A H M van der Helm-van Mil

Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles

Objectives: To study the gene–environment interaction of tobacco exposure and shared epitope on autoantibodies in patients with rheumatoid arthritis and undifferentiated arthritis. Methods: From incident cases of arthritis (n = 1305), patients who did not fulfil any classification criteria (undifferentiated arthritis (n = 486)) and those who fulfilled the American College of Rheumatology criteria for rheumatoid arthritis (n = 407) were identified. IgM rheumatoid factor (RF), anti-cyclic-citrullinated peptide (CCP) antibodies, and HLA-DRB1 alleles were determined. Results: In rheumatoid arthritis, an interaction was found between tobacco exposure and shared epitope for the presence of anti-CCP antibodies, as the odds ratio for anti-CCP antibodies in patients having both tobacco exposure (TE) and shared epitope (SE) was higher than the summed odds ratios of patients having only tobacco exposure or shared epitope (odds ratios: TE+/SE−, 1.07; TE−/SE+, 2.49; and TE+/SE+, 5.27—all relative to TE−/SE−). A similar effect was found for RF, but stratification showed that the interaction primarily associated with the anti-CCP antibody response. In patients with undifferentiated arthritis at two weeks, or with persistent undifferentiated arthritis after one year, no interaction between tobacco exposure and shared epitope was observed for the presence of autoantibodies. Conclusions: Tobacco exposure increases the risk factor for anti-CCP antibodies only in shared epitope positive patients with rheumatoid arthritis. The gene–environment interaction between smoking and shared epitope leading to autoantibodies is specific for rheumatoid arthritis and is not observed in undifferentiated arthritis.

Classification of rheumatoid arthritis: Comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria

OBJECTIVE New criteria to classify rheumatoid arthritis (RA) have been derived in order to increase the specificity and sensitivity for early RA compared with the 1987 American College of Rheumatology (ACR) criteria. The aim of this study was to evaluate differences in classification between the 1987 ACR criteria and the 2010 ACR/European League Against Rheumatism (EULAR) criteria in an early arthritis cohort and to determine the test characteristics of the 2010 ACR/EULAR criteria. METHODS A total of 2,258 patients with early arthritis included in the Leiden Early Arthritis Clinic cohort were studied. Fulfillment of the 1987 and 2010 criteria for the classification of RA was determined at baseline. The diagnosis of each patient at 1 year was assessed. The sensitivity and specificity of the 2010 criteria were determined using the following outcome measures: initiation of methotrexate therapy or any disease-modifying antirheumatic drug (DMARD) therapy during the first year of followup and having persistent arthritis during 5 years of followup. RESULTS At their first presentation, 1,099 patients fulfilled the 2010 criteria, and 726 patients fulfilled the 1987 criteria for RA. Eighty-two of the 726 patients fulfilling the 1987 criteria did not fulfill the 2010 criteria. Sixty-eight percent of the patients who fulfilled the 1987 criteria during the first year of disease but not at baseline did fulfill the 2010 criteria at baseline. In 18% of patients, use of the 2010 classification criteria also led to a revoked classification at 1 year. The sensitivity and specificity of the 2010 criteria were 0.84 and 0.60, respectively, with methotrexate therapy as the outcome and 0.74 and 0.74, respectively, with DMARD therapy as the outcome. With persistent arthritis as the outcome, the sensitivity and specificity of the 2010 criteria were 0.71 and 0.65, respectively. CONCLUSION Compared with the 1987 criteria, the 2010 criteria classify more patients with RA and at an earlier phase of the disease. The discriminative ability of the 2010 criteria is acceptable.

What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review

Objective Initiation of DMARD-therapy in the ‘window of opportunity’ is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. Methods Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). Results Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. Conclusions Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a ‘window of opportunity’.

A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis

Background: Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines and, in general, the presence of high levels of inflammatory markers is associated with a severe disease course and joint damage. Objectives: To evaluate prospectively (a) whether obesity is a risk factor for the development of RA and (b) whether the body mass index (BMI) is associated with the amount of joint destruction in early RA after 3 years’ follow-up. Methods: In a cohort of 570 patients with undifferentiated arthritis, the relation between the BMI and the development of RA during 1 year of follow-up was assessed. In a cohort of 488 patients with early RA the correlation between the BMI and degree of radiological joint destruction (Sharp–van der Heijde score) after 3 years of follow-up was determined. The findings were replicated in an independent cohort of 247 patients with early RA. Results: Obesity did not influence the likelihood of developing RA. In both RA cohorts, the BMI was inversely correlated with the Sharp–van der Heijde score after 3 years’ follow-up (r = −0.15, p = 0.025 for the Leiden EAC and r = −0.27, p<0.001 for the replication cohort). Linear regression analyses in both cohorts showed that the BMI was independently and inversely associated with the level of joint destruction in anti-CCP-positive patients with RA, but not in anti-CCP-negative patients. Conclusions: A high BMI is associated with a less severe disease outcome in anti-CCP-positive patients with RA.

Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts

Background A prolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common ‘the-earlier-the-better principle’, or whether a transient time frame in which the disease is more susceptible to treatment exists, referring to a ‘window of opportunity’. To elucidate this, we evaluated the shape of the associations of symptom duration with persistence of RA. Methods Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARD-free sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratified for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). Results 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom duration with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). Conclusions The association between symptom duration and RA persistence is not linear, suggesting the presence of a confined period in which RA is more susceptible to treatment.

Diagnostic value of anti-MCV antibodies in differentiating early inflammatory arthritis

Objectives To evaluates the diagnostic performance of the anti-CCP2, anti-CCP3 and anti-mutated citrullinated vimentin (anti-MCV) tests in differentiating rheumatoid arthritis (RA) from other forms of arthritis in a clinical setting of early arthritis. Methods In 917 patients with recent-onset arthritis (566 RA, 351 other diseases) and in 99 healthy controls the anti-MCV, anti-CCP2 and anti- CCP3.1 tests were performed and the test characteristics compared. Results Comparison of the tests for differentiating RA from other causes of arthritis showed a lower specificity for anti-MCV (82.9%) than for anti-CCP2 (93.4%) and anti-CCP3.1 (90.0%). Similarly, the positive likelihood ratio for anti-MCV was also lower (3.6, compared with 8.7, 5.8 for anti-CCP2 and anti-CCP3.1). The anti-MCV test had a higher sensitivity (62% vs 56.9% and 58.1%, respectively). In psoriatic arthritis, spondyloarthropathy and other arthritis anti-MCV antibodies had a prevalence of 15.2%, 13.9% and 19.4%. Conclusion The diagnostic performance of the anti-MCV test in the differential diagnosis of early arthritis is lower than that of the anti-CCP tests.

Contribution of Fcγ receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA-positive rheumatoid arthritis

Background: Fcγ receptors (FcγRs) are potent immune modulators. FcγR genes encompass a complex region, polymorphic by both single nucleotide polymorphisms (SNPs) and copy number variation (CNV). The heterogeneity of rheumatoid arthritis (RA) combined with the genetic complexity of FcγR genes may be the cause of inconsistent findings in previous RA studies on FcγR SNPs. There is increasing evidence that anti-citrullinated peptide antibody (ACPA)-positive RA and ACPA-negative RA have a different genetic background. Objective: To investigate whether FcγRIIIA 158V/F SNP associates differently with ACPA-positive and ACPA-negative RA and to assess if the FcγRIIIA gene CNV affects the association of the FcγRIIIA 158V/F SNP with RA and whether the FcγRIIIA gene CNV confers risk for RA. Methods: 945 patients with RA and 388 healthy controls, all Dutch-Caucasians, were included in the study. FcγRIIIA 158V/F SNP was genotyped using Sequenom. CNV of the FcγRIIIA gene was determined in 456 patients with RA and 285 controls using multiplex ligation-dependent probe amplification. Associations between genotypes and RA were analysed, stratifying for the presence/absence of ACPA and CNV. Results: In all patients with RA the FcγRIIIA 158V/F SNP was not associated with RA. In ACPA-positive RA (n = 358), the VV genotype was more prevalent in cases than in controls (18.4% vs 13.2%, OR = 1.5, p = 0.05). After stratification for CNV the VV genotype was associated with RA in general (n = 426) (OR = 1.6, 95% CI 0.97 to 2.6, p = 0.05) and with ACPA-positive RA (n = 135) (OR = 2.1, 95% CI 1.2 to 3.8, p = 0.009) but not with ACPA-negative RA. The distribution of CNV was not significantly different between patients with RA and controls. Conclusion: The FcγRIIIA 158 VV genotype confers risk for ACPA-positive RA; this association increased slightly after correction for CNV of the FcγRIIIA gene. CNV itself is not associated with RA susceptibility.

A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

Introduction Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. Methods We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. Results The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. Conclusions Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.

Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study

Background Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. Method 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. Results Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09-fold rate of joint destruction compared to other patients (p=4.0×10−6, p=3.8×10−4, p=5.0×10−3, p=5.0×10−3 and p=9.4×10−3). Discussion Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p<0.001; rs7665842, p<0.001; rs4371699, p=0.01; rs6821171, p=0.01). These SNPs were also significant after correction for multiple testing. Conclusion Genetic variants in IL-15 are associated with progression of joint destruction in RA.

Pretreatment serum levels of anti-cyclic citrullinated peptide antibodies are associated with the response to methotrexate in recent-onset arthritis

To direct individual treatment decisions in recent-onset rheumatoid arthritis (RA), predictors of treatment response to methotrexate (MTX) need to be identified. Disease activity at baseline, gender and genetic polymorphisms have already been found to be associated with the effect of MTX treatment, but the predictive value of autoimmune antibody status remains less clear.1 2 It has been shown, however, that both the presence and level of anti-cyclic citrullinated peptide antibodies (ACPA) are strongly associated with a worse disease course.3 Therefore, we investigated the potential predictive effect of levels of ACPA in ACPA-positive patients for the response to MTX treatment. As observations from our cohort and others indicate that ACPA levels decrease …