Background: The American College of Rheumatology (ACR) 1987 revised criteria for classification of rheumatoid arthritis (RA) are widely used for diagnosis. Objective: To evaluate the ability of the ACR set of criteria (both list and tree format) to diagnose RA compared to expert opinion according to disease duration.

Methods: A systematic literature review was conducted in Pubmed and Embase databases. All articles reporting the prevalence of RA according to ACR criteria and expert opinion in cohorts of early (< 1 year duration) or established (>1 year) arthritis were analyzed to calculate the sensitivity and specificity of ACR 1987 criteria against the gold standard (expert opinion). A meta-analysis using S-ROC curve was performed and pooled sensitivity and specificity were calculated with confidence intervals.

Results: Among the 138 publications initially identified, 19 were analysable (total:7438 patients, 3883 RA). In early arthritis, pooled sensitivity and specificity of ACR set of criteria were 77% (68-84%) and 77% (68-84%) in the list format versus 80% (72-88%) and 33% (24-43%) in the tree format. In established arthritis, sensitivity and specificity were respectively of 79% (71-85%) and 90% (84-94%) versus 80% (71-85%) and 93% (86-97%). The S-ROC meta-analysis confirmed the statistically significant differences suggesting that diagnostic performances of ACR list criteria are better in established arthritis.

Conclusion: This study indicates that specificity of ACR 1987 criteria in early RA is low, and that these criteria should not be used as diagnostic tools. However, sensitivity and specificity in established RA are higher, which reflects their use as classification criteria gold standard.

Objective: To evaluate the safety of biologic treatments for rheumatoid arthritis (RA) using results from randomized controlled trials (RCTs).

Methods: We searched the literature to December 2007 for RCTs evaluating inhibitors of tumour necrosis factor alpha (anti-TNFs) for RA. Safety data was abstracted and risk estimates were calculated using three approaches, meta-analysis with and without adjustment for exposure and simple exposure adjusted pooling.

Results: Eighteen randomized trials involving 8,808 RA subjects were included. Treatment with recommended doses of anti-TNFs found no increase in the odds of death (OR=1.39, 95%CI 0.74-2.62), serious adverse events (OR=1.11; 95%CI 0.94-1.32), serious infection (OR=1.21; 95%CI 0.89-1.63), lymphoma (OR=1.26; 95%CI 0.52-3.06), non-melanoma skin cancers (OR=1.27; 95%CI 0.67-2.42) or the composite endpoint of non-cutaneous cancers plus melanomas (OR=1.31; 95%CI 0.69-2.48) when evaluated using the unadjusted meta-analytic method. Risk estimates were similar with the other methods. For subjects who received two to three times the recommended doses of anti-TNF the risk of serious infection was increased with the unadjusted meta-analytic and pooled analysis; 2.07 (95%CI:1.31-3.26) and 1.83 (95%CI:1.18-2.85) respectively but not increased in the exposure adjusted meta-analysis 1.99 (95%CI:0.90-4.37). Meta-regression identified that the risk of serious infection with anti-TNF therapy decreases with increasing trial duration (p=0.035).

Conclusion: Meta-analytic and exposure adjusted pooled analyses on over 8,800 RA subjects in RCTs treated over an average of 0.8 years did not identify an increased risk of serious adverse events with recommended doses. High dose anti-TNF therapy was associated with a twofold increase in the risk of serious infections.

Objective: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently promoter variants in the SELS gene were shown to be associated with plasma levels of IL-6, IL-1β and TNF. We hypothesized that these variants could influence RA susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL-1, IL-6 and TNF.

Methods: Genotyping was performed in 988 unrelated healthy controls and 965 RA patients. Stratified analysis was used to test for interactions. We examined both single gene effects and for evidence of epistasis using both the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic.

Results: No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL-1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS- 105 locus) in individuals with the GG/AG genotype at the IL-1B -511 locus was significantly lower than that in individuals having the AA genotype at the IL-1β-511 locus (odds ratio (OR): 0.9 and 2.3 respectively, p=0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p=2x10^-4). No interaction was observed between SELS -105 and IL-6 or TNF variants.

Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL-1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.

Objectives: To investigate the course of hand osteoarthritis (OA) over two years by currently available outcome measures.

Methods: 189 participants of the GARP (Genetics, ARthrosis and Progression) study with hand OA were followed for two years. Self-reported hand pain and functional limitations were assessed with the Australian / Canadian Osteoarthritis Hand Index (AUSCAN LK 3.0). Pain intensity upon lateral pressure in the interphalangeal and thumb base joints was graded on a four-point scale. Osteophytes (0-3) and joint space narrowing (JSN) (0-3) was scored at baseline and after two years in interphalangeal and thumb base joints. Standardised response means (SRM) were calculated.

Results: 172 (91%) patients completed the two-year follow-up (mean age 60.5 years, 78.5 % women). Statistically significant increases in self-reported pain and function scores, in pain intensity scores as well as in osteophyte and JSN total scores were seen over two years. SRMs were 0.25, 0.23, 0.67, 0.34 and 0.35 respectively for self-reported pain and function scores, pain intensity scores, osteophyte and JSN total scores. Radiological progression was not associated with changes in self-reported pain and function. Women in an early post-menopausal stage were especially at risk to progress radiologically.

Conclusions Currently available outcome measures were able to assess progression over the relatively short time period of two years. Radiographic outcomes were more responsive than self-reported outcomes. Pain intensity upon lateral pressure seems to be a responsive measure but need validation.

Objective: To establish whether review articles provide consistent conclusions on associations between work-place psychosocial factors and musculoskeletal pain and, if differences exist, to explore whether this is related to the methods employed.

Methods: Reviews, reported up to February 2007, which included consideration of work-place psychosocial factors and either upper limb, back or knee pain were identified through searches of multiple databases. The specific work-related psychosocial factors considered were job demands, support, job autonomy and job satisfaction. The conclusions of each review for one or more of the psychosocial/musculoskeletal pain were extracted.

Results: 15 review articles were identified which considered one or more of the regional pain syndromes included in the study. For back pain the most consistent conclusions (4 reviews positive from 6) were with high job demands and low job satisfaction. The studies of upper limb pain were exclusively related to shoulder and/or neck pain and the most consistent positive conclusions were with high and low job demands (4 reviews positive out of 6; 2 reviews positive out of 3, respectively). For knee pain only a single review was identified. For individual reviews of back and upper limb pain there were marked differences in the number of associations concluded to be positive between reviews.

Conclusion: The reasons for reviews coming to different conclusions included that they were often evaluating different bodies of evidence (according to their search criteria, the year when the review was conducted, the role that quality assessment played in whether studies contributed to evidence, and the combination of risk factors addressed in individual studies), but more important was whether the review specified explicit criteria for making conclusions on strength of evidence. These conclusions emphasise the importance of developing standardised methods for conducting such evaluations of existing evidence, and the importance of new longitudinal studies to clarify the temporal relationship between psychosocial factors and musculoskeletal pain in the workplace.

Background: Peptidylarginine Deiminase 4 (PAD4) may generate epitopes targeted by anti-citrullinated protein antibodies in rheumatoid arthritis (RA). A subset of RA patients has serum autoantibodies to human recombinant PAD4 (hPAD4). Here, we assessed whether anti-hPAD4 status in RA predicted disease outcome after anti-TNF- therapy.

Methods: We analyzed RA sera obtained at baseline (n=40) and after one year on anti-TNF- therapy (n=33) for anti-hPAD4 IgG. Association analyses between baseline anti-hPAD status and disease progression were performed.

Results: We found that 17 of 40 patients (42.5%) were serum anti-hPAD4 positive at baseline, and the anti-hPAD4 IgG levels were stable over one year on anti-TNF- therapy. At baseline, there were indications that the anti-hPAD4 positive patients had more severe disease than the negative patients. After one year on anti-TNF- therapy, the anti-hPAD4 positive patients displayed persistently elevated DAS28 score and increased progression in the vdHSharp erosion score. Accordingly, more anti-hPAD4 positive than negative patients presented an increase in vdHSharp erosion scores >0 over one year.

Conclusion: Anti-hPAD4 IgG can be detected in a subset of RA sera and the levels are stable after initiation of anti-TNF- therapy. Serum anti-hPAD4 may predict persistent disease activity and radiographic progression in RA patients receiving anti-TNF- therapy.

Background: Macrophage migration inhibitory factor (MIF) has recently emerged as an important cytokine possibly linking rheumatoid arthritis (RA) and atherogenesis. Because atherogenesis is accelerated in RA we investigated whether anti-TNF therapy could lead to sustained downregulation of systemic MIF levels and improvement of lipid profiles.

Methods: Fifty RA patients with active disease (disease activity score 28 (DAS28 "d 3.2)), who started adalimumab therapy 40 mg every other week, were included. At baseline, week 16 and 52 serum levels of MIF and lipids were assessed. In addition, the DAS28 and serum C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were determined.

Results: After 16 weeks of adalimumab therapy, both DAS28 and MIF levels were significantly decreased (P < 0.001 and P = 0.020, respectively). This was sustained up to week 52 (P < 0.001 and P = 0.012, respectively). CRP levels and ESR were significantly reduced after 16 and 52 weeks of adalimumab therapy (P < 0.001). HDL cholesterol levels increased at week 16 (P < 0.001), but returned to baseline at week 52. Apo A-I levels increased at week 16 (P <0.001) and remained stable (P = 0.005). This resulted in an improved apo B/ A-I ratio.

Conclusions: Our results underline sustained downregulation of MIF as a potential new mechanism by which anti-TNF therapy might reduce vascular inflammation, and as such perhaps cardiovascular morbidity in RA patients. This hypothesis is supported by an improved apo B/ A-I ratio as well as reduced CRP levels in our patients.

Objective: To determine the effect of changing from etanercept or methotrexate (MTX) monotherapy to etanercept plus MTX combination therapy on radiographic progression in rheumatoid arthritis (RA) patients.

Methods: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received MTX or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral MTX up to 20 mg/wk. The primary radiographic endpoint was change in modified total Sharp score (TSS), as assessed by blinded readers.

Results: At baseline, patients previously receiving MTX monotherapy (ETN-added, n=52) or etanercept monotherapy (MTX-added, n=68) had moderate disease activity levels (mean disease activity score [DAS] of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (Combination, n=90) had a low disease activity level (mean DAS of 2.0). Addition of etanercept to MTX monotherapy resulted in significant reduction in radiographic progression (P<0.05). Mean TSS changes in the previous year vs the current year were +1.79 vs +0.25 for the ETN-added group (p<0.05); +0.51 vs –0.18 for the MTX-added group (NS); and +0.42 vs +0.24 for the Combination group (NS).

Conclusion: In these RA patients with on average moderate disease activity despite previous MTX monotherapy, combination treatment with etanercept and MTX inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity.

Objectives: To compare the ability of 2 different E-MRI units and conventional radiography (CR) to identify bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) and wrist joints, with computed tomography (CT) as standard reference method.

Methods: 20 RA patients and 5 controls underwent, within 2 weeks, CR, CT and two E-MRI (Esaote Biomedica; Artoscan and MagneVu; MV1000) examination of one hand. In all modalities each bone of wrist and (MCP) joints was blindedly evaluated for erosions. Furthermore, MagneVu images were assessed for the proportion of each bone being visualized.

Results: 550 bones were examined. CT, Artoscan, MagneVu and CR detected 188, 116, 55 and 45 bones with erosions, respectively. The majority were located in the carpal bones.

The sensitivity of Artoscan for detecting erosions was higher than of MagneVu and CR (MCP joints: 0.68, 0.54 and 0.57, respectively; wrists: 0.50, 0.23 and 0.29).

Corresponding specificities for detecting erosions were 0.94, 0.93 and 0.99, respectively, in the MCP joints and 0.92, 0.98 and 0.98 in the wrist.

The MagneVu allowed visualization of 1.5 cm of the ventral-dorsal diameter of the bone. In the wrist 31.6% of bones were visualized entirely and 37.9% of bones were 67-99% visualized. In MCP joints, 84.2% of bones were visualized entirely and 15.8% of bones were 67-99% visualized.

Conclusion: With CT as reference method for detecting erosions in RA hands, Artoscan showed higher sensitivity than MagneVu and CR. All imaging modalities revealed high specificities. The better performance of Artoscan should be considered when selecting imaging method in RA.

Objectives: To evaluate the role of immunological tests for monitoring lupus nephritis (LN) activity.

Methods: C3, C4, anti-dsDNA and anti-C1q antibodies were prospectively performed over 6 years in 228 LN patients.

Results: In membranous LN only anti-C1q antibodies differentiated proteinuric flares from quiescent disease (p=0.02). However, in this group 46% of flares occurred with a normal value of anti-C1q antibodies versus 20% in proliferative LN (p=0.02). In patients with antiphospholipid antibodies (APL), 33% of flares occurred with normal levels of anti-C1q antibodies versus 14.5% in APL-negative patients (p=0.02). In proliferative LN, anti-C1q antibodies showed a slightly better sensitivity and specificity (80.5 and 71% respectively) than other tests for the diagnosis of renal flares. All 4 tests had good negative predictive value (NPV). At univariate analysis anti-C1q was the best renal flare predictor (p<0.0005). At multivariate analysis, the association of anti-C1q with C3 and C4 provided the best performance (p<0.0005,p<0.005,p<0.005 respectively).

Conclusions: Anti-C1q is slightly better than the other tests to confirm the clinical activity of LN, particularly in patients with proliferative LN and in the absence of APL. All 4 "specific" tests had a good NPV, suggesting that, in the presence of normal values of each, active LN is unlikely.

Objectives: Although lumbar spondylosis is a major cause of low back pain and disability in the elderly, few epidemiologic studies have been performed. We investigated the prevalence of radiographic lumbar spondylosis using a large-scale population, and examined the association with low back pain.

Methods: From a nationwide cohort study ROAD (Research on Osteoarthritis Against Disability), 2,288 participants (≥60 years; 818 men and 1,470 women) living in urban, mountainous and seacoast communities were analyzed. The radiographic severity at lumbar intervertebral levels from L1/2 to L5/S was determined by the Kellgren/Lawrence (KL) grading.

Results: In the overall population, prevalence of radiographic spondylosis with KL≥2 and ≥3 at the severest intervertebral level was 75.8 and 50.4%, respectively, and that of low back pain was 28.8%. Although the KL≥2 spondylosis was more prevalent in men, the KL≥2 spondylosis and low back pain were more prevalent in women. Age and body mass index were risk factors for both KL≥2 and KL≥3 spondylosis. Although KL=2 spondylosis was not significantly associated with low back pain compared to KL=0 or 1, KL≥3 spondylosis was related to the pain only in women.

Conclusions: The present cross-sectional study using a large population revealed a high prevalence of radiographic lumbar spondylosis in the elderly. Gender seems to be distinctly associated with KL≥2 and KL≥3 lumbar spondylosis, and disc space narrowing with or without osteophytosis in women may be a risk factor for low back pain.

Objectives: Conventional therapy of Wegener’s granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease.

Methods: A prospective, international, multi-centre, single limb, open label study. Entry required active Wegener’s granulomatosis with a Birmingham Vasculitis Activity Score (BVAS) ≥4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5mg/kg/day, was self-administered by subcutaneous injection in six cycles of 21 days with a seven day washout between cycles. Cycles were stopped early for white blood count < 4,000/mm3. The primary endpoint was complete remission (BVAS=0 for at least 2 months) or partial remission (BVAS<50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for six months.

Results: 42/44 patients (95%) achieved at least partial remission and 20/44 (45%) achieved complete remission. BVAS fell from 12 (4-25), median, range; at baseline to 2 (0-14) at the end of study (p<0.001). Prednisolone doses were reduced from 20 to 8mg/day (p<0.001). Relapses occurred in 18 (43%) patients after a median of 170 (44-316) days after achieving remission. Severe or life-threatening (≥ grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leukopaenias.

Conclusions: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener’s granulomatosis. Adverse events were common but rarely lead to treatment discontinuation.

Background: Defining the remission criteria of rheumatoid arthritis (RA) remains a critical issue. Markers of synovium activity -urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD)- and of cartilage destruction -urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II)- have been shown previously to reflect disease activity and joint damage progression in RA.

Methods: The prospective study cohort was comprised of 66 RA patients treated with infliximab and methotrexate and 76 healthy controls. Measurements of Glc-Gal-PYD and CTX-II were performed on urines collected at baseline and at one year of infliximab therapy.

Results: At baseline, urinary Glc-Gal-PYD and CTX-II levels were significantly higher in RA patients than in controls. The baseline level of urinary Glc-Gal-PYD and CTX-II significantly correlated to bone erosion, joint space narrowing, the total Sharp score, and progression of joint damage. Infliximab therapy reduced Glc-Gal-PYD in patients only with high baseline levels. Patients with more progressive joint destruction had higher Glc-Gly-PYD and CTX-II baseline levels.

Conclusion: These markers of synovial and cartilage were modulated by infliximab therapy. They reflected bone erosion evolution and might be useful for treatment monitoring and evaluation of RA. However, markers also remained high even in clinical responders after infliximab, thus suggesting there is an active persistence of synovitis.

Objective: To estimate the a) prevalence of polymyositis and dermatomyositis using population-based administrative data; b) sensitivity of case ascertainment approaches; c) patient demographics and these parameters.

Methods: We ascertained cases from Quebec physician billing and hospitalization databases (approximately 7.5 million beneficiaries). We compared three different case definition algorithms and also used statistical methods that account for imperfect case ascertainment to generate estimates of disease prevalence and of case ascertainment sensitivity. We developed a hierarchical Bayesian latent class regression model, assessing patient characteristics with respect to these parameter estimates.

Results: Using methods that account for the imperfect nature of both billing and hospitalization databases, we estimated the 2003 prevalence of polymyositis and dermatomyositis to be 21.5/100,000 (95% credible interval [CrI] 19.4, 23.9). Prevalence was higher for women and for older individuals, with a tendency for higher prevalence in urban areas. Prevalence estimates were lowest in young rural men (2.7/100,000, 95 CrI 1.6, 4.1) and highest in older urban women (70/100,000, 95% CrI 61.3, 79.3). Sensitivity of case ascertainment tended to be lower for older versus younger individuals, particularly for rheumatology billing data. Billing data appeared more sensitive in ascertaining cases in urban (versus rural) regions, while hospitalization data seemed most useful in rural areas.

Conclusions: We found marked variations in the prevalence of polymyositis and dermatomyositis according to age, sex, and region. Our methods allow adjustment for the imperfect nature of multiple data sources, and estimation of the sensitivity of different case ascertainment approaches.

Objective: Detection of antibodies to ribonucleoproteins represents a major diagnostic tool in primary Sjögren’s syndrome (pSS). We assessed the added value of using a radioligand assay compared to ELISA to detect antibodies to SSA, SSB and RNP and analyzed the correlation between autoantibody levels, B-cell biomarkers and disease activity.

Patients and methods: Antibodies to SSA, SSB and RNP were assessed in 127 patients with pSS using a radioligand assay (RLA) and ELISA. In parallel, parameters of B cell activation were measured including serum levels of BAFF.

Results: The RLA showed a better sensitivity as compared to ELISA for the detection of antibodies to SSB (59% of positive samples versus 37% respectively) and antibodies to RNP (9% versus 3%). No difference was observed for the sensitivity of detection of antibodies to SSA. Anti-SSA and anti-SSB levels were correlated with both techniques. Mean levels of antibodies to SSA were significantly higher in patients presenting both antibodies to SSA and SSB compared to those exhibiting only antibodies to SSA. Levels of antibodies to SSA and SSB significantly correlated with those of circulating BAFF (r=0.4, P= 0.004 and r= 0.6, P= 0.0001, respectively) and with B cell biomarkers, including levels of gammaglobulins, beta2-microglobulin, and rheumatoid factor.

Conclusion: RLA allowed a quantitative and more sensitive detection of antibodies to SSB and RNP in pSS. Quantitative assessment of autoantibodies might reveal a biomarker of disease activity and help to get further insights into the pathogenesis of the spreading of the autoantibody response.

Objective: Multiple studies indicate the role of the IL-17/IL-23 axis in autoimmune diseases including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype.

Methods: An initial case-control study in 143 Dutch SSc patients and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish SSc patients and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay.

Results: Using a Dutch cohort of SSc patients and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: P=0.02 and P=0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes.

Conclusions: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.

Objectives: Early osteoporotic fractures have a great impact on the disease progression, the first fracture being a major risk factor for further fractures. Subsequently, the efficacy of antiosteoporotic treatments in the younger women appears of utmost interest. Strontium ranelate is an anti-osteoporotic treatment, simultaneously reducing bone resorption while promoting bone formation. Its efficacy against vertebral fractures is presently assessed in a subset of women aged 50 to 65 years.

Methods: SOTI was an international, double-blind, placebo-controlled trial, supporting the efficacy of strontium ranelate 2g/day orally in reducing the risk of vertebral fractures in postmenopausal women with osteoporosis and a prevalent vertebral fracture. 353 of these randomized women, aged 50 to 65 years were included in this analysis over 4 years.

Results: Over 4 years, strontium ranelate significantly reduced the risk of vertebral fracture by 35% (RR=0.65; 95%CI [0.42;0.99], p<0.05). In the strontium ranelate group, the BMD mean change from baseline increased by 15.8% at lumbar spine and 7.1% at femoral neck.

Conclusion: These data demonstrate a significant vertebral antifracture efficacy of strontium ranelate in young postmenopausal women with severe osteoporosis aged 50 to 65 years and confirms the efficacy of this anti-osteoporotic treatment to prevent vertebral fractures, whatever the age of the patients.

Objective: The underlying basis of bone erosion in gout remains speculative. The aim of this study was to understand the mechanisms of bone erosion in gout using non-invasive imaging techniques.

Methods: Paired plain radiographs and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analyzed. Radiographs were scored for erosion (0-5) using the Sharp-van der Heijde method. CT scans were scored for the presence and diameter of bone erosions and tophi. The presence of intraosseous tophus (tophus visualized within bone) was recorded. The relationships between radiographic erosion, CT erosion and tophus scores were analyzed.

Results: With increasing radiographic erosion score, the percentage of joints with intraosseous tophus increased (p<0.0001). For those joints with a radiographic erosion score of 4 or 5, 96/98 (98%) had CT evidence of intraosseous tophus. There was a significant relationship between the radiographic erosion scores and intraosseous tophus size (p<0.0001). For those joints with CT erosion, 194/237 (81.8%) had visible intraosseous tophus. Of the joints with CT erosions >5mm, 106/112 (94.6%) had visible intraosseous tophus, and all (56/56) erosions >7.5mm had intraosseous tophus. There was a strong correlation between CT erosion diameter and intraosseous tophus diameter (r=0.93, p<0.0001). Intraosseous tophi were larger than non-intraosseous tophi, but had similar density and calcification.

Conclusion: There is a strong relationship between bone erosion and the presence of intraosseous tophus. These results strongly implicate tophus infiltration into bone as the dominant mechanism for development of bone erosion and joint damage in gout.

Purpose: Study patterns/predictors of medication use and laboratory monitoring, in gout.

Methods: In a cohort of veterans with diagnosis of gout, prescribed allopurinol, colchicine or probenecid, we examined quality-of-care by examining adherence to evidence-based recommendations, namely: (1) whether patients starting new allopurinol prescription (a) received continuous allopurinol; (b) received colchicine prophylaxis; (c) achieved target uric acid ≤6 mg/dl; and (2) if doses were adjusted for renal insufficiency. Logistic/Poisson regression examined association of socio-demographics, health care utilization and comorbidity with recommendations.

Results: Of the 643 gout patients receiving a new allopurinol prescription, 46% (297/643) had continuous allopurinol prescription, 10% (66/643) received colchicine prophylaxis and 20% (126/643) reached target uric acid of ≤6 mg/dl. During episodes of renal insufficiency, appropriate dose reduction/discontinuation of probenecid was done in 77% (24/31) episodes and of colchicine in 69% (36/52).

Multivariable regression showed higher outpatient utilization, more rheumatology care and lower comorbidity were associated with better quality-of-care: more rheumatology or primary care visits associated with less frequent allopurinol discontinuation, more total outpatient visit days or most frequent visits to rheumatology clinic with higher likelihood of receiving colchicine prophylaxis, and lower Charlson Comorbidity Index or more outpatient visit days with higher odds of reaching uric acid ≤6 mg/dl.

Conclusions: We found important variation in patterns of medication use and monitoring in gout patients, with suboptimal care. A concerted effort is needed to improve overall gout care.

Objective: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease (CHD) than the general population. Systemic inflammation may contribute to this risk. Therefore, this study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in RA patients.

Methods: We performed a case-control study within a large prospective cohort of RA patients. Cases were patients who developed their first MI after the diagnosis of RA, controls were RA patients without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged DAS28 was calculated. The data were analyzed using conditional logistic regression analysis.

Results MI cases had significantly higher age, were more often male, with higher BMI and total cholesterol and lower HDL serum levels than controls. Time-averaged disease activity however was similar for cases and controls. The raw OR for MI in patients with a "high" (> 4.0) versus a "low" ("T 4.0) average DAS28 was 1.2 (95% CI 0.61-2.36). The OR (95%CI) corrected for age, gender, BMI, baseline HAQ and baseline HDL was 0.91 (0.39-2.12).

Conclusion: RA patients with MI had more classical risk factors, but not higher disease activity over time, than control RA patients. Low levels of inflammation may be sufficient for accelerated atherogenesis and excess risk of CVD in RA.

Background: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, MD has also been considered as an IgG4-related disorder.

Objective: To determine the differences between IgG4-related disorders including MD and SS. Patients and Methods: We investigated patients with MD and IgG4-related disorders registered from all over Japan, and set up provisional criteria for the new clinical entity: IgG4-positive multi-organ lymphoproliferative syndrome (IgG4+MOLPS). The preliminary diagnostic criteria include elevated serum IgG4 (>135 mg/dl) and infiltration of IgG4+ plasma cells in the tissue (IgG4+/IgG+ plasma cells >50%) with fibrosis or sclerosis. We compared clinical features, laboratory data and pathologies of 64 patients with IgG4+MOLPS and 31 patients with typical SS.

Results: The incidences of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and anti-nuclear, anti-SS-A/Ro and anti-SS-B/La antibodies were significantly lower in IgG4+MOLPS than typical SS patients. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG2, IgG4 and IgE were significantly elevated in IgG4+MOLPS. Histological specimen from patients with IgG4+MOLPS revealed marked IgG4+ plasma cell infiltration. Many patients with IgG4+MOLPS showed lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG4+ cells were seen in the tissue of typical SS. Thirty-eight patients with IgG4+MOLPS treated with glucocorticoids showed marked clinical improvements.

Conclusion: Despite similarities in the involved organs, there are marked clinical and pathological differences between IgG4+MOLPS and SS. Based on the clinical features and good response to glucocorticoid, we propose a new clinical entity: IgG4+MOLPS.

Objective: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo-controlled, 24-week trial.

Methods: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At Week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis international Society (ASAS) criteria (ASAS20), ASAS40, and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of treatment randomization group.

Results: At Year 2, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders, and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to Year 2, respectively, BASDAI improved from 6.3±1.7 to 2.4±2.3 and BASFI improved from 5.2±2.4 to 2.9±2.5. Adalimumab was well-tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported.

Conclusions: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile.

objectives: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not precisely known. We therefore investigated the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand and cardiovascular disease (CVD) on the other.

Methods: We determined the prevalences of CVD, (i.e. coronary, cerebral and peripheral arterial disease), in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged between 50 and 75 years; the CARRÉ study), and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). RA patients with normal fasting glucose levels from the CARRÉ study (RA, n = 294) were compared to individuals from the Hoorn study with a normal glucose metabolism (non-diabetic, n = 258), and individuals with DM2 (DM2, n = 194).

Results: The prevalence of CVD was 5.0% (95%-CI: 2.3-7.7%) in non-diabetic, 12.4% (95%-CI: 7.5-17.3%) in DM2, and 12.9% (95%-CI: 8.8-17.0%) in RA individuals. With non-diabetic individuals as reference category, the age- and gender-adjusted prevalence odds ratio (ORs) for CVD was 2.3 (95%-CI: 1.1-4.7) for individuals with DM2 and 3.1 (95%-CI: 1.6-6.1) for RA patients. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (ORs: 2.0 (95%-CI: 0.9-4.5) and 2.7 (95%-CI: 1.2-5.9), respectively).

Conclusions: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Objective: To investigate the efficacy and feasibility of an intensive combination therapy in early rheumatoid arthritis (RA) combined with monitoring of both disease activity and cartilage degradation.

Methods: In a pilot trial, 21 patients with active early RA (mean DAS28 5,3; mean disease duration 3 months) were treated with COBRA therapy comprising sulfasalazine, methotrexate and high dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks.

Results: Nineteen of 21 patients (90%) were in remission (DAS28<2,6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS-score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol.

Conclusion: This small pilot study suggests that intensified and tightly controlled COBRA therapy is uniquely effective in early RA.

Objectives: Identified etiological factors for chronic widespread pain (CWP) are largely related to emotional and behavioral factors, but current management leads to modest improvement in symptoms. Vitamin D deficiency has been suggested as a novel modifiable risk factor for CWP. We examine the association between vitamin D status [measured by 25(OH)D] and CWP in a nationwide population sample of white British adults, accounting for potential mediating and confounding lifestyle factors.

Methods: 9377 participants born one week in March, 1958, in England, Scotland or Wales and completing a biomedical assessment at age 45; 6824 eligible participants had data on 25(OH)D and completed pain manikins.

Results: Prevalence of CWP varied by 25(OH)D concentration in women but not in men, with the lowest prevalence observed for females with 75-99 nmol/l (14.6% for <25nmol/l, 14.7% for 25-49 nmol/l, 11.5% for 50-74nmo/l, 7.7% for 75-99 nmol/l, and 9.7% for participants with >100nmol/l). There was an interaction between 25(OH)D concentration and gender in relation to CWP (interaction, p=0.006), which was not fully explained by differences in lifestyle or social factors, adjusted interaction, p= 0.03). For women, the association between 25(OH)D concentration and CWP persisted after full adjustment (OR for <75nmol/l vs. 75-99 nmol/l 1.57, 95%CI 1.09, 2.26), while no evidence for an association was apparent in men (1.03, 0.75, 1.43).

Conclusion: Current vitamin D status was associated with CWP in women but not in men. Follow-up studies are needed to evaluate whether higher vitamin D intake could have beneficial effects on CWP risk.

Background: Increasing evidence for cardiovascular mortality among patients with psoriasis and psoriatic arthritis (PsA) has accumulated, together with evidence for increased frequency of risk factors for cardiovascular disease.

Objectives: To describe cardiovascular morbidity in PsA, determine its prevalence, and identify risk factors for its development.

Methods: At the University of Toronto, patients have been followed prospectively according to a standard protocol including disease related features as well as co-morbidities. Patients with cardiovascular disease (CVD) including myocardial infarction (MI), angina, hypertension (HTN), and cerebrovascular accident (CVA) were identified. The prevalences of CVD morbidities in these patients were compared to data from the Canadian Community Health Survey (CCHS) through Standardized Prevalence Ratios (SPRs). Risk factor analyses are undertaken through use of Cox relative risk regression analysis.

Results: At the time of analysis, 648 patients were registered in the database. After clinic entry, 122 developed hypertension, 38 had an MI, and 5, 21 and 11 had CVA, angina and congestive heart failure (CHF) respectively. A total of 155 patients had at least one of these conditions observed. The SPRs for MI [2.57; 95% CI: (1.73, 3.80)], angina [1.97; : (1.24, 3.12)] and hypertension [1.90; (1.59, 2.27)], were statistically significant, whereas the SPRs for CHF [1.19; : (0.50, 2.86)] and CVA [0.91;: (0.34, 2.43)] were not. Factors associated with CVD included diabetes, hyperlipidemia and high PASI scores.

Conclusion: Patients with PsA are at increased risk of cardiovascular morbidities compared to the general population. In addition to known risk factor for CVD, severe psoriasis is an important predictor in patients with PsA.

Objective: To test whether RA trials treatment efficacy vs. control is better detected for patients with lower tender or swollen joint counts than for higher counts.

Methods: Using data from 6 large multicenter trials (N = 2002) and an intent to treat approach at 6 months, we created within each trial two subtrials, the lower disease activity group (defined by TJC <= overall median )and the higher disease activity group(TJC above median). The same approach was used for SJC . We tested for active treatment - control differences using several RA trial outcome measures: ACR20, EULAR response, ACRHybrid . We compared sample sizes needed for higher TJC and SJC RA trials vs. lower TJC and SJC trials, and explored consistency of results across trials and explanations for results by examining active treatment and control responses.

Results: We found that subtrials of subjects with lower TJC had much higher sensitivity to change than those of subjects with higher TJC across all trials and outcome measures. A trial with lower TJC patients would require a smaller sample size than ones with higher TJC patients. Results were not consistent for SJC subgroups. We found 3 reasons for sensitivity to change of lower TJC: 1) Compared to higher TJC, those with lower TJC showed greater response to active treatment. Subjects with higher TJC on control treatment had 2) greater % improvement and 3) more variable responses than those in the lower TJC group.

Conclusions: In RA trials, patients with lower disease activity within the range of current trial eligibility are more likely to show treatment efficacy than patients with higher disease activity. Lowering thresholds especially for TJC in trials may make it easier to detect treatment effects in RA.

Objective To assess the multiexaminer reproducibility and the accuracy comparing with cadaver anatomic specimens of ultrasound (US) measurement of femoral articular cartilage (FAC) thickness.

Methods: In 8 flexed cadaver knees, FAC thickness was blindly, independently and consecutively measured twice by 10 rheumatologists at the lateral condyle (LC), medial condyle (MC) and intercondylar notch (IN) with US. After the US measurements, the knees were dissected. Articular cartilage integrity was evaluated macroscopically in the femoral condyles. FAC thickness was blindly measured in the specimens using a stereoscopic magnifying loupe and a digitized image software. Interexaminer and intraexaminer reliability of US FAC thickness measurement and agreement between US and anatomic measurements were assessed by estimating the intraclass correlation coefficient (ICC).

Results: Interexaminer ICCs were higher than 0.90 for MC (p<0.001) and IN (p<0.001) and higher than 0.75 for LC (p<0.01). Mean intraexaminer ICCs were 0.832 for MC (p<0.001), 0.696 for LC (p<0.001), and, 0.701 for IN (p<0.001). Agreement between US and anatomic FAC thickness measurements was good for MC (ICC, 0.719; p=0.020) and poor for LC (p=0.285) and IN (p=0.332). Bland-Altman analysis showed that the difference between US and anatomic values was considerably high in the one knee with severely damaged FAC. After eliminating this knee from the analysis, ICCs were 0.883 (p<0.001) for MC, 0.795 (p=0.016) for LC and 0.732 for IN (p=0.071).

Conclusion: US demonstrated a good reproducibility in FAC thickness measurement by multiple examiners. In addition, US FAC thickness measurement was accurate in normal to moderately damaged cartilage.

Objective: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).

Methods: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations through 2 years of treatment (n=245) included American College of Rheumatology (ACR) 20%, 50%, and 70% improvement scores, measures of joint disease and skin disease, disability, and quality of life; modified total Sharp score (mTSS) were available through 2.75 years of treatment for patients who received adalimumab in the 24-week study.

Results: After 24 weeks of double-blind treatment, the mean change in mTSS was –0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152) (p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab- compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of Psoriasis Area and Severity Index (PASI) 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.

Conclusions: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favorable risk–benefit profile in patients with PsA.

Objective: To identify patterns of self-reported health problems relating to dose and duration of GC intake in unselected patients with rheumatoid arthritis from routine practice.

Methods: We analyzed data from 1,066 patients. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing GC treatment for >6 months and current doses of <5, 5-7.5 and >7.5 mg/d prednisone equivalent were compared to a group without any GC treatment for at least 12 months.

Results: The frequency of self-reported health problems was lowest in the group without GC exposition and increased with dosage. We observed two distinct dose-related patterns of adverse events: A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath, and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of >7.5mg/d for glaucoma, depression/ listlessness and increase of blood pressure. Dosages of 5 mg/d or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/d).

Conclusion: The associations found are in agreement with biologic mechanisms and clinical observations. Since there is a paucity of real-life data on adverse effects of GCs prescribed to unselected groups of patients, our data may help the clinician to adapt therapy with GC accordingly and improve the benefit-risk-ratio.

Objectives: Some rheumatoid arthritis (RA) patients lack RA-associated HLA alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.

Methods: We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium.

Results Among 620 patients with one or both parents HLA-genotyped, RA patients informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs. NIPA revealed no significant difference (27% vs. 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women >45 years at onset the reverse was observed (31% vs. 16% compared to 10% vs. 60%, p=0.008). DR4 encoding NIMA vs. NIPA did not differ in men. The SE did not differ in men or women.

Conclusions: Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

Background: Ankylosing spondylitis (AS) is a frequent largely genetically determined rheumatic disease that is characterised by spinal inflammation and new bone formation. However, the exact pathogenesis including pathology is still not clear.

Objective: To analyse tissue obtained at spinal surgery by immunohistochemistry and compare the specimen of patients with AS to those with degenerative disc disease (DDD).

Methods: Bony and soft tissue specimens of 30 AS and 20 DDD patients were obtained during spinal osteotomy from different anatomic regions including articular and spinous processes, interspinous ligaments and intervertebral disks. Immunohistolochemistry was performed with established markers for cathepsin-K, MMP-1, MMP-3 and RANK-ligand.

Results: Cathepsin-K and MMP-1-positive cells were only observed in AS specimen. Cathepsin-K-positive multinucleated cells were detected at articular processes adjacent to fibrous tissues. MMP-1 was expressed in smaller mononuclear cells attached to bone, Invasion of bone by MMP-1 cells was seen at entheseal sites. In the intervertebral disks, most mononuclear cells were cathepsin-K-positive. Isolated cells expressing these matrix degrading enzymes found in DDD never showed signs of invasion. No differences were found for MMP-3 between AS and DDD. Clear expression of RANK ligand was only detected in one AS patient.

Conclusion Cathepsin-K is strongly expressed in different regions of the spine in AS. Mainly mononuclar cells, fibroblast-like cells, and cells attached to bone and at sites of bone remodelling expressed cathepsin K suggestive of high osteoclastic activity. This supports the role of persistent inflammation in the pathogenesis of AS. How these changes relate to osteoproliferation remains to be determined.

Objectives: To identify the position of a gout susceptibility gene.

Methods: We performed a genome-wide scan method using 382 random polymorphic microsatellite markers spread across 22 autosomes in a Taiwanese gout family to screen the gout susceptibility genetic marker. We confirmed its association with gout disease by 33 single nucleotide polymorphisms (SNP) in 148 matched case-control subjects. The gout family was composed of eight gouty patients and ten gout-free subjects and the case-control subjects were 74 male gout patients and 74 healthy controls matched by age.

Results: Analysis of the genome-wide scan result by a non- parametric linkage method found that chromosome 4q21 contains a locus significantly linked with gout disease (D4S3243 at 81,289,553 bp; p = 0.004; LOD score = 5.13). In SNP genotyping analysis at the neighborhood regions of marker D4S3243 for the case-control subjects, the polymorphisms rs7688672 and rs6837293, located on the cGMP-dependent protein kinase II (cGK II) gene, were found to relate significantly to gout disease in a recessive model after adjustment of hyperuricemia (OR=2.89, 95% CI=1.19-7.02 and OR=2.72, 95% CI=1.13-6.54 respectively).

Conclusions: This study suggests the cGK II gene on chromosome 4q21 was most likely to harbor gout disease independent of hyperuricemia and inherited recessively.

Objective: To examine the safety and tolerability of a single intraarticular injection of rAAV2-TNFR:Fc, an adeno-associated virus serotype 2 vector containing the cDNA for the human tumor necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis.

Methods: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumor necrosis factor-alpha (TNF-) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intraarticular injection of rAAV2-TNFR:Fc at 1x10¹⁰ (n=5) or 1x10¹¹ (n=6) DNase resistant particles per mL joint volume or placebo (n=4) into a knee (n=14) or ankle (n=1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a 4-point scale, were evaluated.

Results: Intraarticular injections of rAAV2-TNFR:Fc were well-tolerated with no major safety issues. One event, mild knee pruritis, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. Twelve weeks after injection, a 2-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively.

Conclusion: A single dose of intraarticular rAAV2-TNFR:Fc appears to be safe and well-tolerated in subjects without concurrent systemic TNF- antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.

Objective: Although bone marrow lesions (BMLs) have been implicated in the pathogenesis of OA, their natural history in a healthy population is unknown. This study in a healthy, pain free population aimed to examine the natural history of BMLs; factors associated with incidence and progression of BMLs over 2 years; and whether incident BMLs are associated with the development of pain.

Methods: 271 subjects with no clinical knee OA, being pain free at baseline, underwent magnetic resonance imaging of their dominant knee at baseline and 2 years later. The presence of BMLs was assessed.

Results: In knees initially free of BMLs, incident BMLs developed in 14% of people over the study period. Increased BMI (OR 1.15 (95% CI 1.06-1.2) p=0.001) was associated with incident BMLs. Those who developed a BML were more likely to develop knee pain compared to those in whom no BML developed (OR 4.2 (95% CI 1.2-15.1) p=0.03). Among those in whom BMLs were present at baseline, 46% completely resolved. There was no association between age, gender and BMI and persistence of BMLs over 2 years.

Conclusion: In this healthy population, the rate of incident BMLs is lower than previously described in a population with OA. Incident BMLs are associated with increased BMI and the development of pain. Approximately half the BMLs present at baseline resolved. These data suggest that in pain free people with no clinical knee OA, BMLs are reversible and may provide a target for interventions aimed at the prevention of knee OA.

Objective: Assess the efficacy of anti-tumor necrosis factor (TNF) therapy to induce remission in patients with Takayasu’s arteritis (TAK) refractory to other immunosuppressive therapies.

Methods: Retrospective single-center study of 25 patients with refractory TAK.

Results: Patients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX [median 28 (range 2-84) months] and 9 with ETA [median 28 (range 4-82) months]; 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10mg per day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in 4 patients that initially achieved stable remission. Four patients suffered adverse events, including 1 with opportunistic infections and 1 with breast cancer.

Conclusions: In this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conduct of a randomized controlled trial of anti-TNF therapy in TAK.

Objectives: The risk of subsequent fractures is double the risk of having a first fracture. We analysed whether this risk is constant or not over time.

Methods: A population-based study in 4140 postmenopausal women, aged between 50 and 90 years, on radiographic confirmed clinical fractures from menopause onwards analysed by Cox regression.

Results: 924 (22%) women had a first fracture and 234 (26% of 924) a subsequent fracture. Four percent of all first fractures occurred in each year from menopause onwards, while after a first fracture, 23% of all subsequent fractures occurred within one year and 54% within five years. When calculated from time of a first fracture, the relative risk (RR) of subsequent fracture was 2.1 (95% confidence interval (CI): 1.7-2.6) and remained increased during 15 years. When calculated for specific time intervals after a first fracture, the RR was 5.3 (CI: 4.0-6.6) within one year, 2.8 (CI: 2.0-3.6) within 2-5 years, 1.4 (1.0-1.8) within 6-10 years and 0.41 (CI: 0.29 -0.53) after >10 years.

Conclusions: From menopause onwards, clinical fractures cluster in time indicating the need for early action to prevent subsequent fractures.

Objectives: To assess the associations of body mass index (BMI) with modifiable cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA).

Methods: BMI, disease activity, selected CVD risk factors and CVD medication were assessed in 378 (276 females) RA patients. Patients exceeding accepted thresholds in ≥3 CVD risk factors were classified as having the metabolic syndrome (MetS).

Results: BMI independently associated with hypertension (OR=1.28 (95% CI=1.22-1.34); p=0.001), HDL (OR=1.10 (1.06-1.15); p=0.025), insulin resistance (OR= 1.13 (1.08-1.18); p=0.000) and the MetS (OR=1.15 (1.08-1.21); p=0.000). In multivariable analyses, BMI had the strongest associations with CVD risk factors (F_1-354=8.663, p=0.000), and was followed by lipid-lowering treatment (F_1-354=7.651, p=0.000), age (F_1-354=7.541, p=0.000), antihypertensive treatment (F_1-354=4.997, p=0.000) and gender (F_1-354=4.707, p=0.000). Prevalence of hypertension (p=0.004), insulin resistance (p=0.005) and the MetS (p=0.000) was significantly different between normal, overweight and obese RA patients, and BMI differed significantly according to the number of risk factors present (p=0.000).

Conclusions: Increasing BMI associates with increased CVD risk independently of many confounders. RA-specific BMI cut-off points better identify RA patients at increased CVD risk. Weight-loss regimes should be developed and applied in order to reduce CVD in RA patients.

Objectives: To assess long-term outcome and predictors of prognosis following total knee arthroplasty (TKA) for osteoarthritis.

Methods: We followed-up 325 patients from three English health districts approximately six years after TKA, along with 363 controls selected from the general population. Baseline data, collected by interview and examination, included age, sex, comorbidity, body mass index (BMI), functional status, and pre-operative radiographic severity of osteoarthritis. Functional status at follow-up was assessed by postal questionnaire. Predictors of change in physical function were analysed by linear regression.

Results: Between baseline and follow-up, patients reported an improvement of 6 points in median SF-36 physical function score whereas in controls there was a deterioration of 14 points (p<0.0001). Median SF-36 vitality score declined by 10 points in patients and 5 points in controls (p=0.005), while their median SF-36 mental health scores improved by 12 and 13 points respectively (p=0.2). The improvement in physical function was smaller in obese than in non-obese patients, but compared favourably with a substantial decline in the physical function of obese controls. Better baseline physical function and older age predicted worse changes in physical function in both patients and controls. Improvement in physical function tended to be greater in patients with more severe radiological disease of the knee, and was less in those who reported pain at other joint sites at baseline.

Conclusions: Improvements in physical function following TKA for osteoarthritis are sustained beyond five years. The benefits are apparent in obese as well as non-obese patients, and there seems no justification for withholding TKA from obese patients solely on the grounds of their body mass index.

Objective: To determine whether serum levels of a proliferation-inducing ligand (APRIL) are altered in patients with systemic lupus erythematosus (SLE), and correlate with disease parameters.

Methods: Clinical and biological parameters were analyzed for 43 patients that fulfilled American College of Rheumatology (ACR) criteria for SLE classification and were positive for anti dsDNA antibodies at least once in their medical record. Tests included measurement of serum levels of the TNF family members APRIL and B lymphocyte stimulator (BLyS, a cytokine shown to promote SLE disease).

Results: Median APRIL levels were elevated in SLE patients compared to osteoarthritis patients and healthy controls, but did not correlate with the SLE Disease Activity Index (SLEDAI). APRIL serum levels showed an inverse correlation with BLyS serum levels (r = 0.339; p = 0.03). For SLE patients with positive anti-double-stranded DNA (anti-dsDNA) titers (> 40 UA/ml) at inclusion (n = 25), circulating APRIL was inversely correlated with BLyS levels (r = -0.465; p = 0.022) and anti-dsDNA antibody titers (r = -0.411; p = 0.046). In a follow-up study at their second visit, 27 patients showed an inverse correlation with BLyS (r = 0.398; p = 0.03) and anti-dsDNA (r = -0.408; p = 0.03) titers, as well as an inverse correlation of APRIL serum levels with SLEDAI (r = -0.408; p = 0.01).

Conclusion: The inverse correlation observed between APRIL and BLyS suggests that APRIL acts as a protective factor. APRIL and BLyS may thus have opposite roles in SLE, which must be considered when defining therapeutic applications of these cytokines.

Objectives: to determine whether amongst, middle-aged and elderly males, there is evidence of international differences in prevalence of chronic widespread pain (CWP), and whether any such differences could be explained by psychological, psychosocial factors or differences in physical health status.

Methods: The European Male Ageing Study (EMAS) sampled from population registers in cities (centres) of eight European countries. Each centre recruited an age-stratified sample of men aged 40-79yrs. Information on pain was collected by questionnaire and subjects classified according to whether they satisfied the American College of Rheumatology definition of CWP. Information was collected on social status, mental health, recent life events and co-morbidities.

Results: Across all centres 3963 subjects completed a study questionnaire with participation rates ranging from 24% in Hungary to 72% in Estonia. There were significant differences in prevalence: between 5-7% in centres in Italy, England, Belgium and Sweden, 9%-15% in centres in Spain, Poland and Hungary, and 15% in Estonia. There were strong relationships between poor mental health, adverse recent life events, co-morbidities and CWP. Adjustment for these factors explained between half and all of the excess risk in the Eastern European centres: the excess risk in Poland was explained (OR 1.1, 95% CI (0.9, 1.2)) but their remained excess risk in Hungary (OR 1.6 95% CI (1.4, 1.8) and Estonia (OR 2.6 95% CI (2.2, 2.9)).

Conclusions: This study is the first study able to directly compare the occurrence of CWP internationally. There is an excess prevalence in countries of Eastern Europe and this excess is associated with adverse psychosocial factors as well as poorer psychological and physical health.