Rachel Knevel

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

Long-Term Impact of Delay in Assessment of Patients With Early Arthritis

OBJECTIVE During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD-free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed. METHODS A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined. RESULTS The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C-reactive protein, and the presence of autoantibodies were associated with longer total delay. CONCLUSION Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD-free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA.

Predicting arthritis outcomes—what can be learned from the Leiden Early Arthritis Clinic?

OBJECTIVES In order to allow personalized medicine, adequate prediction of disease outcome is required. In early undifferentiated arthritis (UA), prediction of the development of RA is crucial, and in case of RA predicting the severity of the disease course may guide individualized treatment decisions. METHODS A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfillment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. RESULTS Predictive factors for fulfillment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P<0.001); male gender (P<0.001); longer symptom duration at first visit (P=0.048), involvement of lower extremities (P<0.001); BMI (P<0.001); high acute phase reactants, presence of IgM-RF (P<0.001); anti-CCP2 antibodies (P<0.001); anti-modified citrullinated vimentin antibodies (P<0.001) and HLA-DRB1 shared epitope alleles (P=0.001). A high BMI was associated with a lower rate of joint destruction but with a higher risk of disease persistence. The proportion of variance in joint destruction explained was 32% CONCLUSION Predictors for RA development, previously used to develop a prediction rule in UA patients, are largely similar to predictors for arthritis persistency. Only part of the joint destruction level in RA is explained by the currently known risk factors. New factors need to be identified in order to guide pharmaceutical intervention at the level of individual RA patients.

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.

Extended report: Evidence for treating rheumatoid arthritis to target: results of a systematic literature search

Objectives To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment. Methods We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008). Results The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach. Conclusion Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.

Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis

Objectives To perform a systematic literature review of effective strategies for the treatment of rheumatoid arthritis (RA). Methods As part of a European League Against Rheumatism (EULAR) Task Force investigation, a literature search was carried out from January 1962 until February 2009 in PubMed/Ovid Embase/Cochrane and EULAR/American College of Rheumatism (ACR)) abstracts (2007/2008) for studies with a treatment strategy adjusted to target a predefined outcome. Articles were systematically reviewed and clinical outcome, physical function and structural damage were compared between intensive and less intensive strategies. The results were evaluated by an expert panel to consolidate evidence on treatment strategies in RA. Results The search identified two different kinds of treatment strategies: strategies in which the reason for treatment adjustment differed between the study arms (‘steering strategies’, n=13) and strategies in which all trial arms used the same clinical outcome to adjust treatment with different pharmacological treatments (‘medication strategies’, n=7). Both intensive steering strategies and intensive medication strategies resulted in better outcome than less intensive strategies in patients with early active RA. Conclusion Intensive steering strategies and intensive medication strategies produce a better clinical outcome, improved physical function and less structural damage than conventional steering or treatment. Proof in favour of any steering method is lacking and the best medication sequence is still not known.

Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity

Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts.

A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

IntroductionThe severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.MethodsIn total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.ResultsNo associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.ConclusionVariants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

Baseline Serum Adipokine Levels Predict Radiographic Progression in Early Rheumatoid Arthritis

OBJECTIVE Adipose tissue can secrete soluble mediators (adipokines) with potent immune regulatory functions. Some adipokines have been previously associated with radiographic damage in patients with rheumatoid arthritis (RA). In the present study, we investigated the capacity of baseline adipokine levels to predict radiographic progression over a period of 4 years and studied their contribution relative to that of other known risk factors, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies. METHODS Serum concentrations of leptin, visfatin, resistin, adiponectin, adipsin, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) were determined in serum samples obtained at baseline from 253 patients with RA from the Early Arthritis Cohort. The association between levels of these adipokines and radiographic progression was determined using a multivariate normal regression model correcting for age, sex, treatment strategy, body mass index (BMI), and the presence of anti-CCP antibodies. RESULTS Levels of IL-6, TNFα, visfatin, and adiponectin were positively associated with radiographic progression over 4 years. This association was independent of BMI. However, only adiponectin levels remained significantly associated with radiographic progression when the model was corrected for the presence of anti-CCP antibodies, whereas a trend was observed for IL-6. The association of both TNFα and visfatin with radiographic damage disappeared after correction for the presence of anti-CCP antibodies, which is consistent with the fact that the levels of both cytokines correlated significantly with anti-CCP antibody levels in these patients. CONCLUSION Our results indicate that adipokines are predictors of radiographic progression in RA, possibly through distinct underlying biologic mechanisms.

EULAR definition of erosive disease in light of the 2010 ACR/EULAR rheumatoid arthritis classification criteria

The aim of this report was to propose a definition for erosive disease in the context of inflammatory arthritis in light of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria for use in clinical practice and studies. A EULAR task force was formed including 16 rheumatologists and one rheumatology fellow. The process was both evidence based and consensus based, and included, between March 2010 and April 2012, analyses of data from two cohorts, two face-to-face meetings, one online voting and one teleconference. The Leiden Early Arthritis Cohort and the French ESPOIR cohort were used for the evidence-based part. The outcome measures, which were initiation of methotrexate therapy, or any disease-modifying antirheumatic drug therapy within the first year of disease and arthritis persistency over 5 years, were studied with the aim to give the best definition of erosive disease. A decision was made to select a definition with a high specificity and focus on patients who did not otherwise fulfil the 2010 ACR/EULAR RA criteria (<6 points). By a unanimous vote the following definition was selected: erosive disease for use in the 2010 ACR/EULAR RA classification criteria is defined when an erosion (defined as a cortical break) is seen in at least three separate joints at any of the following sites: the proximal interphalangeal, the metacarpophalangeal, the wrist (counted as one joint) and the metatarsophalangeal joints on radiographs of both hands and feet. A highly specific definition for erosive disease has thus been formulated.