in 2 patients having substantial benefit.

Objective: Rheumatoid arthritis is characterized by antibodies to citrullinated proteins (ACPA) and rheumatoid factor (RF) in the preclinical phase. Therefore, an intervention aimed at decreasing autoantibody levels in persons at risk may be effective in preventing progression to arthritis.

Methods: 83 arthralgia patients positive for ACPA or IgM-RF were randomly allocated to intramuscular injections of 100 mg dexamethasone or placebo at t=0 and 6 weeks. The primary endpoint was a 50% antibody reduction or normalization at 6 months.

Results: The primary endpoint was reached in one patient in each group. Patients treated with dexamethasone had reductions of antibody levels after 1 month (ACPA -22% and IgM-RF -14%), which persisted at 6 months for ACPA. During a median follow-up of 26 months, arthritis development in both groups was similar (20 vs. 22%).

Conclusion: In autoantibody positive arthralgia patients, dexamethasone treatment decreases ACPA and IgM-RF levels, but does not prevent arthritis development.

Background: Anti-citrullinated protein antibodies (ACPA) are associated with increased risk for rheumatoid arthritis. We prospectively investigated the effect of ACPA presence and levels on arthritis development in arthralgia patients.

Methods: Arthralgia patients positive for ACPA or IgM rheumatoid factor (IgM-RF) were tested for the shared epitope (SE) and were prospectively followed for at least 12 months. Absence of clinical arthritis at inclusion and arthritis development during follow-up were independently confirmed by two investigators. Cox-regression hazard analyses were used to calculate hazard ratios (HR) for arthritis development.

Results: 147 arthralgia patients were included (52 ACPA positive, 50 IgM-RF positive and 45 positive for both antibodies). After a median follow-up of 28 months (interquartile range [IQR] 19-39), 29 patients developed arthritis in a median of 4 (IQR 3-6) joints and 26 (90%) of these were ACPA positive. The presence of ACPA (HR 6.0; 95% confidence interval [95% CI] 1.8-20.1; P = 0.003), but not of IgM-RF (HR 1.4, 95% CI 0.6-3.1) nor the SE (HR 1.5, 95% CI 0.7-3.0) was associated with arthritis development. Within the group of ACPA positive patients, the risk for arthritis was enhanced by the presence of IgM-RF (HR 3.0; 95% CI 1.3-6.9; P = 0.01 and high ACPA levels (HR 1.7; 95% CI 1.1-2.5; P = 0.008), but not the SE (HR 1.0; 95% C.I. 0.5-2.1; P = 1.0).

Conclusion: In arthralgia patients the presence of ACPA, (but not of IgM-RF or SE) predicts arthritis development. The risk in ACPA positive patients may be further increased by the concomitant presence of IgM-RF or high levels of ACPA.

Objectives: To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of SLE patients.

Methods: The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the ACR case definitions and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient perceived impact determined by the SF-36.

Results: There were 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years. The mean disease duration at enrollment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years 486/1206 (40.3%) patients had ≥1 NP events which were attributed to SLE in 13.0%-23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study.

Conclusions: NP events in SLE patients are variable in frequency, most commonly present early in the disease course and adversely impact patients¡ quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.

Objective: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX).

Methods Patients receiving stable doses of MTX were randomized to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily [qd]) or matching placebo. The primary efficacy measure was the proportion of patients with ≥ 20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, DAS/EULAR response, and individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing, and immunology assessments.

Results On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31-43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections.

Conclusion: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

Objective: To examine the association of methotrexate (MTX) and TNF antagonists with risk of infectious outcomes including opportunistic infections in patients with rheumatoid arthritis (RA).

Methods: RA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry prescribed MTX, TNF antagonists or other disease modifying anti-rheumatic drugs (DMARDs) were included. The primary outcomes were incident overall and opportunistic infections. Incident rate ratios were calculated using Generalized Estimating Equation (GEE) Poisson regression models adjusted for demographics, comorbidities and RA disease activity measures.

Results: A total of 7,971 RA patients were followed. Adjusted rate of infections per 100 person-years was increased among MTX (30.9, 95% CI [29.2, 32.7]), TNF antagonist (40.1, 95% CI [37.0, 43.4]) and combination MTX/TNF antagonist users (37.1, 95% CI [34.9, 39.3]) versus other nonbiologic DMARD users (24.5, 95% CI [21.8, 27.5]). The adjusted incidence rate ratio (IRR) was increased for patients prescribed MTX (IRR 1.30, 95% CI 1.12-1.50) and TNF antagonists (IRR 1.52, 95% CI 1.30-1.78) compared to other DMARD users. For opportunistic infections, TNF antagonist use (IRR 1.67, 95% CI 0.95-2.94) was associated with increased risk. Prednisone use was associated with an increased risk of opportunistic infection (IRR 1.63, 95% CI 1.20-2.21) and an increased risk of overall infection at doses > 10 mg daily (IRR 1.30, 95% CI 1.11-1.53).

Conclusions: MTX, TNF antagonists and prednisone at doses >10 mg daily were associated with increased risks of overall infections. Low-dose prednisone and TNF antagonists, but not MTX, increased risk for opportunistic infections.

Objective: To assess the impact of different subsets of symptomatic hand osteoarthritis (OA) on pain and disability.

Methods: From 308 hand OA patients a group with CMCJ symptoms only (group I, n=20) was identified as well as groups with symptoms at the interphalangeal joints (IPJs) only (group II, n=138), and symptoms at both sites (group III, n=150). Hand pain and function, assessed with the AUSCAN, were compared between groups using linear mixed models. Radiological OA was assessed using the Kellgren-Lawrence grading scale.

Results: Mean (SD) AUSCAN scores for group I, II and III were 23.1 (11.7), 18.3 (11.9) and 26.4 (12.5), respectively. After adjustment for age, gender, BMI, family effects and number of symptomatic hand joints, significant differences in AUSCAN scores of 7.4 (95% CI 1.8-13.0) between group I and II, and 5.7 (95% CI 2.7-8.6) between group II and III were found. AUSCAN scores were 5.8 (95% CI 3.1-8.6) higher for patients with versus patients without CMCJ symptoms. Kellgren-Lawrence scores did not differ between groups.

Conclusion: In symptomatic hand OA, CMCJ OA contributes more to pain and disability than IPJ OA. Hence, treatment of CMCJ OA should be emphasized, even if it coincides with IPJ OA.

Objective: Tibiofemoral alignment plays a role in knee OA, but which factors contribute to alignment is unknown. We investigated familial aggregation of tibiofemoral alignment in participants of the GARP (Genetics ARthrosis and Progression) study.

Methods: The tibio-femoral anatomical angle on semi-flexed knee radiographs was measured in sibling pairs (mean age 60 years, 81% women) with primary OA with multiple joint involvement. Radiographic OA was assessed according to the Kellgren-Lawrence (KL) method. Heritability estimates of the tibiofemoral angle were calculated by comparing twice the between sibling variance divided by the total variance; adjustments were made for age, gender, body mass index, history of meniscectomy, lower limb fracture and in analyses including all knees, for KL score.

Results: We studied 360 subjects representing 180 families. The mean (sd) tibiofemoral angle of right and left knees in the probands was 182.7° (2.9) and 182.8 (2.8) respectively; similar angles were measured in the siblings. Radiographic knee OA (KL score ≥ 2) was present in 27% of the knees. Stratified analyses in sib pairs with non-osteoarthritic right or left knees revealed adjusted heritability estimates of the tibiofemoral angle of the right and left knees of 0.42 (95%CI 0.02-0.82) and 0.56 (95%CI 0.19-0.92). In addition adjusted heritability estimates of the tibiofemoral angle in all right and left knees were calculated, being 0.48 (95%CI 0.18-0.78) and 0.50 (95%CI 0.21-0.79), respectively.

Conclusion: The alignment of the tibiofemoral joint is influenced by familial factors, implying that tibiofemoral malalignment may add to the genetic predisposition for knee OA development. These results need to be confirmed in other study populations.

Objective: Achieving joint regeneration in rheumatoid arthritis (RA) represents a future challenge. Autologous synovial mesenchymal stem cells (MSCs) could be therapeutically exploited. However, the inflammatory milieu in the RA synovium could adversely affect endogenous MSC function. To test this hypothesis, the frequency and multipotency of RA synovial MSCs was evaluated in relation to existing synovial inflammation.

Methods: Synovial inflammation was measured using arthroscopic visual analogue score (VAS) and further validated using immunohistochemistry and flow cytometry. Highly-proliferative clonogenic in vivo MSCs were enumerated following fluorescence-activated cell sorting and expansion for 20 population doublings. MSC multipotency was quantified following standard in vitro culture-expansion and trilineage differentiation assays. Real-time PCR, flow cytometry and ELISA were used to evaluate pro- and anti-chondrogenic molecules in standard polyclonal synovial MSCs.

Results: Arthroscopic visual score of inflammation (VAS) significantly correlated with synovial macrophage infiltration. In RA, synovial MSC chondrogenesis was inhibited in direct relation to VAS (r=-0.777, p<0.05) and reduced compared to control OA-MSCs (p<0.05). In vivo MSCs resided in the synovial fibroblastic/stromal fraction (CD45-CD31-) and were reduced in frequency in relation to VAS (r=-0.695, p<0.05). In RA-MSCs, CD44 levels correlated negatively with inflammation and positively with chondrogenesis (r=-0.830 and r=0.865, respectively). Cytokine production and Sox9 expression was similar between RA- and OA-MSCs.

Conclusions: Our findings demonstrate a negative relationship between synovial MSC chondrogenic and clonogenic capacities and the magnitude of synovitis in RA. Effective suppression of joint inflammation is therefore necessary for the development of autologous MSC therapies aimed at cartilage regeneration in RA.

Objective: The Health Assessment Questionnaire Disability Index (HAQ-DI) is the most widely used measure of function in rheumatoid arthritis (RA). To enhance the incorporation of patients’ view in outcome assessment, this study aimed to evaluate individualized forms of the HAQ-DI.

Patients and methods: HAQ-DI data were prospectively obtained from 370 RA outpatients treated with leflunomide over a 6-month period. At baseline and final visits, patients had to rate the importance they attached to each activity addressed by the 20 HAQ-DI items, and to select the 5 activities they considered the most important. Different individualized scales were evaluated: scales preserving all domains, in which the score for each item is multiplied by or added to its importance; and scales involving for each patient only the 5 most important items. The psychometric properties of theses scales were compared to those of the HAQ-DI.

Results: For each HAQ-DI item, severity and importance scores were weakly correlated. Scores for all individualized scales were highly correlated with the HAQ-DI score (rho>0.75). All scales had a good internal consistency (Cronbach’s alpha: 0.87 to 0.88). Compared to the HAQ-DI, individualized scales did not have better sensitivity to change (standardized response mean: 0.64 to 0.69 vs. 0.74).

Conclusion Individualized scales have similar properties as the HAQ-DI. However, individualized questionnaires measuring importance gave complementary information to the measure of disability. Therefore, even if individualization is probably not needed for group assessment in all randomized controlled trials, the use of individualized questionnaires could be clinically relevant for individual RA patients.

Objective: Pregnant women with systemic sclerosis (SSc; scleroderma) have increased risk of premature delivery and small full-term infants. During placental development, angiogenesis and vascular remodelling are essential for a successful pregnancy outcome. We analysed the pathological changes and expression of angiogenic factors in SSc placentas.

Methods: Placenta biopsies were obtained from 3 SSc patients and 4 healthy uncomplicated pregnancies after delivery at 34-38 weeks of gestation. Sections were stained with Masson's trichrome and PhosphoTungstic-Acid-Haematoxylin and immunostained for CTGF, -SMA, VEGF, PlGF, VEGFR-1 and VEGFR-2.

Results: Pathological findings were signs of decidual vasculopathy, increased syncytiotrophoblast knotting, placental infarcts and villous hypoplasia. Severe and diffuse perivascular and stromal fibrosis of decidua and chorionic villi, as well as extensive deposition of fibrinoid material around decidual vessels and in intervillous spaces were observed. Strong CTGF expression in vessel wall, decidual cells and fibroblasts, and -SMA+ myofibroblasts were found. VEGF and VEGFR-2 expression was stronger in SSc than in healthy placentas, while VEGFR-1 expression was similar to controls. PlGF immunopositivity was weaker in SSc.

Conclusion: In SSc placentas, severe fibrosis and abnormal vascular remodelling were detected. This may result in reduced blood flow leading to deep sufferance of maternal placenta and possible premature delivery.

Objective: One of the aims of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA)-risk locus in Caucasian, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analyzed.

Methods: We conducted a multi-center association study consisting of four RA case-control series (4397 cases and 2857 controls) and three SLE case-control series (591 cases and 2199 shared controls). Genotyping was performed using TaqMan genotyping assay for two SNPs that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay.

Results: Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between SLE patients and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in our study, while they decreased the risk in the original studies. We found significant difference between the risk-allele carrier and non-carrier of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymophoblastoid cell lines (P = 0.04).

Conclusion: Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.

Background: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and other spondylarthritides (SpA) impose great impact on the individual in addition to the costs on society, which may be reduced by effective pharmacological treatment. Industry independent health economic studies should complement studies sponsored by industry.

Objective: To study secular trends in baseline health utilities in patients commencing TNF blockade for arthritis in clinical practice over 7 years; to address utility changes during treatment; to investigate the influence of previous treatment courses; to study the feasibility of health utility measures, and to compare them across diagnostic entities.

Methods EuroQoL 5 Dimensions (EQ-5D) utility data were collected from a structured clinical follow-up program of anti-TNF treated patients with RA (N=2554), PsA (N=574) or SpA (N=586). Time trends were calculated. Completer analysis was used.

Results There were weak or non-significant secular trends for increasing baseline utilities over time for RA, PsA and SpA. Maximum gain in utilities occurred already after 2 weeks for all diagnoses and remained stable for patients remaining on therapy. First and second anti-TNF courses performed similarly.

Conclusions: Utilities at inclusion remained largely unchanged for RA, PsA and SpA over 7 years. Improvement occurred early during treatment and not beyond 6 weeks at the group level. Improvement during the first course was not consistently greater than the second. There were no major differences between RA, PsA and SpA. EQ-5D proved feasible and applicable across these diagnoses. These "real world" data may be useful for health economic modelling.

Objectives: To characterize and quantify short term changes in local inflammation using magnetic resonance imaging (MRI), and to correlate the findings with clinical disease activity in response to infliximab in patients with spondyloarthritis (SPA).

Methods: 28 consecutive patients with established SPA under successful long-term treatment with infliximab underwent MRI immediately before and one week after re-administration of the TNF blocker. CRP and BASDAI were assessed at both time points. The MRI protocol included coronal and sagittal turbo-STIR images as well as contrast-enhanced sagittal T1 weighted, fat suppressed images. Images were assessed in independent sessions using the ASspiMRI-a score, the signal-difference-to-noise ratios (SDNRs) and volumetry to assess oedematous and inflamed tissues.

Results: BASDAI values were expectedly low at study entry (3.3±2.3). One week after administration of infliximab, 46% of the patients reached a BASDAI 20, 39% a BASDAI 50. Kappa values for qualitative assessments and all measurements were excellent (range between 0.83 and 1.0) The ASspiMRI-a dropped most in the thoracic (3.3 points), less in the lumbar (1.21 points) and least in the cervical spine (0.38 points). The decrease of the ASspiMRIa, the SDNRs and the inflamed volumes in response to infliximab re-treatment was significant (p<0.01). BASDAI showed a weak correlation with the ASspiMRIa (r=0.41).

Conclusions: MRI proves to be a valid method to assess and quantify short term effects of therapy in SPA. Comparison between MRI and BASDAI changes show that the BASDAI may underestimate local inflammation. It suggests an explanation for the structural disease progression despite clinical remission.

Objective: To study whether Dickkopf (DKK)- 1, an inhibitor of Wnt signaling, is involved in the fusion of sacroiliac joints.

Methods: Mice transgenic for tumor necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated by vehicle, anti- TNF antibody or anti- DKK1 antibody. Sacroiliac joints were analyzed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, β-catenin and DKK-1 was assessed by immunohistochemistry.

Results: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclasts numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 has no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints.

Conclusion: DKK1 influences inflammatory remodeling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signaling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis of humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of spondyloarthritides.

Objective: To identify target antigens of anti-fibroblasts antibodies (AFAs) in systemic sclerosis (SSc) patients.

Patients and methods: In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension [PAH] and 12 without) and 36 idiopathic PAH (IPAH) patients, tested in pooled sera for groups of 3, were compared to a sera pool from 14 healthy controls (HCs). Serum IgG reactivity was analyzed by use of a 2-D electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for 2 groups - 158 SSc, 67 IPAH and 100 HCs; and 35 SSc and 50 HCs - was tested against -enolase from Saccharomyces cerevisiae (Sc) and human recombinant (rHu) -enolase, respectively, on ELISA.

Results: In the first part, we identified -enolase as a main target antigen of AFAs from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) IPAH patients and 4/100 (4%) HCs (p<0.0001) had anti-Sc -enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HCs had anti-rHu -enolase antibodies (p=0.001). In SSc, the presence of anti-Sc -enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2 vs. 89.7%, p=0.0001) and diffusion capacity for carbon monoxide (47.4 vs. 62.3%, p=0.0009)], and anti-topoisomerase 1 antibodies (46 vs. 21%, p=0.005) but not anti-centromere Abs (11 vs. 34%, p=0.006). Results were similar with rHu -enolase testing.

Conclusion: In SSc, AFAs recognize -enolase and are associated with ILD and anti-topoisomerase antibodies.

Objectives: The primary objective was to compare a single, 6 mL, intra-articular (IA) injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis (OA). The safety of a repeat injection of hylan G-F 20 was also assessed.

Methods: Patients with primary OA knee pain were randomised to arthrocentesis plus a 6 mL IA injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/ one blinded observer) study. Results were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in WOMAC A pain. Secondary outcome measures included WOMAC A1 and C, patient (PGA) and clinical observer (COGA) global assessments, and OMERACT-OARSI responder rates. A 4-week, open, repeat treatment phase evaluated safety only.

Results: Two hundred and fifty three patients (Kellgren-Lawrence Grade II or III) were randomised. Patients receiving hylan G-F 20 experienced statistically significantly greater improvement in WOMAC A pain scores (-0.15, SE 0.076, p=0.047), and several of the secondary outcome measures (WOMAC A1, PGA, and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase.

Conclusions: This placebo-controlled study demonstrated that, in patients with knee OA, a single 6 mL IA injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference v placebo.

Objectives: The anti-IL-6 receptor antibody tocilizumab inhibits signaling of IL-6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. The AMBITION study evaluated tocilizumab monotherapy efficacy and safety vs. methotrexate in patients with active RA, who had not previously failed methotrexate/biologics treatment.

Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomized 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at Week 24.

Results: The intent-to-treat analysis demonstrated that tocilizumab was superior to methotrexate treatment with a higher ACR20 response (69.9 vs. 52.5%; P<0.0001), and DAS28<2.6 rate (33.6 vs. 12.1%) at Week 24. Mean high sensitivity C-reactive protein (hsCRP) was within the normal range from Week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events (AEs) with tocilizumab was 3.8% vs. methotrexate, 2.8% (p=0.50), and of serious infections, 1.4% vs. 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs. 0.4%) and increased total cholesterol ≥240 mg/dL (13.2% vs. 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs. 2.5%), respectively.

Conclusion: Tocilizumab monotherapy is superior to methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favorable benefit-risk, in patients who have not previously failed methotrexate or biologics treatment.

Objectives: To compare effects of etanercept (ETN) 50-mg once-weekly plus methotrexate (MTX) versus MTX alone on patient-reported outcomes (PROs) and the relationship between remission and PRO improvement.

Methods: In this double-blind, randomized clinical trial (COMET), PROs included: the Health Assessment Questionnaire (HAQ), EuroQoL health status, fatigue and pain visual analogue scales, Hospital Anxiety and Depression Scale, and Medical Outcomes Short-Form-36. Mean changes from baseline were analyzed by analysis of covariance using last observation carried forward. Results from week-52 are presented.

Results: Most PROs demonstrated significantly greater improvements with ETN+MTX than MTX alone including physical functioning, pain, fatigue, and overall health status. Significantly greater improvement in HAQ score was observed in the ETN+MTX than the MTX group ( 1.02 vs -0.72; P<.001) and a greater proportion reached the minimal clinically important difference of 0.22 (88% vs 78%; P<.006). The relationship between PRO score and clinical status indicated that improvement was greatest among patients achieving remission.

Conclusions: Early treatment with ETN+MTX leads to significantly greater improvements in multiple dimensions of PROs than MTX alone. The close relationship between disease activity and PRO improvement suggests that early treatment, with remission as a goal, should maximize the chance of restoring normal functioning and HRQoL.

Objectives: To demonstrate that a single-chain antibody (scFv) against TNF- (ESBA105) has efficacy comparable to a full length anti-TNF- IgG (infliximab). Furthermore, to evaluate whether ESBA105 has all properties required for local treatment of arthritis and to investigate its discriminative tissue penetration properties.

Methods: In vivo efficacy was measured in arthritis of the knee joint induced by intra-articular (i.a.) injection of recombinant human TNF- (rhTNF-) in Lewis rats. Cartilage penetration of scFv (ESBA105) and full length IgG (infliximab) were studied in bovine cartilage specimens ex vivo. Tissue penetration, biodistribution and pharmacokinetics of ESBA105 were followed and compared after i.a. and i.v. administration.

Results: In cell culture, ESBA105 showed highly similar TNF- inhibitory potency as infliximab. In vivo, ESBA105 inhibited rhTNF- induced synovial inflammation in rats with efficacy again comparable to infliximab. An 11-fold molar excess of ESBA105 over rhTNF- resulted in 90% inhibition of knee joint swelling, inflammatory infiltrates as well as proteoglycan loss from cartilage. In ex vivo studies of bovine cartilage, ESBA105 penetrated well into cartilage whereas infliximab remained on the surface of the cartilage. In vivo, following [¹²⁵I]-ESBA105 i.a. injection into the knee joint of rabbits, rapid penetration into synovial tissue, cartilage and surrounding tissues was observed.

Conclusions: ESBA105 potently inhibits inflammation and prevents cartilage damage triggered by TNF-. In contrast to a full length IgG, ESBA105 also penetrates into cartilage and can be expected to reverse the TNF- induced catabolic state of articular cartilage in arthritides.

Objective: To review the diagnostic and prognostic value of anti-MCV in rheumatoid arthritis taken into account the already available serology.

Methods: Medline was searched through Pubmed (1966- May 2008) for anti-MCV and related terms, arthritis and arthropathies. Studies with anti-MCV, arthritis/arthropathy, and primary data on diagnosis and/or prognosis were included. Their methodological quality was assessed using the QUADAS for diagnostic studies and the modified Hayden list for prognostic studies.

Results: Of 14 eligible studies, 11 included diagnostic data and 3 included prognostic data. No study evaluated anti-MCV as added diagnostic test to the already available anti-CCP and rheumatoid factor serology. One study included the optimal patient spectrum resulting in sensitivity of 0.59 and specificity of 0.98. Ten diagnostic case-control studies using the same anti-MCV kit showed a sensitivity of 0.64-0.84 and a specificity of 0.79-0.96. This almost equalled the performance of anti-CCP in the same studies. The prognostic evaluation of anti-MCV was limited by differences in study methodology, outcome and statistical modelling. Individual studies showed moderate associations for anti-MCV and radiological progression with the strength of the association comparable to that of anti-CCP.

Conclusion: Study heterogeneity, choice of study population and methodological limitations limited overall conclusions about the true diagnostic and prognostic test performance of anti-MCV. Evidence from the diagnostic case-control studies suggests that anti-MCV may be used as an alternative for anti-CCP.

Objective: About 15- 20 % of patients with giant-cell arteritis (GCA) develop ischemic complications often preceded by transient ischemia. We investigated the expression of the endothelin (ET) system in GCA lesions, to assess its relationship with the development of ischemic complications.

Methods: Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-proven GCA and 16 healthy donors. ET-1, endothelin converting enzyme (ECE-1) and ET receptor (ETAR and ETBR) mRNAs were measured by real-time quantitative RT-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and western-blot.

Results: ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared to controls (0.28±0.098 [x±SEM] vs 0.98±0.32 fmol/mg, p=0.028). ECE-1, ETAR and ETBR /actin ratios (western-blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared to control arteries. When investigating mechanisms underlying these results, we found that PDGF and IL-1β, present in GCA lesions, down-regulated ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased ET tissue concentration (0.87±0.2 vs 0.52±0.08;p=0.6). Plasma ET concentrations were higher in patients with ischemic complications (1.049±0.48 vs 1.205±0.63 pg/mL,p= 0.032).

Conclusions: The ET system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to ET during initial treatment.

Objectives: While reproductive factors might plausibly be involved in the etiology of rheumatoid ar-thritis (RA), the female predominance remains unexplained. We aimed to address the possible impact of livebirths, pregnancy losses, and pregnancy complications on subsequent risk of RA in a nationwide cohort study.

Methods: National register data were used to link reproductive histories and later RA hospitalizations in a cohort of 4.4 million Danes. As our measure of relative risk associated with different reproductive histories we used ratios of first inpatient RA hospitalization rates (RRs) with 95% confidence intervals (CIs) obtained in Poisson regression analysis.

Results: Overall, 7,017 women and 3,041 men were hospitalized with RA during 1977-2004 (88.8 mil-lion person-years). RA risk was inversely associated with age at birth of first child in both women and men (P-trend <0.001). Overall, nulliparity and histories of pregnancy loss were not associated with RA risk but, compared with one-child mothers, women with two (RR=0.84; 95% CI: 0.78-0.90) or three (RR=0.83; 0.77-0.91) children were at reduced risk. RA risk was elevated among women with a history of hyperemesis (RR=1.70; 1.06-2.54), gestational hypertension (RR=1.49; 1.06-2.02), or pre-eclampsia (RR=1.42; 1.08-1.84).

Conclusions: One-child mothers and young parents were at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of significantly elevated RA risk in women whose pregnancies were complicated by hyperemesis, gestational hypertension, or pre-eclampsia might reflect reduced immune adaptability to pregnancy in RA disposed women or a role of fetal microchimerism in the etiology of RA.

Objective: BAK1 is a Bcl-2 family proapoptotic member suggested as a candidate gene for autoimmune diseases. We studied the influence of BAK1 polymorphisms on the risk to develop autoimmune rheumatic diseases (AIRDs) in women.

Methods: A total of 719 Colombian women were included: 209 had systemic lupus erythematosus, 99 primary Sjögren’s syndrome, 159 rheumatoid arthritis and 252 were healthy matched controls. Tag single nucleotide polymorphisms (SNPs) and potentially functional variants were typed by TaqMan® allele discrimination assays. HLA-DRB1 and -DQB1 typing was done by reverse dot-blot hybridization and linkage disequilibrium (LD) with BAK1 SNPs was assessed.

Results: SNPs rs513349 [OR=0.57(0.46-0.72), p=8.57x10^-7] and rs5745582 [OR=1.61(1.26-2.04), p=1.08x10^-4] were associated with the AIRDs included in this study. There was a significant increase of the rs513349G-rs561276C-rs5745582A (GCA) haplotype in each patient cohort as compared to controls [OR=1.95(1.50-2.54), p=2.38x10^-5]. These SNPs were not in LD with HLA-DRB1 or -DQB1 genes.

Conclusions: Our results indicate that the BAK1 polymorphisms influence the risk of acquiring AIRDs in the population studied and are consistent with the paradigm that autoimmune diseases are likely to share common susceptibility variants.

Objectives: To determine whether changes in levels of anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) are associated with the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and with the subsequent flare postpartum.

Methods: Disease activity scores from the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA)-study of 118 patients were available for analysis. Before conception (if applicable), at each trimester and at 6, 12 and 26 weeks postpartum levels of the autoantibodies anti-CCP, IgM-RF, IgG-RF and IgA-RF were determined. Responses in disease activity were classified according EULAR response criteria during pregnancy and postpartum, and associated with the presence or absence of autoantibodies.

Results: The median levels of anti-CCP and all subclasses of RF during pregnancy were stable, whereas postpartum the levels of anti-CCP, IgM-RF and IgA-RF declined. A significantly higher percentage of women without autoantibodies (both anti-CCP and RF negative) improved compared with women positive for either or both autoantibodies (75% vs 39%, p=0.01). The occurrence of a flare postpartum was comparable between these groups.

Conclusions: Improvement of disease activity of RA during pregnancy was not associated with changes in levels of autoantibodies during pregnancy, however, improvement may occur more frequently in the absence of anti-CCP and RF.

Objective: To report on results of a standardized consensus process agreeing on concepts typical and/or relevant when classifying functioning and health in patients with ankylosing spondylitis (AS) based on the International Classification of Functioning and Health (ICF).

Methods: Experts in AS from different professional and geographic backgrounds attended a consensus conference and were divided over three working groups. Rheumatologists were selected from the members of Assessment of SpondyloArthritis international Society (ASAS). Other health professionals were recommended by ASAS members. The aim was to compose three working groups with five to seven participants to allow everybody’s contribution in the discussions. Experts selected ICF categories that were considered typical and/or relevant for AS during a standardized consensus process by integrating evidence from preceding studies in alternating working group- and plenary discussions. A Comprehensive ICF Core Set was selected for the comprehensive classification of functioning and a Brief ICF Core Set for application in trials.

Results: The conference was attended by 19 experts from 12 countries. Eighty categories were included in the Comprehensive Core Set of which 23 body functions, 19 body structures, 24 activities and participation, and 14 environmental factors. Nineteen categories were selected for the Brief Core Set of which 6 body functions, 4 body structures, 7 activities and participation, and 2 environmental factors.

Conclusion: The Comprehensive and Brief ICF Core Sets for AS are now available and aim to represent the external reference to define consequences of AS on functioning.

Objectives: In the bio-psycho-social model of health, the role of contextual factors, either environmental or personal is recognized. The objective of this study was to assess the impact of a number of contextual factors on self-reported disease specific and generic health-related quality of life in patients with ankylosing spondylitis (AS).

Methods: 522 patients with AS from Canada and Australia completed a postal questionnaire including socio-demographic variables, disease activity (BASDAI), function (BASFI), health-related quality of life (ASQoL and EQ-5D) and helplessness (RAI/helplessness). The contribution of contextual factors (nationality, ethnicity, marital status, education, employment and helplessness) in addition to functioning and disability (BASDAI and BASFI) to health-related quality of life was analyzed using multivariate regression analyses. Interactions between contextual variables were explored.

Results: Contextual factors explained 37 and 47% of the variance in EQ-5D and ASQoL, respectively. Helplessness and employment were the most important contextual factors. Their role was independent of the strong effect disease activity (BASDAI) and functional limitations (BASFI). When ASQoL was the outcome, an interaction was seen between employment and education and when EQ-5D was the outcome, an interaction was seen between helplessness and education.

Conclusions: Of the contextual factors explored in this study, helplessness and employment had an important and independent contribution to health-related quality of life. In patients with lower education, the effect of not being employed on ASQoL and the effect of helplessness on EQ-5D were stronger. Contextual factors, especially helplessness and employment, should receive more attention when interpreting data on health-related quality of life.

Study objectives and methods: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in SSc, we first queried the EUSTAR database. In a second phase, we performed a case-control study of a patient subset, to further identify independent factors associated with LV dysfunction by simple and multiple regression.

Results: Among 7,073 patients, 383 (5.4%) had a LV ejection fraction (EF) <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension (PAH) were associated with LV dysfunction. In a second phase, 129 SSc patients with LVEF <55% were compared with 256 SSc patients with normal LVEF. Male sex (OR 3.48; 95% CI1.74-6.98), age (OR 1.03; 95% CI 1.01-1.06), digital ulcerations (OR 1.91; 95% CI 1.05-3.50), myositis (OR 2.88; 95% CI 1.15-7.19), and calcium channel blockers (CCB) use (OR 0.41; 95% CI 0.22-0.74) were independent factors associated with LV dysfunction.

Conclusion: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with increased prevalence of LV dysfunction. Conversely, CCB use may appear as protective.

Objectives: The present study aimed to evaluate the prevalence and associations of renal dysfunction in patients with rheumatoid arthritis (RA). It specifically addressed the hypotheses that renal dysfunction in these patients may associate with the presence of insulin resistance, dyslipidaemia, uric acid levels and/or current levels of systemic inflammation.

Methods: Renal function was assessed by estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation in 400 consecutive RA patients for this cross-sectional, single-centre study. Risk factors for renal dysfunction were recorded/measured in all participants. Correlations between GFR and other variables were analyzed by Pearson or Spearman test as appropriate. Linear regression was used to test the independence of the associations between GFR and other variables.

Results: In this RA patient cohort, 67.75% of patients had a reduced GFR of <90ml/min/1.73m2 and 12.75% had a GFR<60ml/min/1.73m2. Multivariable analysis revealed significant associations between GFR and age (β=-0.370, p<0.001), female sex (β=-0.181, p=0.002), total cholesterol (β=-0.112, p=0.022), serum uric acid (SUA) (β=-0.425, p<0.001) and the presence of extra-articular disease - apart from sicca and/or nodules - (β=-0.084, p=0.040).

Conclusions: Renal dysfunction in RA is quite common and associates with classical cardiovascular risk factors such as advanced age and dyslipidaemia, levels of SUA, and the presence of extra-articular disease. Renal dysfunction was not related to other RA-related factors including disease activity and duration, disability, and past or present use of nephrotoxic medications.

Key words: rheumatoid arthritis, renal dysfunction, GFR, cardiovascular disease.

Objectives: In synovial tissues of rheumatoid arthritis (RA) patients strong expression of laminins and integrins co-localizes with elevated expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through elevated expression of cytokines and chemoattractant factors, one of which is IL-16. We therefore investigated regulatory pathways of IL-16 in SF from RA and osteoarthritis (OA) patients.

Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. Expression of IL-16 was investigated by quantitative RT-PCR, immunoblotting, and ELISA; its biological activity was determined by a cell migration assay. Cell - matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signaling pathways were studied by immunoblotting and with pharmacological blocking reagents.

Results: The stimulation of SF with TGF-β1 and growth on laminin-111 (LM-111) significantly increased the expression of IL-16. In RA-SF, binding to LM-111 induced significantly more IL-16 mRNA than in OA-SF (p<0.05). The IL-16 cytokine was detected in supernatants of TGF-β1-activated and in LM-111 plus TGF-β1-activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL-16 regulation involved p38MAPK, ERK1/2 and SMAD2 signaling, but not NFB.

Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β1 triggers a significant IL-16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL-16 induction represents a novel pathway leading to IL-16 production in RA-SF but not in OA-SF, and it operates independently of NFB signaling.

Objective: To characterize the circulating cytokine profile and the cellular source of circulating cytokines in polymyalgia rheumatica (PMR).

Methods: The study included 34 patients with active untreated PMR and 17 age-matched healthy controls (HC). Circulating cytokines were measured by CBA and ELISA. Intracellular cytokines were assessed in CD3+ and CD14+ cells by flow cytometry. Cytokines in cell culture supernatants were also determined after polyclonal stimulation of patient’s PBMC.

Results: Circulating levels of IL-6 were significantly higher in active PMR compared to HC. Corticosteroid (CS) treatment was followed by a decrease of IL-6. Intracellular cytokine staining showed that circulating monocytes did not produce higher amounts of proinflammatory cytokines in PMR patients than in HC. There was a discordance between serum levels and cytokine-producing monocyte and T cells and we were not able to demonstrate a Th1 bias in the peripheral compartment.

Conclusion: Active PMR is characterized by increased serum levels of IL-6, but not of other pro-inflammatory cytokines, that are rapidly suppressed by CS therapy. Probably, as circulating monocytes do not show increased production of proinflammatory cytokines, IL-6 might be mainly produced in the inflamed tissue. The study of the circulating cytokine profile and its cellular source may provide a clue to new therapeutic options.

Objective: Genome-wide studies identified the chromosomal region 16p13 in type 1 diabetes (T1D) and multiple sclerosis (MS) susceptibility. This region includes the CLEC16A/KIAA0350 gene and an adjacent gene, MHC2TA (MHC class II transactivator), previously associated with MS and rheumatoid arthritis (RA) susceptibility. We tested the role of CLEC16A polymorphisms in T1D, MS and RA pathogenesis and its relationship with the association reported with a MHC2TA haplotype.

Methods: CLEC16A (rs2903692/rs6498169/rs11074956) polymorphisms were analyzed in 435 MS, 316 T1D and 600 RA patients and in 550 ethnically matched controls. The MHC2TA rs3087456G/rs4774C risk haplotype was studied in an independent RA cohort.

Results: rs2903692 conferred a protective effect to T1D, MS and RA patients. The described association of rs6498169 with MS was replicated in MS and in RA cohorts. We validated the effect of the MHC2TA rs3087456G/rs4774C haplotype on RA susceptibility and found the haplotype in negative linkage disequilibrium with the CLEC16A rs2903692A/rs6498169A haplotype.

Conclusion: Associations of CLEC16A polymorphisms with T1D and MS were successfully replicated in our Spanish population. We described the novel association of rs6498169 with RA predisposition, consistent with previous MHC2TA results. Our data evidence the influence of variants within this chromosomal region on the development of complex diseases.

Objective: To analyze the mitochondrial DNA (mtDNA) haplogroups of patients with hip osteoarthritis (OA) and those of healthy controls in a Spanish population.

Methods: We assigned mtDNA haplogroups to 550 cases of hip OA and 505 clinically asymptomatic controls. Sets of controls with healthy knees and hips (n = 179) and knee and/or hip OA patients (n = 977) were also analyzed in a multivariate analysis, after adjusting for sex, age and smoking.

Results: Individuals carrying haplogroup J showed a significantly decreased risk of developing hip OA (OR = 0.661; 95% CI: 0.440 – 0.993; p = 0.045). In addition to haplogroup J, smoking protects from the development of hip OA (OR = 0.543; 95% CI: 0.311 – 0.946; p = 0.031). However, no relationship was found between RA and mtDNA haplogroups.

Conclusion: The results of this study support the hypothesis that the mtDNA haplogroups play a role in the complex osteoarthritic process.

Objective: To define the effects of withdrawing DMARD treatment from patients with established RA receiving stable, effective long-term DMARD treatment.

Methods: A systematic literature search was conducted. Studies were included that were of high quality and enrolled adults with RA over 2 years duration. A meta-analysis was performed on the number of disease flares in groups withdrawn from DMARD treatment compared to those who continued to receive DMARDs.

Results: The RCT data were pooled into a meta-analysis and this showed that patients who withdrew from DMARDs had a significantly worse risk of disease flare or deterioration than those who continued DMARD treatment.

Conclusion: We recommend that in patients who have their disease adequately controlled by DMARDs and wish to reduce the dose or withdraw them, this should be done cautiously. Their disease activity should be monitored carefully so that they recommence DMARD therapy in the event of disease flare or deterioration.

Objective: To assess whether the removal of aids/devices and/or help from another person in the Childhood Health Assessment Questionnaire (C-HAQ) leads to a significant change in the Disability Index (DI) score and responsiveness in juvenile idiopathic arthritis (JIA).

Methods: We compared the C-HAQ DI score changes in a cross-sectional sample of 2,663 children with JIA and in 530 active JIA patients from a methotrexate (MTX) trial.

Results: MTX trial patients had higher disease activity and disability compared to the cross-sectional sample. The frequency of aids/devices (range 1.2-10.2%) was similar between the 2 samples, while help (range 5.3-38.1%) was more frequently used in the MTX group. Correlation between disease severity variables and the two different C-HAQ DI scoring methods did not change substantially. There was a decrease in the C-HAQ DI score for both the cross-sectional (mean score from 0.64 with the original method to 0.54 without aids/devices and help, p <0.0001) and the MTX sample (mean score from 1.23 to 1.07, p <0.0001). A linear regression analysis of the original C-HAQ DI score versus the score without aids/devices and help demonstrated the substantial overlapping of the different scoring methods. Responsiveness in the responders to MTX treatment did not change with the different C-HAQ DI scoring methods (range 0.86-0.82).

Conclusion: The removal of aids/devices and help from the C-HAQ does not alter the interpretation of disability at a group level. The simplified C-HAQ is a more feasible and valid alternative for the evaluation of disability in JIA patients.

Objective: To assess the impact of digital ulcers (DUs) on disability and health-related quality of life (HRQoL) in systemic sclerosis (SSc).

Methods: We evaluated 213 SSc patients at 4 annual meetings of a patient society between 2004 and 2007 (177) or during hospital stay (36). HRQoL was assessed by the SF-36, global disability by the health assessment questionnaire (HAQ), hand disability by the Cochin Hand Function Scale (CHFS) and global hand and wrist mobility by the Kapandji index.

Results: Sixty-seven (31.4%) patients had at least one DU at the time of evaluation. Patients with DUs showed significantly more pitting scars (p<0.001) and calcinosis (p<0.0001) than others. Patients with DU had significantly greater HAQ (1.218±0.723 vs. 0.930±0.717, p=0.008), CHFS (27.38±20.68 vs. 16.73±18.19, p<0.0001) and aesthetic prejudice (6.1±2.2 vs 3.9±2.5, p<0.0001) scores than others. Hand and wrist mobility were significantly diminished in patients with DU (Kapandji score 75.3±22.8 vs 81.7±19.2, p<0.0001). The presence of a DU did not alter significantly the physical component, but influenced the mental component (43.38±12.53 vs 39.58±9.54, p=0.026) of the SF36.

Conclusion: SSc patients with DUs have reduced wrist and hand mobility, increased global and hand disabilities and decreased mental component of HRQoL.

Objective: Despite considerable work on defining disease pathways, several aspects of collagen-induced arthritis (CIA) remain poorly defined, in particular those contributing to the initiation phase of the disease. It is thought that in CIA the activation of circulating leukocytes, their interaction with the endothelial lining followed by subsequent transendothelial migration and infiltration into tissue represents the first and determining step in a complex sequence of processes mediating tissue injury. In this study we attempted to define the genetic basis of this stage of disease using genetic linkage studies, in-vivo imaging and expression profiling.

Methods: A genome scan with 132 informative markers was performed on 155 (DBA/1JxFVB/N) F2 mice. Linkage analysis was performed by combining genotyping data from the genome scan and the phenotypic data of leukocyte adherence, leukocyte rolling fraction, functional capillary density, centre line red blood cell velocity and capillary width as well as the expression level of the selected genes Cd44, Il13r1, Ccr3, Defb3, Sele, Sell, Selp, Xcl1, Il1β, Tnf and Ifn as traits.

Results: Multiple classical quantitative trail loci (QTL) controlling leukocyte-endothelial cell interactions were identified on chromosomes 8 and 17 as well as expression QTL (eQTL) controlling the expression of several differentially expressed adhesion molecules and cytokines on chromosomes 1, 2, 5, 6, 7, 8, 12, 15,16 and 17.

Conclusion: The study describes for the first time QTLs controlling the CIA initiating leukocyte-endothelial cell interaction.

Objectives: To explore potential T cell epitopes of the core protein of human cartilage proteoglycan aggrecan (PG) in patients with rheumatoid arthritis (RA) or osteoarthritis (OA).

Methods: Peptide-specific T cell proliferation and cytokine/chemokine production in response to PG-specific peptides were measured in RA and OA patients, and in healthy controls.

Results: Peptides representing amino acid regions 16-39 and 263-282 of PG were most frequently recognized by T cells in a subset of patients with RA or OA. Peripheral blood mononuclear cells (PBMC) from these PG-reactive RA and OA patients showed increased production of proinflammatory cytokines/chemokines in response to PG peptide stimulation. As PG p263-282 was found to show high sequence homology with Yersinia Yop protein, the corresponding bacterial (yersinia) peptide was also tested. Remarkably, RA and OA patients responding to the yersinia peptide also responded to p263-282 of PG suggesting a possibility of molecular mimicry in these patients.

Conclusions: These results indicate that PG-specific peptides, located in the G1 domain of PG, can induce (auto)antigenic T cell responses in RA and OA patients. Thus these peptides might be involved in the immune pathogenesis and/or cartilage degradation in RA and OA.

Background: Acquired resistance to glucocorticoids (GCs) constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classical steroids. We sought to unravel how two glucocorticoid receptor (GR) activating compounds, Dexamethasone (DEX) and CompoundA (CpdA), influence GR levels and how this can be correlated to their gene regulatory potential.

Methods: CpdA and DEX were applied in a short-term and in a long-term treatment protocol. Via Q-PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the GR protein levels in both conditions (ex vivo). Additionally, we examined the effect of systemic administration of DEX and CpdA, in concentrations effective to inhibit collagen-induced arthritis (CIA), in DBA/1 mice on GR levels (in vivo).

Results: CpdA does not induce a homologous down-regulation of GR in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to DEX, showing a direct link between prolonged DEX treatment, decreasing GR levels, and the abolishment of inflammatory gene repression in FLS. We additionally observed that the acquired low receptor levels after prolonged DEX treatment are still sufficient to sustain the transactivation of endogenous GRE-driven genes in FLS, a mechanism partially held accountable for the metabolic side effects.

Conclusion CpdA is less likely to evoke therapy resistance, as it does not lead to homologous GR down-regulation, which is in contrast to classical GCs.

Background: Joint destruction occurs frequently in patients with psoriatic arthritis (PsA). In addition to providing insight into pathogenesis, bone marrow oedema (BMO), synovitis, effusion, and joint erosion may be used as outcome measures in PsA.

Objective: To assess the impact of adalimumab on BMO, synovitis, effusion and erosions in PsA, as measured by magnetic resonance imaging (MRI).

Methods: Fifteen patients with active PsA (≥3 tender and ≥3 swollen joints) were enrolled in an open-label pilot study. Each received adalimumab subcutaneously every other week for 24 weeks. Gadolinium-enhanced MR images were obtained at baseline and 24 weeks.

Results: MR images were available for 11 patients, pre- and post-therapy. BMO and effusion scores improved markedly after 24 weeks of adalimumab, while no significant change was noted in erosion score. An unanticipated finding, however, was lack of improvement in the MRI synovitis score, despite synovitis improvements in 9 of 19 locations evaluated.

Conclusions: Improvement in BMO and unchanged erosion scores may explain the "anti-erosive" effects of adalimumab in PsA. Persistence of BMO and synovitis on MRI suggests ongoing disease activity and supports continuation of long-term anti-TNF therapy.

Objectives: Th17 cells are an effector T-cell population that plays a role in several chronic inflammatory conditions and are dependent on IL-23 for their survival and expansion. More recently, a genetic association was discovered between polymorphisms in the gene coding for the IL-23R and spondyloarthritis (SpA). Our aim was to evaluate the role of Th17 associated cytokines in SpA pathogenesis by measuring their levels in the joints and circulation of SpA patients as well as correlating them with disease activity parameters.

Methods: Paired synovial fluid (SF), serum and synovial biopsies were obtained from 30 non-PsA (non-psoriatic arthritis) SpA, 22 PsA and 22 rheumatoid arthritis (RA) patients. Interleukin-17, IL-23 and CCL20 were measured by ELISA in the SF and serum of the patients and correlated with systemic and local parameters of disease activity.

Results: SF IL-17 levels tended to be higher in non-PsA SpA compared to PsA and RA patients, whereas SF IL-23 levels were similar.

Concentrations of CCL20, a major Th17 attracting chemokine, tended to be higher in the joints of RA than in SpA patients. Interestingly, levels of CCL20 were markedly higher in synovial fluid as opposed to serum.

In addition, there was a remarkable association between the expression of the Th17 cytokine system and the presence of intimal lining layer hyperplasia in RA.

Also in the serum, there was a tendency for higher IL-23 levels in RA, which correlated strongly with disease activity parameters.

Conclusions: Th17 related cytokines are expressed in joints of SpA as well as RA patients. IL-23 levels, however, correlate with disease activity parameters in RA only. These results point towards a differential regulation of the Th17 cytokine system in SpA compared to RA.

Objective: Interleukin-18 (IL-18) is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis (RA). Recently, a soluble form of the IL-18Receptor accessory protein (sIL-18Rβ) with unknown function has been identified. In this study, we examined the ability of sIL-18Rβ to inhibit IL-18 biological activities and modulate immune responses during collagen-induced arthritis (CIA).

Methods: Adenoviruses encoding sIL-18Rβ were administered intravenously in type II collagen-immunized DBA/1 mice. Humoral responses were analyzed by determining anti-bovine type II collagen antibody levels (anti-BCII) by ELISA. Cytokine production by splenic T cells and cytokine levels in serum were measured by Luminex multi-analyte technology. CD4⁺CD25⁺Foxp3+ regulatory T cells (Treg) were measured by flow cytometry.

Results: Intravenous delivery of Ad5.sIL-18Rβ in collagen-immunized mice led to enhanced transgene expression in splenic APCs. A co-culture of these sIL-18Rβ-transduced APCs with purified splenic CD3⁺ T cells led to a marked inhibition of IL-18-induced IFN, IL-4 and IL-17 production by CD3⁺ T cells. Remarkably, systemic treatment with Ad5.sIL-18Rβ caused an exacerbation of arthritis and histological evaluation of knee joints showed increased cartilage and bone erosion. No significant differences were observed in anti-BCII antibodies, but the aggravation was accompanied by decreased IFN (-30%) and IL-4 (-44%), and increased IL-17 (+84%) production by splenic CD3⁺ T cells. Additionally, reduced circulating levels of CD4⁺CD25⁺Foxp3⁺ Treg and anti-inflammatory IL-10 was shown.

Conclusion: This study identifies sIL-18Rβ as a novel IL-18 inhibitor, that promotes CIA after intravenous overexpression by affecting Treg levels and supporting a Th17 response.

Objectives: Chronic inflammation is a major risk factor of systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly TNF and IL-1 are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined.

Methods: To determine whether TNF directly triggers bone loss or requires interleukin-1 (IL-1), we crossed human tumor necrosis factor alpha (hTNFtg) mice with mice lacking IL-1 and IL-1β (IL-1^-/-hTNFtg). Systemic bone architecture was evaluated using computed tomography analysis, static and dynamic bone histomorphometry as well as serum markers of bone metabolism.

Results: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were both thinner and decreased in numbers resulting in an increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice as compared to wildtype mice. In contrast, IL-1^-/-hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL-1 completely reverted increased osteoclast formation and bone resorption in hTNFtg mice as well as the increased levels of RANKL in these mice. Both structural parameters as well as osteoclast and osteoblast numbers were indistinguishable from wildtype mice.

Conclusion: These data indicate that IL-1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL-1, which suggests that IL-1 is an essential mediator of inflammatory osteopenia.

Objectives: Monitoring of peripheral B cell subsets in patients with SLE revealed an activity-related expansion of CD27⁺⁺CD20^-CD19^dim Ig-secreting cells. A similar subset has also been identified 6-8 days after tetanus/diphtheria vaccination in normal individuals and in patients with infectious disease.

Methods: We analyzed this subset further focussing on the HLA-DR surface expression in a cohort of 25 patients with SLE.

Results: This study revealed that 86% (range: 59-97%) of CD27⁺⁺CD20^-CD19^dim cells express high levels of HLA-DR, are also expanded in the bone marrow (BM), and represent plasmablasts enriched with anti-dsDNA secreting cells. The remaining CD27⁺⁺CD20^-CD19^dim cells were HLA-DR^low and represent mature plasma cells. Importantly, HLA-DR^high plasmablasts showed a closer correlation with lupus activity and anti-dsDNA levels than the previously identified CD27⁺⁺CD20^-CD19^dim cells.

Conclusion: HLA-DR^highCD27⁺⁺CD20^-CD19^dim plasmablasts represent a more precise indicator of lupus activity and suggest that there is an overproduction or lack of negative selection of these cells in SLE.

Objectives: To examine whether the quantity of cartilage or semiquantitative scores actually differ in knees with mild radiographic osteoarthritis (OA) compared with knees without OA.

Methods: Framingham OA Study participants had knee tibiofemoral MRI-based measurements of cartilage. Using 3D FLASH-water excitation sequences, cartilage volume (VC), thickness (ThCtAB) and subregional ThCtAB were measured and cartilage scored semiquantitatively (using WORMS). Using weight bearing radiographs, we defined mild OA as K/L=2 and nonOA as K/L=0. Differences between OA and nonOA knees in median cartilage measurements were tested using the Wilcoxon rank sum test.

Results: Among 948 participants (one knee each), neither VC nor regional thickness (ThCtAB) were different in mild versus nonOA knees. In mild OA, cartilage erosions in focal areas were missed when cartilage was quantified over large regions like the medial tibia. For some but not all subregions of cartilage, especially among men, ThCtAB was lower (p<.05) in mild OA than nonOA knees. Because semiquantitative scores captured focal erosions, median WORMS scores were higher in mild OA than nonOA (all p<.05). In moderate/severe OA (K/L grades 3 or 4), OA knees had much lower ThCtAB and higher WORMS scores than knees with nonOA.

Conclusions: In mild OA, the focal loss of cartilage is missed by quantitative measures of cartilage volume or thickness over broad areas. Regional cartilage volume and thickness (e.g. medial tibia) are not different in mild OA versus nonOA. Subregional thickness may be decreased in mild OA. Semiquantitative scoring which assesses focal cartilage damage differentiates mild OA from nonOA.

Background: This study compared the performance of 2 interferon- release assays (IGRAs) and conventional screening tests in patients with inflammatory arthritis undergoing screening for latent tuberculosis infection (LTBI) before treatment with anti-TNF compounds.

Methods: Successive patients were subjected to conventional LTBI screening, including a tuberculin skin test (TST). The T-SPOT.TB test was performed on all patients and the QuantiFERON-TB Gold test was performed on a large subset. The results of the IGRAs were compared to the results of conventional screening tests.

Results: A total 150 patients were evaluated. The majority (57.9%) had rheumatoid arthritis (RA). Previous vaccination with Bacille Calmette-Guerin was confirmed in 82% of patients. No patient had received prior anti-TB treatment. A total 57 patients (38.0%) had at least one positive conventional risk factor. In contrast, an unequivocally positive T-SPOT.TB test was observed in only 14 (9.8%). There was 98.2% agreement between the two IGRAs. Statistically significant associations were observed between each of the IGRAs and both TST and risk history, but not CXR. A positive IGRA result was significantly associated with increased age. No patient developed reactivation of TB during the follow-up period.

Interpretation: This study provides compelling evidence to suggest that IGRAs may have utility when screening for LTBI before anti-TNF therapy in patients with immune-mediated inflammatory diseases. The observations reported here also highlight the inadequate performance of CXR as a marker of LTBI.

Objectives: To assess whether smoking is a risk factor for developing RA, especially for RA patients who are rheumatoid factor-positive (RF+).

Design: Meta-analysis

Methods: Data Sources: Observational studies that examining the association between smoking history and the risk for developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books, and a reference search.

Data extraction: Two authors independently extracted the followings; authors? names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design, and area where the study was conducted. Data syntheses: Data syntheses were based upon the DerSimonian-Laird random effect model. Summarized syntheses effects were expressed by odds ratios.

Results: Sixteen studies were selected from among 433 retrieved articles. Data syntheses were based on the random effect model. For male, summary ORs for ever, current, and past smokers were 1.89 (95% confidence interval [CI], 1.56-2.28), 1.87(1.49-2.34) and 1.76(1.33-2.31), respectively. For RF+ RA, the summary ORs for ever, current, past smokers were 3.02(2.35-3.88), 3.91(2.78-5.50), and 2.46(1.74-3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31(1.55-3.41). For female, summary ORs for ever, current, and past smokers were 1.27(1.12-1.44), 1.31(1.12-1.54) and 1.22(1.06-1.40), respectively. For RF+ RA, the summary ORs for ever,current, and past smokers were 1.34(0.99-1.80), 1.29(0.94-1.77), and 1.21(0.83-1.77). Summary OR for 20 or more pack-years of smoking was 1.75(1.52-2.02).

Conclusions: Smoking is a risk factor for RA for both male and is especially strongly associated with RA for RF+ male and both male and female heavy smokers.

Objective: To evaluate gender differences in DAS28, HAQ and SOFI and to relate these scores to radiographic joint destruction.

Methods: 549 patients with early RA (62% women) from the BARFOT study were included. At baseline, 1, 2 and 5 years DAS28, HAQ, SOFI and radiographs of hands and feet were performed. The radiographs were scored using the van der Heijde Sharp score.

Results: In women DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were significantly higher in women. SOFI was worse in men during the first 2 years, depending on higher upper limb scores. Total Sharp score (TotSharp), erosion score and joint space narrowing did not differ between the sexes at any time point. DAS28 AUC correlated significantly with TotSharp at 5 years in both genders (r=0.316, r=0.313) mainly owing to swollen joints and ESR. SOFI AUC correlated significantly with TotSharp in women (r=0.135-0.220) but not in men.

Conclusion: Despite similar degree of radiographic joint destruction women had, compared with men, worse scores for DAS28 and HAQ, possibly due to higher pain perception and less muscular strength and maybe because men overestimate their functional capacity.

Objective: Aberrant signaling along the p21RAS/MAP kinase pathway has been demonstrated in SLE. We examined whether expression and activity of the MAP kinases ERK and JNK reflect disease activity in SLE patients.

Methods: Blood samples of 42 outpatient SLE patients were prospectively collected during 4 consecutive visits. The control group included 20 healthy subjects. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Expression of total ERK and JNK kinases and their active forms (pERK and pJNK) were determined in whole protein lysates of peripheral blood mononuclear cells.

Results: The mean levels of the active kinases pERK and pJNK were significantly increased in patients with active disease (SLEDAI 4-20) as compared to patients with inactive disease (SLEDAI 0-3) p=0.04 as well as to healthy controls p=0.03 and p=0.003, respectively. The percentage of activated forms of ERK and JNK of the total expression of these MAP kinases was also gradually increased reaching 50% for pERK and over 40% for pJNK in SLE patients with moderate to severe disease (SLEDAI 7-20) p=0.005, p=0.005 and p=0.02, p=0.05 as compared to controls and inactive patients, respectively. A decrease of more than 3 SLEDAI points was associated with a significant reduction in the expression of both total and activated forms of ERK and JNK p= 0.03, p=0.01, respectively.

Conclusions: Our results demonstrate that ERK and JNK activity reflect disease activity in SLE patients. These MAP kinases may serve as additional tools for the evaluation of disease activity and management of these patients.

Objectives: To assess subclinical central nervous system (CNS) involvement in primary Sjögren’s syndrome (pSS), by comparing standard brain magnetic resonance imaging (MRI), in-depth neuropsychological testing and ^99mTc–ECD brain SPECT of pSS patients to matched controls.

Methods: We prospectively investigated 10 women (<55 years old), with pSS defined using European–American criteria, presence of anti-SSA and/or anti-SSB antibodies and no history of neurological involvement, and compared them to 10 age- and sex-matched controls. All subjects underwent, within 1 month, brain MRI, neuropsychological testing, including overall evaluation and focal cognitive function assessment, and ^99mTc–ECD brain SPECT.

Results: ^99mTc–ECD brain-SPECT abnormalities were significantly more frequent in pSS patients than controls (p<0.05). Cognitive dysfunctions, mainly expressed as executive and visuospatial disorders, were also significantly more frequent in pSS patients (p<0.01). Notably, between-group comparisons enabled a significant correlation to be established between neuropsychological assessment and ^99mTc–ECD brain-SPECT abnormalities in pSS patients (rs = 0.49, p<0.01). MRI abnormalities in patients and controls did not differ significantly.

Conclusion: Neuropsychological testing and ^99mTc–ECD brain SPECT seem to represent the most sensitive tools to detect subclinical CNS dysfunction in pSS. The strong correlation between cortical hypoperfusion in ^99mTc–ECD brain SPECT and cognitive dysfunction suggests an organic etiology of CNS dysfunction in pSS. These data should be confirmed in a larger study.

Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc). Symptoms of coronary artery disease (CAD) and PAH are closely related and cardiac catheterization is needed to confirm their diagnosis.

Objectives: Investigation of the extent of overlap between CAD and PAH in patients with SSc. Methods: Based on non-invasive investigations, 20 patients out of 120 were supposed to have PAH ('suspected PAH' group). Another 10 patients showed the signs of coronary disease ('suspected CAD' Group). In these 30 patients, both right heart catheterization and coronary angiography were performed, and the coronary flow reserve (CFR) was assessed by thermodilution technique.

Results: In the 'suspected PAH' and the 'suspected CAD' groups, PAH was found in 12/20 and 2/10 cases, coronary artery stenosis was in 9/20 and 6/10 cases. Severely reduced CFR was revealed in 7/20 and 3/10 cases, respectively.

Conclusions: PAH, CAD, and reduced CFR show a considerable overlap in symptomatic SSc patients. The current non-invasive investigations are neither sensitive nor specific enough to make an appropriate distinction between these different disease manifestations. A more invasive approach, such as coronary angiography at the initial catheterization, is required to properly characterize and treat the different forms of cardiac involvement in SSc.

Objective: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomized prospective trial comparing low-dose (LD) versus high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis.

Patients and methods: Data regarding survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomized in the ELNT, except in 6 lost to follow-up.

Results: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (11% vs 4%, 14% vs 11% and 5% vs 9%, respectively) nor did mean serum creatinine, 24-h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressants and blood pressure lowering drugs. We confirm, after 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy.

Conclusion: Our data confirm that a LD IVCY regimen followed by AZA – the "Euro-Lupus regimen" – achieves good clinical results in the very long-term.

Objectives: To compare the efficacy of disease activity score (DAS)-driven therapy and routine care in patients with recent-onset rheumatoid arthritis.

Methods: Patients with recent-onset rheumatoid arthritis receiving traditional antirheumatic therapy from either the BeSt study[1], a randomized controlled trial comparing different treatment strategies (group A) or 2 Early Arthritis Clinics (group B) were included. In group A, systematic DAS-driven treatment adjustments aimed to achieve low disease activity (DAS ≤2.4). In group B, treatment was left to the discretion of the treating physician. We evaluated functional ability (HAQ), disease activity score in 28 joints (DAS28) and Sharp/van der Heijde radiographic score (SHS).

Results: At baseline, patients in group A (n=234) and group B (n=201) had comparable demographic characteristics and a mean HAQ of 1.4. Group A had a longer median disease duration than group B (0.5 vs 0.4 year, p=0.016), a higher mean DAS28 (6.1 vs 5.6, p<0.001), more rheumatoid factor positive patients (66% vs 42%, p<0.001) and more erosive patients (71% vs 53%, p<0.001). After 1 year, the HAQ improvement was 0.7 vs 0.5 (p=0.029), and the percentage in remission (DAS28<2.6) 31% vs 18% (p<0.005) in groups A and B, respectively. In group A, the median SHS progression was 2.0 (expected progression 7.0), in group B, the SHS progression was 1.0 (expected progression 4.4).

Conclusions: In patients with recent onset rheumatoid arthritis receiving traditional therapy, systematic DAS-driven therapy results in significantly better clinical improvement and possibly improves the suppression of joint damage progression.

Objective: To investigate the role of Junctional adhesion molecule A (JAM-A) in the pathogenesis of systemic sclerosis (SSc).

Methods: Biopsies from proximal and distal arm skin and serum were obtained from patients with SSc and normal (NL) volunteers. To determine the expression of JAM-A on SSc dermal fibroblasts and in SSc skin, cell surface ELISAs and immunohistology were performed. An ELISA was designed to determine the amount of soluble JAM-A (sJAM-A) in serum. Myeloid U937 cell-SSc dermal fibroblast and skin adhesion assays were performed to determine the role of JAM-A in myeloid cell adhesion.

Results: The stratum granulosum and dermal endothelial cells (ECs) from distal arm SSc skin exhibited significantly decreased expression of JAM-A compared to NL. However, sJAM-A was elevated in the serum of patients with SSc compared to NL. Conversely, JAM-A was increased on the surface of SSc compared to NL dermal fibroblasts. JAM-A accounted for a significant portion of U937 binding to SSc dermal fibroblasts. In addition, JAM-A contributed to U937 adhesion to both distal and proximal SSc skin.

Conclusions: JAM-A expression is dysregulated in SSc skin. Decreased expression of JAM-A on SSc ECs may result in a reduced response to proangiogenic basic fibroblast growth factor. While increased JAM-A expression on SSc fibroblasts may serve to retain myeloid cells, which in turn secrete angiogenic factors.

Objective: To investigate time courses of autoantibody profiles in patients with early arthritis.

Patients and methods: Two hundred patients with very early arthritis (<3 months duration), among them 102 patients with a final diagnosis of rheumatoid arthritis (RA) and 98 with other rheumatic diseases, were followed up for several years. First follow-up testing was done in all patients (mean 5 months from baseline), and 82 RA and 35 non-RA patients were available for last follow-up testing (mean 32 months from baseline). IgM-rheumatoid factor (RF) was measured by nephelometry, IgA-RF, IgG-RF and anti-citrullinated peptide antibodies (ACPA) by ELISA, and anti-RA33 antibodies were determined by immunoblotting.

Results: At baseline, IgA-RF was detectable in 29% and IgG-RF in 14% of RA patients while IgM-RF>50 IU/ml (RF50) was positive in 45% of the patients; specificities were 97%, 99% and 96%, respectively. However, the vast majority of IgA- or IgG-RF positive patients were also positive for RF50 or ACPA. During follow-up prevalence of ACPA slightly increased while prevalence of all RF subtypes and anti-RA33 decreased. Remarkably, the number of patients positive for RF50 and/or ACPA remained constant; and these patients had a highly increased risk for developing erosive disease, in contrast to patients solely positive for anti-RA33.

Conclusions: Testing for RF subtypes did not provide additional diagnostic information. Patients positive for RF50 and/or ACPA had an unfavourable prognosis, irrespectively of changes in the antibody profile during follow-up, whereas anti-RA33 positivity was inversely associated with erosiveness both at baseline and at later time points.

Background: Previous studies have reported an interaction between ever cigarette smoking and the presence of the HLA-DRB1 shared epitope (SE) genotype and RA risk. To address the effect of dosage, we conducted a case control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE.

Methods: Blood was obtained from 32,826 women in the Nurses’ Health Study and 29,611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched on age, menopausal status, and postmenopausal hormone use. High resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, and HLA-SE *smoking interactions, and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. We tested for additive and multiplicative interactions.

Results: 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. We observed a modest additive interaction between ever smoking and HLA-SE in seropositive RA risk. We found a strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p = 0.0002) between heavy smoking (> 10 pack-years) and any HLA-SE in seropositive RA risk, and significant multiplicative interaction (p = 0.05). The highest risk was in heavy smokers with double copy HLA-SE (OR 7.47 [95% CI, 2.77-20.11]).

Conclusion: We observed a strong gene-environment interaction between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene-smoking interactions.

Objectives: The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognized the importance of variation in diagnostic and therapeutic performance across disciplines, have found consensus in starting task forces aiming at achieving diagnostic and therapeutic uniformity, and have identified medical conditions with which representatives of both organizations will frequently be confronted in common clinical practice.

The aim was to establish recommendations for the diagnosis and initial management of patients presenting with acute or recent onset swelling of the knee.

Methods and results: The EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations were followed. Eleven rheumatologists from 11 countries and 12 orthopedic surgeons from 7 countries met twice under the leadership of two conveners, a clinical epidemiologist and a research fellow. After carefully defining the content and procedures of the task force, research questions were developed, a comprehensive literature search was performed and the results were presented to the entire committee. Subsequently, a set of 10 recommendations was formulated based on evidence from the literature if available, and after discussion and consensus building.

Conclusion: This is the first combined interdisciplinary project of rheumatologists and orthopedic surgeons, successfully aiming at achieving consensus in the diagnosis and initial management of patients presenting with acute or recent onset swelling of the knee.

Objective: To create minimal disease activity (MDA) criteria for psoriatic arthritis (PsA). With recent therapeutic advances, this is now a goal for treatment and may represent a measure to compare therapies. It defines a satisfactory state of disease activity, rather than a change, and encompasses all aspects of disease.

Methods: 40 patient profiles were sampled from an observational PsA database. Sixty experts in PsA classified these as whether in MDA or not. A ≥70% consensus was accepted, identifying 13 profiles in MDA. Summary statistics created possible cut points for the definition. Considering the number of measures that must be met, 35 candidate definitions were created and tested using receiver operating characteristic curves (ROC) for sensitivity and specificity.

Results: Four candidate definitions showed high area under the curve values on ROC testing. Definitions with high outlying values were excluded as they were not considered to represent MDA. Aiming for high specificity to reduce false positives resulted in a preference for the following definition: A patient is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count ≤1; swollen joint count ≤1; PASI ≤1 or BSA ≤3; patient pain VAS ≤15; patient global disease activity VAS ≤20; HAQ ≤0.5; tender entheseal points ≤1.

Conclusion: This study provides the first definition of a "state" of MDA in PsA and defines a target for treatment. It must now be validated in other populations and tested in clinical trials.

Introduction: Potential hepatotoxicity associated with disease modifying anti-rheumatic drugs [DMARDs] requires laboratory monitoring. In rheumatoid and psoriatic arthritis [RA, PsA] patients, we examined the incidence of elevated alanine/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF), and MTX+LEF vs. other DMARDs.

Methods: RA and PsA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1 or 2-fold time above the upper limits of normal (ULN). Odds ratios [OR] between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalized estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared to each individually.

Results: Elevated ALT/AST levels (>1x ULN) occurred in 22, 17, 31, and 14% RA patients receiving MTX, LEF, MTX+LEF, or neither, respectively; elevations were 2.76 fold (95% CI 1.84 - 4.15) more likely in PsA patients. Elevations > 2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared to 5% with the combination. After multivariable adjustment and compared with either monotherapy, combination MTX + LEF was associated with greater risk according to MTX dose used as part of the combination: MTX 10-17.5mg/week, OR=2.91 (95% confidence interval [CI] 1.23-6.90) and MTX ≥20 mg/week, OR=3.98 (95% CI: 1.72-9.24).

Conclusions: 14-35% of RA and PsA patients initiating DMARD therapy developed abnormal ALT/AST levels. Risks were incrementally greater in those with PsA and in those receiving MTX (≥ 10mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.

Objective: This study investigated the association between clinically assessed finger joint involvement (joint counts) and patient outcome measures in hand osteoarthritis (HOA).

Methods: Women with HOA (n=190) (between 50 and 70 years of age, mean 61.6 years) completed a clinical examination, which included assessment of finger joints (DIP, PIP, MCP and CMC) with regard to tenderness/pain, soft tissue swelling, bony enlargement and limited motion, measurement of grip strength and completion of a booklet with questionnaires (AUSCAN, AIMS2, HAQ, SF-36, VAS pain).

Results: DIP joints were most frequently affected. Presence of pain in any PIP or DIP finger joint was associated with worse health status. The three other categories of joint findings were generally also associated to worse health status, but associations were mostly not statistically significant. Correlations between tender and swollen joint counts in most finger joint areas and scores of specific outcome measures (AUSCAN, AIMS2 hand + finger), VAS pain and grip-strength were mild to moderate, whereas correlations between joint counts and scores of general physical function, general pain and other dimensions of health (AIMS2 and SF 36) were generally low.

Conclusion: The association between painful CMC, PIP and DIP joint counts and worse scores for key dimensions of health was moderate.

Objective: To investigate the expression of TNF like weak inducer of apoptosis (TWEAK) and its receptor Fn14 in the inflamed synovium of patients with arthritis, as TWEAK blockade had a beneficial effect in an animal model of RA.

Methods: Synovial tissue (ST) biopsies were obtained from 6 early, methotrexate naive RA patients as well as 13 RA patients and 16 patients with psoriatic arthritis (PsA) who were matched for treatment and disease duration. Serial ST samples were obtained from a separate cohort of 13 RA patients before and after infliximab treatment. TWEAK and Fn14 expression was evaluated by immunohistochemistry and digital image analysis.

Results: TWEAK and Fn14 were clearly expressed in ST of RA and PsA patients. TWEAK expression was significantly higher in RA (sub)lining compared to PsA (P = 0.005 and P = 0.014, respectively), but Fn14 expression was comparable. Double immunofluorescence showed TWEAK and Fn14 expression on fibroblast-like synoviocytes and macrophages, but not T cells. Of interest, persistent TWEAK and Fn14 expression was found after anti-TNF therapy.

Conclusions: TWEAK and Fn14 are abundantly expressed in the inflamed synovium of RA and PsA patients. This raises the possibility that blocking TWEAK/Fn14 signalling could be of therapeutic benefit in inflammatory arthritis.

Objectives: Previous studies suggest that high systemic bone mineral density (BMD) is associated with incident knee OA defined by osteophytes, but not with joint space narrowing (JSN), and are inconsistent regarding BMD and progression of existing OA. We tested the association of BMD with incident and progressive tibiofemoral OA in a large, prospective study of men and women ages 50-79 with, or at risk for, knee OA.

Methods: Baseline and 30-month weight-bearing PA and lateral knee x-rays were scored for K-L grade, JSN and osteophytes. Incident OA was defined as the development of K-L grade ≥2 at follow-up. All knees were classified for increases in grade of JSN and osteophytes from baseline. The association of gender-specific quartiles of baseline BMD with risk of incident and progressive OA was analyzed using logistic regression, adjusting for covariates.

Results: The mean age of 1,754 subjects was 63.2 (SD, 7.8) and BMI 29.9 (SD, 5.4). In knees without baseline OA, higher femoral neck and whole body BMD were associated with an increased risk of incident OA and increases in grade of JSN and osteophytes (p < 0.01 for trends); adjusted odds were 2.3 to 2.9-fold greater in the highest vs. the lowest BMD quartiles. In knees with existing OA, progression was not significantly related to BMD.

Conclusions: In knees without OA, higher systemic BMD was associated with a greater risk of the onset of JSN and K-L grade ≥2. The role of systemic BMD in early knee OA pathogenesis warrants further investigation.

Objective: Ankylosing spondylitis (AS) and periodontal disease (PD) are characterized by dysregulation of the host inflammatory response, resulting in soft and hard connective tissue destruction. AS has been related to other inflammatory diseases, however, there is a paucity of data on whether AS is associated with inflammatory PD.

Methods: The association between AS and PD was examined in 48 patients with AS and 48 healthy controls, matched on age and gender. AS was diagnosed according to the modified New York criteria. Periodontal examination included probing pocket depth (PPD), clinical attachment loss (CAL), plaque index (PI) and bleeding on probing (BOP). Potential risk factors of PD such as smoking, low education, alcohol consumption, Body Mass Index (BMI), as well as chronic diseases associated with PD and AS were assessed through questionnaires.

Results: In stepwise logistic regression, including AS status, age, gender, education, smoking, alcohol consumption, and BMI, only AS status, age, and education remained significant predictors of PD. Patients with AS had a significantly 6.81-fold increased odds (95 %-CI 1.96-23.67) of PD (defined as mean attachment loss > 3 mm) compared to controls. The strength of the association was attenuated but remained statistically significant after further adjustment for plaque accumulation (odds ratio 5.48; 95 %-CI 1.37-22.00).

Conclusion: The present study shows that AS patients have a significantly higher risk of PD, strongly suggesting the need of a close collaboration between rheumatologists, periodontists and dental hygienists when treating AS patients.

Patient-reported outcomes are valuable for management of chronic diseases like Systematic Lupus Erythematosus (SLE), but no measures to our knowledge have been validated for use in US-based SLE patients.

Objectives: To adapt and assess the validity and reliability of an SLE-specific quality of life (QoL) measure developed in the United Kingdom, the LupusQoL©, for use in US-based SLE patients.

Methods: Debriefing interviews of SLE subjects guided the language modifications of the tool. The LupusQol-US©, SF-36 and EQ5D were administered. Internal consistency (ICR) and test-retest (TRR) reliability, convergent and discriminative validity were examined. Factor analyses were performed.

Results: The mean (SD) age of the 185 SLE subjects was 42.5± 12.9 years. ICR and TRT of the 8 domains ranged from 0.85 to 0.94 and 0.68-0.92 respectively. Related domains on the SF-36 correlated with the LupusQoL© domains (Physical Health and Physical Function r= 0.73, Physical Health and Role Physical r= 0.57, Emotional Health and Mental Health r= 0.72, Emotional Health and Role Emotional r=0.48, Pain and Bodily Pain r=0.66, Fatigue and Vitality r=0.70, Planning and Social Functioning r=0.58). Most LupusQoL-US domains were able to discriminate between subjects with varied disease activity and damage. Principal component analysis revealed five factors in the US version, with physical function, pain and planning items loading on one factor.

Conclusions: These data provide evidence to support the psychometric properties of the LupusQoL-US©, suggesting its utility as an assessment tool for SLE patients in the US.

Objectives: Adult mesenchymal stem cells were recently found to suppress effector T-cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autorreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterize the immunosuppresive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from RA patients.

Methods: We investigated the effects of hASCs on collagen-reactive RA human T-cell proliferation and cytokine production, as well as on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from RA patients.

Results: hASCs suppressed antigen-specific response of T cells from RA patients. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the number of IL-10-producing T cells and monocytes significantly augmented upon hASC-treatment. The suppressive activity of hASCs was both cell-to-cell contact-dependent and -independent. hASCs also stimulated the generation of FoxP3-expressing CD4+CD25+ regulatory T cells with capacity to suppress collagen-specific T-cell responses. Finally, hASCs donwregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from RA patients.

Conclusions: Our work identifies to hASCs as key regulators of immune tolerance with capacity to suppress T-cell and inflammatory responses to induce the generation/activation of antigen-specific regulatory T cells.

Objectives: Studying the gene expression changes following infliximab infusion for ankylosing spondylitis patients could provide novel insights into this disease.

Methods: Sixteen AS patients who received infliximab were enrolled in the study. Microarray analysis was done on peripheral blood RNA at baseline and 2 weeks post-infliximab to screen for changes in gene expression and selected results were confirmed by qRT-PCR. Soluble LIGHT (sLIGHT) in corresponding serum samples was estimated by ELISA and compared to clinical data. The fold change in sLIGHT was correlated by Spearman’s correlation to the fold change in ESR, CRP and BASDAI.

Results: At 2 weeks following infliximab, 69% of the patients (11/16) achieved an ASAS20 response. Compared to baseline, six candidate genes were differentially expressed by microarray analysis; four of which were validated by qRT-PCR. LIGHT expression showed the most significant difference. There was a good correlation between the baseline values of sLIGHT versus CRP (R=0.60; p=0.01) and ESR (R=0.51; p=0.04). The fold change in sLIGHT correlated with change in both CRP (R=0.71, p=0.002) and ESR (R=0.77, p<0.001).

Conclusion: The gene expression of LIGHT was significantly downregulated by infliximab and the changes in sLIGHT correlated well with changes in other m