Dirkjan van Schaardenburg

EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix ‘pre-RA with:’ could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.

The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept

Objective The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a second TNF inhibitor will be effective. Methods This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab (‘switchers’), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28). Results After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1±1.3 vs ΔDAS28=2.0±1.3; p=0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28=1.2±1.3 vs ΔDAS28=2.1±1.3; p=0.001) and switchers with antibodies (ΔDAS28=1.2±1.3 vs ΔDAS28=2.0±1.3; p=0.017). Conclusion Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.

Development of the anti–citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis

OBJECTIVE To examine how anti-citrullinated protein antibody (ACPA) epitope spreading takes place prior to the onset of clinical rheumatoid arthritis (RA), and to analyze the pattern of autoantigen reactivity at the beginning of the immune response. METHODS Multiple consecutive serum samples from 79 RA patients who had donated blood before disease onset were available for analysis. Fifty-three patients tested positive for ACPAs prior to the onset of clinical RA. For these patients, a median of 6 (interquartile range 4-9) sequential pre-RA serum samples obtained 1-2 years apart were tested. Reactivity to 5 distinct citrullinated peptides was measured by enzyme-linked immunosorbent assay. Two peptides were derived from fibrinogen, 1 from vimentin, 1 from α-enolase, and 1 from filaggrin. RESULTS In 25 of 53 ACPA-positive patients, seroconversion from ACPA absence to ACPA presence was observed. In 72% of these patients, the immune response started with reactivity to 1 peptide, without preference for a particular peptide. The number of peptides recognized increased over time, without a dominant epitope-spreading pattern. ACPAs appeared in low levels several years prior to the diagnosis of RA. Antibody titers increased markedly ∼2-4 years before diagnosis. CONCLUSION Our findings indicate that ACPA epitope spreading occurs over several years prior to the onset of clinical RA. The initial autoimmune response is mostly directed toward only 1 autoantigen, but this is not always the same antigen. The marked increase in ACPA titers a few years prior to the diagnosis of RA suggests a second stage in disease development, which might be due to a variety of factors.

The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia

Objectives To determine the fine specificity of anti-citrullinated protein antibodies (ACPA) in the early phase of arthritis development, the ACPA repertoire in arthralgia patients and the association with arthritis development were studied. Methods A total of 244 patients with arthralgia positive for anti-cyclic citrullinated peptide antibodies (aCCPs) and/or IgM rheumatoid factor (IgM-RF), without arthritis were included. Development of arthritis was defined as presence of one or more swollen joints at clinical examination during follow-up. Sera were tested at baseline for reactivity to five citrullinated peptides derived from fibrinogen (three), vimentin (one) and α-enolase (one) and five corresponding arginine peptides in an ELISA. Results In all, 69 patients (28%) developed arthritis in a median of 3 joints after a median follow-up of 11 (IQR 5–20) months. Reactivity to each peptide was significantly associated with arthritis development (p<0.001). The ACPA repertoire did not differ between patients who did or did not develop arthritis. Among aCCP-positive patients, patients recognising two or more additional citrullinated peptides developed arthritis more often (p=0.04). The number of recognised peptides was positively associated with the aCCP level (p<0.001). Crossreactivity between different peptides was minimal. Conclusions Arthritis development is not associated with recognition of a specific citrullinated peptide once joint complaints are present. The ACPA repertoire in some patients with arthralgia is expanded. High aCCP levels are associated with a qualitatively broad ACPA repertoire. Patients with an extended ACPA repertoire have a higher risk of developing arthritis.

Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis

Objective The presence of anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) years before the clinical diagnosis of rheumatoid arthritis (RA) suggests they are possibly involved in the pathogenic process underlying RA. In this study, we analysed whether anti-carbamylated protein (anti-CarP) antibodies, a novel autoantibody system against carbamylated proteins, can also be detected in healthy individuals before they developed RA. Methods Multiple sera from asymptomatic blood donors prior to the onset of their RA symptoms and sera from age-matched and sex-matched controls were tested for the presence of antibodies directed against carbamylated-fetal calf serum (Ca-FCS), carbamylated-fibrinogen (Ca-Fib), cyclic citrullinated-peptide 2 and IgM-RF. Results Anti-Ca-FCS and anti-Ca-Fib antibodies were each present in 27% and 38% of the last serum samples of blood donors prior to the diagnosis of RA. Both anti-Ca-FCS and anti-Ca-Fib antibodies could be detected many years before the onset of RA. Anti-CarP antibodies as well as ACPA are, on average, detected earlier than IgM-RF. Conclusions In addition to ACPA and IgM-RF, also the newly identified anti-CarP antibodies appear many years before the diagnosis of RA.

A prediction rule for the development of arthritis in seropositive arthralgia patients

Objective To predict the development of arthritis in anticyclic citrullinated peptide antibodies and/or IgM rheumatoid factor positive (seropositive) arthralgia patients. Methods A prediction rule was developed using a prospective cohort of 374 seropositive arthralgia patients, followed for the development of arthritis. The model was created with backward stepwise Cox regression with 18 variables. Results 131 patients (35%) developed arthritis after a median of 12 months. The prediction model consisted of nine variables: Rheumatoid Arthritis in a first degree family member, alcohol non-use, duration of symptoms <12 months, presence of intermittent symptoms, arthralgia in upper and lower extremities, visual analogue scale pain ≥50, presence of morning stiffness ≥1 h, history of swollen joints as reported by the patient and antibody status. A simplified prediction rule was made ranging from 0 to 13 points. The area under the curve value (95% CI) of this prediction rule was 0.82 (0.75–0.89) after 5 years. Harrells C (95% CI) was 0.78 (0.73–0.84). Patients could be categorised in three risk groups: low (0–4 points), intermediate (5–6 points) and high risk (7–13 points). With the low risk group as a reference, the intermediate risk group had a hazard ratio (HR; 95% CI) of 4.52 (2.42–8.77) and the high risk group had a HR of 14.86 (8.40–28.32). Conclusions In patients presenting with seropositive arthralgia, the risk of developing arthritis can be predicted. The prediction rule that was made in this patient group can help (1) to inform patients and (2) to select high-risk patients for intervention studies before clinical arthritis occurs.

Antibodies to mutated citrullinated vimentin and disease activity score in early arthritis: a cohort study

IntroductionThe aim of our study was to investigate the association between arthritic disease activity and antibodies to mutated citrullinated vimentin (anti-MCV), because such a relation has been suggested.MethodsAnti-MCV levels were measured in 162 patients with early arthritis (123 with rheumatoid arthritis and 39 with undifferentiated arthritis) at baseline and at 1 and 2 years of follow up. Disease activity was measured using the disease activity score (Disease Activity Score based on 28 joints [DAS28]) and serum C-reactive protein. General estimation equation analysis was used to assess the relation between anti-MCV levels and DAS28 over time.ResultsBoth, anti-MCV levels and DAS28 exhibited a significant decrease during the first and second year. However, the association between anti-MCV levels and DAS28, adjusted for dependency on sequential measurements within one individual, was very low (β = 0.00075). In a population of patients with rheumatoid arthritis or undifferentiated arthritis, anti-MCV had a specificity of 92.3% and a sensitivity of 59.3% when using the recommended cut-off of 20 U/ml. Specificity and sensitivity of antibodies against second-generation cyclic citrullinated peptide, using the recommended cut-off value of 25 U/ml, were 92.1% and 55.3%, respectively. Anti-MCV-positive early arthritis patients had significantly higher Sharp-van der Heijde score, erythrocyte sedimentation rate and C-reactive protein levels than did anti-MCV-negative patients at all time points (P < 0.005), but DAS28 was higher in anti-MCV-positive patients at 2 years of follow up only (P < 0.05).ConclusionBecause the correlation between anti-MCV levels and parameters of disease activity was very low, we conclude that it is not useful to monitor disease activity with anti-MCV levels.

Smoking and overweight determine the likelihood of developing rheumatoid arthritis

Objectives Rheumatoid arthritis (RA) is a prototypic chronic inflammatory disease with a debilitating course if untreated. A genetic predisposition for RA is known, and its occurrence is associated with the presence of autoantibodies in the serum and with environmental factors. It is unknown if smoking and overweight are contributory factors for developing RA in individuals with RA-specific autoantibodies in the serum. Methods Fifty-five individuals at risk for developing RA, based on the presence of RA-specific autoantibodies in the serum, who never had any evidence of arthritis upon physical examination, were followed over time. Smoking was assessed as being never or ever smoker and body mass index as <25 (normal) or ≥25 kg/m2 (overweight). Clinical endpoint was the occurrence of arthritis. Proportional hazard regression analysis was performed to investigate the potential of (combinations of) variables in predicting the onset of arthritis over time. Results After a median follow up time of 13 (IQR 6–27) months, 15 individuals (27%) developed arthritis. Smoking was associated with the development of arthritis (HR (95% CI): 9.6 (1.3 to 73.0); p=0.029). Overweight was, independently of smoking, associated with arthritis (HR (95% CI): 5.6 (1.3 to 25.0); p=0.023). The overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight. Conclusions This is the first prospective study showing that smoking and overweight increase the risk of development of arthritis in a cohort of autoantibody-positive individuals at risk for developing RA. These results show the importance of life style factors in development of RA and should be critically evaluated in future clinical research aimed at disease prevention.

Prognosis of limitations in activities in osteoarthritis of the hip or knee: a 3-year cohort study

UNLABELLED van Dijk GM, Veenhof C, Spreeuwenberg P, Coene N, Burger BJ, van Schaardenburg D, van den Ende CH, Lankhorst GJ, Dekker J, on behalf of the CARPA Study Group. Prognosis of limitations in activities in osteoarthritis of the hip or knee: a 3-year cohort study. OBJECTIVE To describe the course of limitations in activities in elderly patients with osteoarthritis (OA) of the hip or knee over a follow-up period of 3 years, and to identify prognostic factors of the course of limitations in activities, focusing on body functions, comorbidity, and cognitive functioning. DESIGN A longitudinal cohort study with 3 years of follow-up. Measurements were conducted annually. Statistical analyses included t tests, univariate regression analyses, and multivariate regression analyses. SETTING Rehabilitation centers and hospitals (Departments of Orthopedics, Rheumatology, and Rehabilitation) in The Netherlands. PARTICIPANTS Patients (N=237) with hip or knee OA. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Patient-perceived change, self-reported limitations in activities measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and observed limitations in activities (timed walking test). Prognostic factors: demographic data, clinical data, body function (pain, muscle strength, range of motion [ROM]), comorbidity, and cognitive functioning (cognitive decline, memory, attention). RESULTS Self-reported limitations in activities measured by the WOMAC improved slightly after 3-year follow-up. In knee OA, reduced ROM at 1-year follow-up (beta=.120), increased pain at 1-year follow-up (beta=-.177), and higher morbidity count (beta=-.180) predicted worsening of self-reported limitations in activities. In hip OA, reduced ROM at 1-year follow-up (beta=.201 for hip external rotation and beta=.144 for knee extension), increased pain at 1-year follow-up (beta=-.134), higher morbidity count (beta=-.220), or the presence of moderate to severe cardiac disease (beta=-.214) and poorer cognitive functioning (beta=.181) predicted worsening of self-reported limitations in activities. Performance-based limitations in activities measured by the timed walking test did not change after 3 years of follow-up. In knee OA, decreased muscle strength at 1-year follow-up (beta=-.272) and higher morbidity count (beta=.199) predicted worsening of performance-based limitations in activities. In hip OA, better ROM (beta=.182), higher morbidity count (beta=.232), or the presence of moderate to severe cardiac and eye-ear-nose-throat disease (beta=.210 and beta=.188, respectively) and older age (beta=.355) predicted worsening of performance-based limitations in activities. CONCLUSIONS Overall, at the group level, limitations in activities of patients with OA of the hip or knee recruited from hospitals and rehabilitation centers seem fairly stable during the first 3 years of follow-up. However, at the level of individual patients, considerable variation occurs. Prognostic factors for worsening of limitations in activities include increased pain, reduced ROM, and decreased muscle strength at 1-year follow-up; higher morbidity count; and to a lesser extent poor cognitive functioning.

Brief Report: Anti–Carbamylated Protein Antibodies Are Present in Arthralgia Patients and Predict the Development of Rheumatoid Arthritis

OBJECTIVE Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti-carbamylated protein (anti-CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti-CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA. METHODS Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM-RF) and/or anti-cyclic citrullinated peptide 2 (anti-CCP-2) and 32 healthy controls were tested for anti-CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM-RF positive/anti-CCP-2 antibody negative and 229 were anti-CCP-2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti-CarP antibodies and those who were negative for anti-CarP antibodies during followup. RESULTS Anti-CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6-24). The presence of anti-CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti-CCP-2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06-2.29], P=0.023), as well as in the anti-CCP-2 antibody-positive subgroup (odds ratio 2.231 [95% confidence interval 1.31-3.79], P=0.003). CONCLUSION Anti-CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti-CCP-2 antibodies.