94 874 participants were included from the Nurses' Health Study II over a 14-year period (1991–2005). Information on smoking was collected biennially during follow-up. The incidence of clinician-diagnosed PsA was ascertained and confirmed by self-reported questionnaires.

During 1 303 970 person-years' follow-up, the authors identified 157 incident PsA cases. Among total participants, smoking was associated with an elevated risk of incident PsA. Compared with never smokers, the RR was 1.54 for past smokers (95% CI 1.06 to 2.24) and 3.13 for current smokers (95% CI 2.08 to 4.71). With increasing smoking duration or pack-years, the risk of PsA increased monotonically (p for trend <0.0001). The increase in risk was particularly significant for PsA cases with more severe phenotypes. Secondary analysis among participants developing psoriasis during the follow-up replicated the association, demonstrating an increased risk of PsA among psoriasis cases. The risk was significant for those with higher cumulative measures of smoking or PsA cases with more severe phenotypes.

In this study smoking was found to be associated with a risk of PsA and cumulative measures of smoking were also associated with a higher risk of PsA among women.

647 patients with early inflammatory back pain (IBP) fulfilling at least one of the internationally accepted SpA criteria and with available smoking data were included in the analyses. Clinical, demographic and imaging parameters were compared between smokers and non-smokers at a cross-sectional level. Variables with significant differences in univariate analyses were used as dependent variables in multivariate linear and logistic regression models adjusted for potential confounding/contributing factors.

Multivariate analysis showed that smoking was associated with an earlier onset of IBP (regression coefficient (B)=(–1.46), p=0.04), higher disease activity (ankylosing spondylitis disease activity score B=0.20, p=0.03; Bath ankylosing spondylitis disease activity index B=0.50, p=0.003), worse functional status (Bath ankylosing spondylitis functional index B=0.38, p=0.02), more frequent MRI inflammation of the sacroiliac joints (OR 1.57, p=0.02) and the spine (OR 2.33, p<0.001), more frequent MRI structural lesions of the sacroiliac joints (OR 1.54, p=0.03) and the spine (OR 2.02, p=0.01), and higher modified Stoke ankylosing spondylitis spine score (B=0.54, p=0.03) reflecting radiographic structural damage of the spine. Smoking was also associated with poorer quality of life (Euro-quality of life questionnaire B=1.38, p<0.001, short form 36 physical B=(–4.89), p<0.001, and mental component score B=(–5.90), p<0.001).

In early axial SpA patients, smoking was independently associated with earlier onset of IBP, higher disease activity, increased axial inflammation on MRI, increased axial structural damage on MRI and radiographs, poorer functional status and poorer quality of life.

269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6–8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1.

The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively.

In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns.

To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.

51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

A cohort of RA patients was classified into three ‘regional radiographic damage progression’ groups: predominantly progression in feet, similar progression in hands and feet and predominantly progression in hands; both in early (0–2 years) and later (2–5 years) disease. Baseline and mean DAS28, individual DAS28 variables and tender joint counts (TJC) and swollen joint counts (SJC) of the feet were compared between groups. The longitudinal relation of DAS28 with radiographic damage was investigated using a mixed model analysis with rheumatoid factor status, baseline joint damage and TJC and SJC of the feet as covariates.

Early (n=265) and later (n=200) in the disease course, by definition, the classification procedure resulted in 25% as predominantly foot, 25% as predominantly hand and 50% as similar progressors. In early RA predominantly foot progressors had higher TJC and SJC of the feet compared with predominantly hand progressors (p<0.001), but DAS28 was similar. This was not seen in later disease. The longitudinal relation between DAS28 and radiographic progression was influenced by the region of progression (predominantly foot progressors vs others, p<0.001), suggesting that DAS28 underestimates disease activity in predominantly foot progressors. In this group, joint counts for the feet were independently related to radiographic progression.

DAS28 underestimates actual disease activity and expected joint damage of individual early RA patients predominantly with disease in the feet.

A systematic review of the literature from 1990 to 2008 was conducted using MEDLINE and EMBASE databases. The search strategy focused on RA, joint damage and disability. Only longitudinal studies or randomised clinical trials with 1 year or more of follow-up containing data correlating joint damage and disability were included. The comparisons were categorised in four ways: baseline damage versus disability at end of follow-up (correlation A); damage versus disability measured cross-sectionally at each of several time points (correlation B); changes in damage versus final disability (correlation C) and changes in damage versus changes in disability (correlation D).

From a total of 1902 abstracts, 42 studies met the inclusion/exclusion criteria. More than 50% of the studies that measured baseline damage to later disability (A) reported a statistically significant association. Correlation was significant when measured at multiple time points over time (B; 16/19 studies). Statistically significant associations between changes in damage and either disability at end of follow-up or changes in disability were also found (C and D; 11/13 studies).

While many of the studies did not include multivariate analysis with confounder adjustment, the published evidence indicates a link between joint damage and functional disability and that an increase in joint damage is associated with an increase in disability over time. Treatments to limit progressive joint damage may lead to better joint function and improved patient outcome with less disability.

The study aims to investigate whether in early RA a treatment strategy aiming at Disease Activity Score (DAS) 28 <2.6 is more effective than ‘usual care’ treatment for reaching clinical remission after 1 year.

Two early RA inception cohorts from two different regions including patients who fulfilled the American College of Rheumatology criteria for RA were compared. Patients in the tight-control cohort (n=126) were treated according to a DAS28-driven step-up treatment strategy starting with methotrexate, addition of sulphasalazine (SSZ) and exchange of SSZ by anti-tumour necrosis factor in case of failure. Patients in the usual-care cohort (n=126) were treated with methotrexate or SSZ, without DAS28-guided treatment decisions. The primary outcome was the percentage remission (DAS28<2.6) at 1 year. Time to first remission and change in DAS28 were secondary outcomes.

After 1 year, 55% of tight-control patients had a DAS28<2.6 versus 30% of usual care patients (OR 3.1, 95% CI 1.8 to 5.2). The median time to first remission was 25 weeks for tight control and more than 52 weeks for usual care (p<0.0001). The DAS28 decreased with –2.5 in tight control and –1.5 in usual care (p<0.0001).

In early RA, a tight control treatment strategy aiming for remission leads to more rapid DAS28 remission and higher percentages of remission after 1 year than does a usual care treatment.

During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested.

1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not.

In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

In this phase IIIb, open-label, single-arm trial, patients who completed ≥4 years of intravenous abatacept (in long-term extensions of two phase III studies) were enrolled to receive SC abatacept (125 mg/week). The primary objective was safety during the first 3 months after switching from intravenous therapy.

123 patients entered the study (mean Disease Activity Score 28 (based on C reactive protein) and HAQ-DI of 3.4 and 0.94, respectively). At month 3, 120 (97.6%) patients were continuing to receive SC abatacept; no patients discontinued due to lack of efficacy. Adverse events (AEs) were reported in 49 (39.8%) patients through month 3. One patient (0.8%) discontinued due to an AE and one patient (0.8%) experienced a serious AE. Two (1.6%) patients had SC injection site reactions (erythema, pain), both with mild intensity. Clinical efficacy was maintained throughout. Limited impact on immunogenicity was observed when switching routes of administration.

These data demonstrate that patients can switch from long-term monthly intravenous abatacept to a weekly fixed dose of 125 mg SC abatacept with no increased safety concerns. This study further supports SC abatacept as an alternative treatment option for patients with RA.

To assess the change in lipid levels with TNFi treatment in patients with RA by systematic review and meta-analysis.

A Medline search was performed for articles published up to March 2011. Reports describing values for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), atherogenic index (AI) and apolipoprotein B/A (apoB/A) collected before and after TNFi initiation were included. Data were analysed according to short-, mid- and long-term treatment. Statistical analysis of pre–post data was performed by comprehensive meta-analysis. A random effects model was used when there was evidence of heterogeneity.

The search retrieved 32 articles, of which 13 prospective before/after studies were analysed. Long-term TNFi treatment was associated with increased levels of HDL (+0.27 mmol/l, p<0.0001) and TC (+0.27 mmol/l, p=0.03), whereas LDL levels and AI remained unchanged. After long-term treatment, TG levels increased (+0.28 mmol/l, p<0.001) and apoB/A decreased (–0.3, p<0.0001).

The presumed cardioprotective effects of TNFi in RA do not seem to be explained by quantitative lipid changes since long-term treatment has no effect on LDL levels or on AI. Increased HDL levels could have some beneficial effects, but this needs to be confirmed by prospective studies with long-term follow-up.

Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting.

SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84).

Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer.

SMART is a randomised open trial assessing two strategies of re-treatment in patients responding to 1 g infusion of RTX with methotrexate on days 1 and 15 after failure, intolerance or contraindication to tumour necrosis factor (TNF) blockers. Among the 224 patients included, 111 could be genotyped and were included in an ancillary study of SMART. Univariate and multivariate analyses adjusted on disease activity score on 28 joints were performed to assess whether FCGR3A-158V/F polymorphism was associated with European League Against Rheumatism response at week 24.

Among the 111 patients, 90 (81%) were responders of whom 30 (27%) were good responders. V allele carriage was significantly associated with a higher response rate (91% of responders vs 70%, OR 4.6 (95% CI 1.5 to 13.6), p=0.006). These results were also confirmed in rheumatoid factor-positive patients (93% vs 74%, p=0.025). In multivariate analysis, V allele carriage was independently associated with response to RTX (OR 3.8 (95% CI 1.2 to 11.7), p=0.023).

The 158V/F polymorphism of FCGR3A seems to influence the response to RTX in patients with RA after failure, intolerance or contraindication to TNF blockers.

Patients were randomly assigned to subcutaneous injections of placebo (n=78), golimumab 50 mg (n=138), or golimumab 100 mg (n=140) every 4 weeks. An MRI substudy comprising 98 patients (placebo n=23, 50 mg n=37, 100 mg n=38) at eligible MRI substudy sites had serial spine MRI scans (sagittal plane, 1.5T scanners, T1 and short tau inversion recovery sequences) at baseline and weeks 14 and 104. Two blinded (treatment, image order) readers independently evaluated MRI spinal inflammation using AS spine MRI-activity (ASspiMRI-a) scores; reader scores were averaged. Changes from baseline to weeks 14 and 104 were compared among treatment groups using analysis of variance on van der Waerden normal scores both with (post-hoc) and without (prespecified) adjustment for baseline ASspiMRI-a scores.

Median baseline ASspiMRI-a scores were lower in the 100 mg (3.5) than placebo (6.8) and 50 mg (7.8) groups. Median decreases in activity scores from baseline to week 14 were –0.5 for placebo, –3.5 for 50 mg (p=0.047 vs placebo), and –1.5 for 100 mg (p=0.14 vs placebo). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed with both 50 mg (p=0.011) and 100 mg (p=0.002) versus placebo. ASspiMRI-a scores improvement achieved with golimumab was maintained at week 104. Improvement in ASspiMRI-a scores correlated with improvement in the recently developed AS disease activity score (ASDAS) and C-reactive protein (CRP) levels but not with other key AS clinical outcomes.

Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.

Seven single-nucleotide polymorphisms (SNP) and a variable number tandem repeat located in the IL-1 gene cluster were genotyped in 185 independent spondyloarthritis trios. Family-based association test (FBAT) was computed using the FBAT software. Analysis was carried in spondyloarthritis as a whole and also in AS. A case–control replication study was performed for four of the SNP, in an independent sample of 414 spondyloarthritis and 264 controls. A combined analysis of both studies was performed.

The SNP rs2856836 in IL1A was significantly associated with spondyloarthritis (p=0.009) and AS (p=0.010) in the family study. The case–control study revealed an association between another IL1A variant (rs1894399) and AS (p=0.035), and between IL1F10.3 (rs3811058) and spondyloarthritis (p=0.041). By combining family and case–control studies an association between AS and IL1A was confirmed (rs1894399, p=0.024), whereas non-AS was more significantly associated with IL1F10.3 (p=0.0043). Family-based and case–control studies revealed significant association between the two most frequent haplotypes combining the four SNP of the replication study and both spondyloarthritis (p=0.0054 and p=0.038) and AS phenotypes (p=0.018 and 0.0036).

This study is the first to demonstrate an association between several polymorphisms located in the IL-1 gene cluster and spondyloarthritis as a whole. The IL1A locus was strongly associated with AS phenotype, whereas IL1F10 was associated with non-AS.

Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSSTM).

The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab.

Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients.

Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo.

Eighty-five patients (77 women) with mean (SD) age of 68.8 (5.6) years underwent contrast-enhanced MRI of the interphalangeal joints (dominant hand) and clinical joint assessment. One investigator read the MRIs for presence/severity of osteophytes, joint space narrowing, erosions, bone attrition, cysts, malalignment, synovitis, flexor tenosynovitis, bone marrow lesions (BMLs) and ligament discontinuity according to the proposed Oslo hand OA MRI score. Pain and physical function were assessed by joint palpation (tenderness yes/no), self-reported questionnaires (Australian/Canadian (AUSCAN) hand index, Functional Index of hand osteoarthritis (FIHOA), Arthritis Impact Measurement Scale-2 (AIMS-2) hand/finger) and grip strength. Logistic regression with generalised estimating equations was used to explore associations between the presence of MRI features and joint tenderness, and linear regression for associations between the burden of MRI abnormalities and patient-reported outcomes and grip strength (adjusted for age and sex). MRI features with p<0.25 were introduced into a multivariate model. The final model included features with p≤0.10 (backward selection).

MRI-defined moderate/severe synovitis (OR=2.4; p<0.001), BMLs (OR=1.5; p=0.06), erosions (OR=1.4; p=0.05), attrition (OR=2.5; p<0.001) and osteophytes (OR=1.4; p=0.10) were associated with joint tenderness independently of each other (final model adjusted for age and sex). The sum score of MRI-defined attrition was associated with FIHOA (B=0.58; p=0.005), while the sum score of osteophytes was associated with grip strength (B=–0.39; p<0.001). No significant associations were found with AUSCAN pain/physical function or AIMS-2 hand/finger subscales.

MRI-defined synovitis, BMLs, erosions and attrition were associated with joint tenderness. Synovitis and BMLs may be targets for therapeutic interventions in hand OA.

Data from the prospective Rotterdam cohort study (including subjects aged ≥55 years) were used. Analysis was performed on 623 subjects with knee complaints at baseline and their data at 6-year follow-up (T1; n=607) and at 11-year follow-up (T2; n=457). At baseline, none had radiological OA (rOA=Kellgren and Lawrence (KL) grade ≥2) in the painful joint. At follow-up, predictors for rOA were determined using multivariate ordinal logistic regression analysis.

At T1, 8.5% of the group had developed knee rOA and, by T2, this had increased to 23%. Determinants remaining significant in the multivariate analysis were female gender (OR 1.95, 95% CI 1.15 to 3.36), other joint complaints (OR 2.22, 95% CI 1.12 to 4.35) and KL grade 1 at baseline in the painful knee joint (OR 7.14, 95% CI 4.55 to 11.1). All outcomes are adjusted for all included determinants.

The best predictors of development of knee rOA are a combination of female gender, other joint complaints and KL grade 1 in the painful joint. KL grade 1 in combination with knee pain should be considered as early OA in patient management.

In a randomised controlled trial, the VTP—a 10-session mindfulness-based group intervention including a booster session after 6 months—was compared with a control group that received routine care plus a CD for voluntary use with mindfulness-based home exercises. The primary outcome was psychological distress measured by the General Health Questionnaire-20. Self-efficacy (pain and symptoms) and emotion-focused coping (emotional processing and expression) were used as co-primary outcomes. Secondary outcomes included pain, fatigue, patient global disease activity, self-care ability and well-being. Effects were estimated by mixed models repeated measures post-intervention and at 12-month follow-up.

Of 73 participants randomised, 68 completed assessments post-intervention and 67 at 12 months. Significant treatment effects in favour of the VTP group were found post-treatment and maintained at 12 months in psychological distress (adjusted mean between-group difference –3.7, 95% CI –6.3 to –1.1), self-efficacy pain (9.1, 95% CI 3.4 to 14.8) and symptoms (13.1, 95% CI 6.7 to 19.3), emotional processing (0.3, 95% CI 0.02 to 0.5), fatigue (–1.1, 95% CI –1.8 to –0.4), self-care ability (1.0, 95% CI 0.5 to 1.6) and overall well-being (0.6, 95% CI 0.1 to 1.2). No significant group differences were found in emotional expression, pain or disease activity.

The VTP improved most primary and secondary outcomes compared with individual use of CD exercises. Improvements were maintained at 12 months, suggesting that the VTP is a beneficial complement to existing treatments for patients with inflammatory rheumatic joint diseases.

Pregnant women in their first trimester were screened using a two-step approach using a self-administered 10-item questionnaire and subsequent testing for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant) and evaluation by a rheumatologist. Overall, the complications of pregnancy evaluated included fetal loss, pre-eclampsia, gestational diabetes, fetal growth restriction, delivery at less than 34 weeks, neonatal resuscitation and admission to the neonatal intensive care unit.

Out of the 2458 women screened, the authors identified 62 (2.5%) women with previously undiagnosed undifferentiated connective tissue disease (UCTD) and 24 (0.98%) women with previously undiagnosed definite systemic rheumatic disease. The prevalences were seven (0.28%) for systemic lupus erythematosus and Sjogren's syndrome, six (0.24%) for rheumatoid arthritis, three (0.12%) for antiphospholipid syndrome and one (0.04%) for systemic sclerosis. In multiple exact logistic regression, after adjustment for potential confounders, the OR of overall complications of pregnancy were 2.81 (95% CI 1.29 to 6.18) in women with UCTD and 4.57 (95% CI 1.57 to 13.57) in those with definite diseases, respectively, compared with asymptomatic controls.

In our population approximately 2.5% and 1% of first trimester pregnant women had a previously undiagnosed UCTD and definite systemic rheumatic disease, respectively. These conditions were associated with significant negative effects on the outcome of pregnancy.

The association between gout and mortality was examined in a prospective cohort, the Singapore Chinese Health Study, comprising 63 257 Singapore Chinese individuals, aged 45–74 years during the enrolment period of 1993–8. All enrollees were interviewed in person on lifestyle factors, current diet and medical histories. All surviving cohort members were contacted by telephone during 1999–2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Cause-specific mortality in the cohort was identified via record linkage with the nationwide death registry, up to 31 December 2009.

Out of 52 322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean follow-up period of 8.1 years, there were 6660 deaths. Relative to non-gout subjects, subjects with gout had a higher risk of death (HR 1.18; 95% CI 1.06 to 1.32), and specifically from death due to coronary heart disease (CHD) (HR 1.38, 95% CI 1.10 to 1.73) and kidney disease (HR 5.81, 95% CI 3.61 to 9.37). All gout–mortality risk associations were present in both genders but the risk estimates appeared higher for women.

Gout is an independent risk factor for mortality, and specifically for death due to CHD and kidney disease.

This was a 3-month randomised double-blind controlled trial of milk products for prevention of gout flares. One hundred and twenty patients with recurrent gout flares were randomised to one of three arms: lactose powder control, SMP control and SMP enriched with GMP and G600 (SMP/GMP/G600). The primary end point was change in the frequency of gout flares using a daily flare diary measured monthly for 3 months.

The frequency of gout flares reduced in all three groups over the 3-month study period compared with baseline. Over the 3-month study period there was a significantly greater reduction in gout flares in the SMP/GMP/G600 group (analysis of covariance p_group=0.031, Tukey post hoc test compared with lactose control, p=0.044). Following treatment with SMP/GMP/G600 over the 3-month period, greater improvements were also observed in pain and fractional excretion of uric acid, with trends to greater improvement in tender joint count. Similar adverse event rates and discontinuation rates were observed between the three groups.

This is the first reported controlled trial of dietary intervention in patients with gout, and suggests that SMP enriched with GMP and G600 may reduce the frequency of gout flares.

573 patients with fibromyalgia according to 1990 American College of Rheumatology criteria were enrolled at 108 centres in eight countries. Subjects were randomly assigned to placebo, SXB 4.5 g/night or SXB 6 g/night. The primary efficacy endpoint was the proportion of subjects with ≥30% reduction in pain visual analogue scale from baseline to treatment end. Other efficacy assessments included function, sleep quality, effect of sleep on function, fatigue, tenderness, health-related quality of life and subject's impression of change in overall wellbeing.

Significant improvements in pain, sleep and other symptoms associated with fibromyalgia were seen in SXB treated subjects compared with placebo. The proportion of subjects with ≥30% pain reduction was 42.0% for SXB4.5 g/night (p=0.002) and 51.4% for SXB6 g/night (p<0.001) versus 26.8% for placebo. Quality of sleep (Jenkins sleep scale) improved by 20% for SXB4.5 g/night (p≤0.001) and 25% for SXB6 g/night (p≤0.001) versus 0.5% for placebo. Adverse events with an incidence ≥5% and twice placebo were nausea, dizziness, vomiting, insomnia, anxiety, somnolence, fatigue, muscle spasms and peripheral oedema.

These results, combined with findings from previous phase 2 and 3 studies, provide supportive evidence that SXB therapy affordsimportant benefits across multiple symptoms in subjects with fibromyalgia.

As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis. Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used.

In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin's lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis, 89% of 27 patients with untreated GCA and PMR were positive.

Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA.

Measles, mumps, rubella (MMR) and diphtheria–tetanus toxoid (DT)-specific immunoglobulin G antibody concentrations were compared between 400 patients with JIA and 2176 healthy controls aged 1–19 years. Stored patient samples from the period 1997–2006 were obtained from one Dutch centre for paediatric rheumatology. Healthy control samples had been evaluated previously in a nationwide cohort. Participants had been vaccinated according to the Dutch immunisation programme. Antibody concentrations were measured by ELISA (MMR) or multiplex immunoassay (DT).

Corrected for age and the number of vaccinations, lower vaccine-specific geometric mean antibody concentrations (GMC) were found in patients with JIA against mumps, rubella, diphtheria and tetanus (p≤0.001). Measles-specific GMC were higher (p<0.001) compared with healthy controls. The prevalence of protective antibody concentrations was significantly lower in patients for mumps (OR 0.4; 95% CI 0.3 to 0.6), rubella (OR 0.4; 0.3 to 0.7), diphtheria (OR 0.1; 0.06 to 0.2) and tetanus (OR 0.1; 0.05 to 0.3). Seroprotection rates against measles did not differ between patients and healthy controls (OR 1.4; 0.8 to 2.5). Methotrexate and glucocorticosteroid use did not affect pathogen-specific GMC or seroprotection rates.

Patients with JIA had lower antibody concentrations and seroprotection rates than healthy controls against mumps, rubella, diphtheria and tetanus, but not measles. In these patients, regular assessment of antibody concentrations and further research on responses to other (booster) vaccines are warranted.

Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised.

Median duration of follow-up was 4.3 years (IQR, 2.95–5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs.

Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation.

557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure.

Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.

87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality.

After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome.

Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.

To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse.

Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor α, and methotrexate treatment was analysed and diagnostic power to predict flares was tested.

MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p<0.001) (mean±95% CI 12.030±3.090 ng/ml) during disease flares compared with patients with inactive disease (864±86 ng/ml). During clinical remission MRP8/14 serum levels of >740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p<0.001).

MRP8/14 serum concentrations correlate closely with response to drug treatment and disease activity and therefore might be an additional measurement for monitoring anti-inflammatory treatment of individual patients with SJIA. MRP8/14 serum concentrations are the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during times of clinically inactive disease.

527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing.

Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS.

A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

Data assessed at week 52 for baseline disease duration effect included remission (disease activity score (DAS)28 <2.6, SDAI ≤3.3, Boolean), low disease activity (LDA; DAS28 <3.2), Boolean components of remission and radiographic non-progression. Subjects who discontinued because of lack of efficacy were included as non-responders.

Higher proportions of VERA subjects achieved LDA (79%) and DAS28 remission (70%) than ERA (62%, 48%, respectively, p<0.05) with ETN+MTX. Such high responses with MTX monotherapy were not observed (VERA, LDA=47%, DAS28 remission=35%; ERA, 47% and 32% respectively, p>0.70 for each). Regardless of disease duration, no radiographic progression was seen in 80% of subjects with ETN+MTX. In contrast, a higher proportion of VERA subjects showed no radiographic progression compared with ERA subjects treated with MTX (73.9% vs 50%, p=0.01).

Treatment of VERA with ETN+MTX provides qualitatively improved clinical outcomes not seen with MTX monotherapy, supporting the pivotal role of TNF inhibition in early disease.

To analyse the feasibility of detecting this autoantibody in patient serum samples using new assays with commercially available recombinant TIF1.

The study included 90 Spanish patients with dermatomyositis (DM), classified as clinically amyopathic DM, CAM, or DM without cancer. Anti-TIF1 antibodies were detected by ELISA and immunoblot techniques and compared with anti-p155 antibody detection by protein immunoprecipitation assays with radiolabelled HeLa cells. The coefficient was used to compare the agreement between the different tests.

Serum samples from 23 (25.6%) and 20 (22.2%) patients with DM recognised TIF1 by ELISA and immunoblot, respectively. ELISA (=0.91) and immunoblot (=0.88) showed excellent agreement with immunoprecipitation analysis (anti-p155). Good concordance (=0.91) was also seen between ELISA and immunoblot.

Excellent agreement was found between anti-p155 detected by immunoprecipitation and anti-TIF1 detected by ELISA or immunoblot. These data indicate that identification of this autoantibody can be reliably performed in a standard laboratory setting, with potential application in clinical practice for cancer screening in adult patients with DM.

To compare drug retention rates of non-aTNF-Bio with alternative aTNF.

All patients within the Swiss RA cohort (SCQM-RA) treated with an alternative biotherapy after a prior inadequate response to aTNF were analysed. The drug retention of alternative aTNF was compared with non-aTNF-Bio using Cox proportional hazards models, adjusted for potential confounders.

1485 treatment courses after aTNF failure were available for analysis, 853 with alternative aTNF and 632 with non-aTNF-Bio. The median drug retention was 32 months (IQR 14–54) on non-aTNF-Bio versus 21 months (IQR 8–53) on alternative aTNF, or a 50% reduction drug discontinuation risk in favour of non-aTNF-Bio (adjusted hazard ratio (HR) for non-aTNF-Bio: 0.50 (95% CI 0.41 to 0.62)). This effect appears to be modified by the type of prior aTNF failure, with a larger difference in favour of non-aTNF-Bio in patients having experienced a primary failure with a previous aTNF (HR: 0.33 (95% CI 0.24 to 0.47), p<0.001).

After inadequate response to aTNF, and particularly after primary failure, patients on a non-aTNF-Bio agent have significantly higher drug retention rates.

Longitudinal.

Barwon Statistical Division, Victoria, Australia.

101 asymptomatic women aged 35–49 years (2007–2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study.

Blood samples obtained 10 years before (1994–1997) and stored at –80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation.

Knee cartilage volume, measured by MRI.

A higher lnPTH was associated with reduced medial—but not lateral—cartilage volume (regression coefficient±SD, p value: –72.2±33.6 mm³, p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (–80.8±34.4 mm³, p=0.02) and 25(OH)D with seasonal adjustment (–72.7±35.1 mm³, p=0.04), calcium supplementation and prevalent osteophytes did not affect the results.

A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.

The human tumour necrosis factor (TNF) transgenic (hTNFtg) mouse model of RA was used to analyse the time course of pannus attachment to the cartilage and cartilage destruction, respectively, and crossed hTNFtg mice with interleukin (IL)-1^–/– animals were used to investigate the role of IL-1 on these TNF-induced mechanisms in vivo. In addition, an in vitro attachment assay using synovial fibroblasts (SFs) from hTNFtg mice and freshly isolated articular cartilage was used to determine the role of proteoglycan loss in attachment of SFs and the role of the transmembrane heparan sulfate proteoglycan syndecan-4.

In vivo analyses of hTNFtg mice showed that proteoglycan loss induced by IL-1 precedes and constitutes an important prerequisite for these processes as, in hTNFtg mice, IL-1 deficiency protected from the loss of cartilage proteoglycans and almost completely prevented the attachment and subsequent invasion of inflamed synovial tissue into cartilage. In vitro studies confirmed that loss of cartilage proteoglycans is required for attachment of SFs and that syndecan-4 is prominently involved in SF attachment and activation.

The results of this study suggest that the loss of cartilage proteoglycans is an early event in the course of destructive arthritis that facilitates the attachment of the inflamed synovial membrane and also initiates matrix degradation and inflammation through cell–matrix interactions.

To evaluate cytokine production by IPFP in response to interleukin (IL)1β and investigate the ability to modulate this response with an agonist for peroxisome proliferator activated receptor α (PPARα), which is also activated by lipid-lowering drugs such as fibrates.

Cytokine secretion of IPFP was analysed in the medium of explant cultures of 29 osteoarthritic patients. IPFP (five donors) and synovium (six donors) were cultured with IL-1β and PPARα agonist Wy14643. Gene expression of IL-1β, monocyte chemoattractant protein (MCP1), (IL-6, tumour necrosis factor (TNF)α, leptin, vascular endothelial growth factor (VEGF), IL-10, prostaglandin-endoperoxide synthase (PTGS)2 and release of TNFα, MCP1 and prostaglandin E₂ were compared with unstimulated IPFP and synovium explants.

IPFP released large amounts of inflammatory cytokines, adipokines and growth factors. IL-1β increased gene expression of PTGS2, TNFα, IL-1β, IL-6 and VEGF and increased TNFα release in IPFP. MCP1, leptin, IL-10 gene expression and MCP1, leptin and PGE₂ release did not increase significantly. Synovium responded to IL-1β similarly to IPFP, except for VEGF gene expression. Wy14643 decreased gene expression of PTGS2, IL-1β, TNFα, MCP1, VEGF and leptin in IPFP explants and IL-1β, TNFα, IL-6, IL-10 and VEGF in synovium that responded to IL-1β.

IPFP is an active tissue within the joint. IPFP cytokine production is increased by IL-1β and decreased by a PPARα agonist. The effects were similar to effects seen in synovium. Fibrates may represent a potential disease-modifying drug for OA by modulating inflammatory properties of IPFP and synovium.

To study the antifibrotic potency of sGC stimulators.

The effect of the sGC stimulator BAY 41-2272 on the release of collagen from dermal fibroblasts was examined. The antifibrotic effects of BAY 41-2272 on prevention and regression of fibrosis in bleomycin-induced dermal fibrosis and in Tsk-1 mice were also studied. Telemetric blood pressure studies in conscious mice were used to study potential hypotensive effects of sGC stimulation.

sGC stimulation with BAY 41-2272 dose-dependently inhibited collagen release in dermal fibroblasts from patients with SSc and healthy individuals. Furthermore, BAY 41-2272 stopped the development of bleomycin-induced dermal fibrosis and skin fibrosis in Tsk-1 mice, preventing dermal and hypodermal thickening, reducing the numbers of myofibroblasts and reducing the hydroxyproline content. In addition, BAY 41-2272 was highly effective in the treatment of established fibrosis in the modified models of bleomycin-induced skin fibrosis and Tsk-1 mice. Treatment with sGC stimulators was well tolerated. Relevant antifibrotic doses of BAY 41-2272 did not affect systemic blood pressure and heart rate in mice.

These findings demonstrate potent antifibrotic effects and good tolerability of sGC stimulators in various experimental models of SSc. Given their potential vasoactive properties, sGC stimulators may be promising candidates for the dual treatment of fibrosis and vascular disease in SSc.

The presence of infiltrating immune cells and IL-7Rα cells in inflamed LSG of patients with pSS (n=12) and nSS-sicca controls (n=7) was studied by immunohistochemistry and fluorescence activated cell sorting analysis upon tissue digestion (n=15 and n=13, respectively). Additionally, the correlations of IL-7Rα cells with hallmark disease parameters of pSS, major infiltrating inflammatory cells and IL-7 were assessed.

In the LSG of patients with pSS increased numbers of IL-7Rα cells were found as compared with nSS-sicca patients. IL7Rα cells strongly correlated with the lymphocytic focus score, IL-7 expression, the decrease in percentage of IgA plasma cells and numbers of CD3 T cells, CD20 B cells, and CD1a and CD208 myeloid dendritic cells. Analysis of isolated cells from the LSG demonstrated strongly increased percentages of IL-7Rα CD3 T cells in pSS as compared with nSS, showing abundant IL-7Rα expression on both CD4 and CD8 T cells. Other CD45 leucocytes and CD45- tissue cells scarcely expressed IL-7Rα. Percentages of IL-7Rα T cells also significantly correlated with glandular inflammation.

This study shows the presence of increased IL-7Rα T cells in the LSG of patients with pSS and their association with the severity of sialadenitis, disease parameters and IL-7 expression. Considering the immunostimulatory ability of IL-7Rα T cells and IL-7, this suggests that IL-7(R)-dependent T cell-driven immune activation plays an important role in inflammation in pSS.

A total population of 3974 individuals (1355 SSc patients, 2619 controls) was studied. Genotype data for 23 SNP spanning the CAV1–CAV2 gene locus were obtained from a genome-wide scan conducted in a French population (564 SSc patients, 1776 controls). Three CAV1 SNP (rs926198, rs959173, rs9920) displaying the most significant associations with SSc and/or clinical phenotypes were then genotyped in an Italian population (791 SSc patients, 843 controls). CAV1 protein expression in skin biopsies was investigated by immunohistochemistry and western blotting.

In the French population, the CAV1 rs959173 C minor allele showed a significant protective association with susceptibility to SSc (OR 0.71, 95% CI 0.59 to 0.86, p_adjusted=0.009), and with the subset of patients with limited cutaneous SSc (OR 0.71, 95% CI 0.56 to 0.89, p_adjusted=0.018). The association was replicated in the Italian population and strengthened in the combined populations through Cochran–Mantel–Haenszel meta-analysis (SSc: pooled OR 0.81, 95% CI 0.71 to 0.92, p=0.0018; limited cutaneous SSc: pooled OR 0.80, 95% CI 0.69 to 0.93, p=0.0053). Genotype/protein expression correlations revealed that the rs959173 C protective allele was associated with increased CAV1 protein expression.

These results add CAV1 to the list of SSc susceptibility genes and provide further evidence for the contribution of this pathway in the fibrotic process that characterises SSc pathogenesis.

Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test.

In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3x10^–5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays.

These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR₂ on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA.

Patients with RA had elevated but variable surface expression of PAR₂ on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86–4.10%) vs 0.06% (0.03–0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR₂ expression in patients with RA compared with controls (3.05% (0.36–11.82%) vs 0.08% (0.02–0.28%), p<0.0001). For both subsets, PAR₂ expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR₂ expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR₂ expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR₂ expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR₂ agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05).

These findings are consistent with a pathogenic role for PAR₂ in RA.

Muscle biopsies from 17 patients before and after conventional IS treatment and seven healthy individuals were investigated by immunohistochemistry using antibodies against IL-15 and IL-15Rα. Quantification was performed by computerised image analysis. Cellular localisation of IL-15 was determined by double immunofluorescence. Clinical outcome was measured by the functional index and serum creatine kinase. Human myotubes were cultured and IL-15 staining was performed by immunocytochemistry.

IL-15 was observed in mononuclear inflammatory cells of muscle tissue while IL-15Rα was localised to mononuclear inflammatory cells, capillaries and large vessels. Double staining showed localisation of IL-15 to CD163+ macrophages. A significantly larger number of IL-15 and IL-15Rα-positive cells were seen in muscle tissue of patients compared with healthy individuals. Baseline IL-15 expression correlated negatively with improvement in muscle function. After conventional IS treatment, a significantly lower number of IL-15 and IL-15Rα-positive cells was found. However, compared with controls, eight of 17 patients still had more IL-15-positive cells and less muscle function improvement was shown in this group of patients, both in short-term and long-term observations. Human differentiated myotubes were negative for IL-15 staining.

IL-15 and its receptor are expressed in the muscle tissue of patients with myositis and IL-15 expression is correlated with improvement in muscle function. IL-15 may play a role in the pathogenesis of myositis and could be a biological treatment target, at least in a subgroup of patients with polymyositis or dermatomyositis.

Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls.

Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue.

MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.

Human chondrocytes were stimulated with IL-1β in vitro. Total RNA was prepared using Trizol reagent. Gene expression was quantified using TaqMan Assays and miRNA targets were identified using bioinformatics. Transfection with reporter construct and premiRNA and antimiRNA was employed to verify suppression of target mRNA. Expression of COX-2 proteins was determined by immunoblotting. The role of activated p38-MAPKs was evaluated using specific inhibitor.

The 3'UTR of COX-2 mRNA contained the ‘seed-matched’ sequences for miR-199a* and miR-101_3. Increased expression of COX-2 correlated with the downregulation of miR-199a* and miR-101_3 in IL-1β-stimulated normal and OA chondrocytes. miR-199a* directly suppressed the luciferase activity of a COX-2 3'UTR reporter construct and inhibited the IL-1β-induced expression of COX-2 protein in OA chondrocytes. Modulation of miR-199a* expression also caused significant inhibition of IL-1β-induced upregulation of mPGES1 and prostaglandin E₂ production in OA chondrocytes. Activation of p38-MAPK downregulated the expression of miR-199a* and induced COX-2 expression. Treatment with antimiR-101_3 increased COX-2 expression in IL-1β-stimulated chondrocytes, but overexpression of miR-101_3 had no significant effect on COX-2 protein expression.

miR-199a* is a direct regulator of COX-2 expression in OA chondrocytes. IL-1β-induced activation of p38-MAPK correlates inversely with miR199a* expression levels. miR-199a* may be an important regulator of human cartilage homeostasis and a new target for OA therapy.

To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis.

Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO^–/– mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO^–/– mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms

In both models, 12/15-LO^–/– mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO^–/– fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects.

These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.

Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC).

In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2–70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5–24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28–40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0–8%) between synovium and blood (p=0.01).

In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.

The patients who fulfilled the diagnosis criteria proposed by Benhamou et al6 had active disease defined...]]> 2012-05-07T09:17:28-07:00 info:doi/10.1136/annrheumdis-2011-200743 hwp:master-id:annrheumdis;annrheumdis-2011-200743 BMJ Publishing Group Ltd 2012-06-01 Letters 71 6 1098 1100 http://ard.bmj.com/cgi/content/short/71/6/1100?rss=1 Endothelial cell (EC) dysfunction (ECD) occurs in antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV)1 2 but improves with anti-tumour necrosis factor α (anti-TNFα) treatment,1 suggesting a key role for this cytokine. TNFα and interleukin 1 can induce secretion of acid sphingomyelinase (ASM) from ECs,3 4 which are the major source of this enzyme. ASM potently depresses calcium signals in lymphocytes5 and in EC (Church et al, unpublished observations). We hypothesised that endothelial inflammation in AASV would raise circulating levels of secretory sphingomyelinase (S-SMase), perpetuating vascular dysfunction.

Plasma from 18 patients with active AASV undergoing plasmapheresis (15 men, 3 women) were compared with 7 inflammatory renal disease controls and 9 healthy individuals. Sera were also collected from 20 AASV patients (9 women and 11 men) during active disease, after 14 weeks of immunosuppressive therapy and from patients in established...]]> 2012-05-07T09:17:28-07:00 info:doi/10.1136/annrheumdis-2011-200445 hwp:master-id:annrheumdis;annrheumdis-2011-200445 BMJ Publishing Group Ltd 2012-06-01 Letters 71 6 1100 1102 http://ard.bmj.com/cgi/content/short/71/6/1102?rss=1 Increased mortality in rheumatoid arthritis (RA) patients can be partly attributed to an accompanying increase in cardiovascular risk. On account of the increased cardiovascular risks and chronic inflammation, patients with RA may be more likely to contract other conditions with shared risk factors, such as erectile dysfunction (ED). However, although previous studies have reported sexual dysfunction among RA patients,1–4 no study has explored the possible association between ED and RA to date. This study set out to investigate this putative association by using a population-based dataset and case–control design.

We conducted this study by using administrative claims data sourced from the Taiwan Longitudinal Health Insurance Database 2000 (LHID2000). The LHID2000 includes all the claims data and registration files of 1 000 000 individuals under the Taiwan National Health Insurance programme. We identified 6310 patients (between 18 and 80 years of age)...]]> 2012-05-07T09:17:28-07:00 info:doi/10.1136/annrheumdis-2011-200890 hwp:master-id:annrheumdis;annrheumdis-2011-200890 BMJ Publishing Group Ltd 2012-06-01 Letters 71 6 1102 1103 http://ard.bmj.com/cgi/content/short/71/6/1103?rss=1 One of the major aims of the Assessment of SpondyloArthritis International Society (ASAS)is to facilitate/improve the conduct of clinical trials in the field of spondyloarthritis.1 Apart from the elaboration of classification and response criteria,2 3 ASAS has initiated actions in order to improve the conduct of clinical studies/trials.4 5 Based on the observation of a high interstudy variability in the collection of several data relevant to the field of spondyloarthritis, a previous initiative focused on the technique of collection of the information related to non-steroidal anti-inflammatory (NSAID) intake6 which will allow the calculation of an NSAID scoring system.7 8 ASAS has also considered two other frequent areas for which improvement/standardisation was required.

The first area was the huge intervariability of the technique of collection of specific spondyloarthritis features such as episodes of uveitis...]]> 2012-05-07T09:17:28-07:00 info:doi/10.1136/annrheumdis-2011-201038 hwp:master-id:annrheumdis;annrheumdis-2011-201038 BMJ Publishing Group Ltd 2012-06-01 Letters 71 6 1103 1104 http://ard.bmj.com/cgi/content/short/71/6/1106-a?rss=1 Nicolino Ruperto, Daniel J Lovell, Ruben Cuttica, et al. Long-Term Efficacy and Safety of Infliximab plus Methotrexate for The Treatment of Polyarticular Course Juvenile Rheumatoid Arthritis: Findings from an Open-Label Treatment Extension. Ann Rheum Dis 2010;69:3 585–857. This article was published in print with an incorrect DOI of 10.1136/ard.2009.104562. The correct DOI is 10.1136/ard.2008.100354.