Trial designWe present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of... Show moreTrial designWe present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis.MethodsThe study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other's assessments for the duration of the study.ConclusionsThere is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the at risk state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA.Trial registrationCurrent Controlled Trials, ID: ISRCTN46017566. Registered on 4 July 2014. Show less
OBJECTIVES: Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and are present years before onset of symptoms. Avidity of (auto) antibodies can have a... Show moreOBJECTIVES: Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and are present years before onset of symptoms. Avidity of (auto) antibodies can have a strong impact on their effector potency. Here, we analyzed the avidity of ACPA in pre-disease, early-disease and established RA samples as well as avidity maturation in time in samples of healthy subjects that later developed RA. METHODS: We measured ACPA avidity in samples from ACPA-positive healthy individuals, symptomatic individuals and patients with established RA derived from five collections from The Netherlands, Canada and Austria. Furthermore, we determined the dynamics of avidity maturation of ACPA from the stage of pre-disease to established disease in one case from the native North American population and 10 cases from a Dutch blood donor cohort. RESULTS: The overall ACPA response was characterized by low avidity antibodies. Individuals with higher avidity ACPA were confined to symptomatic patients, while low avidity ACPA were observed in both healthy subjects and patients. In longitudinal samples obtained from subjects prior to disease onset, the ACPA avidity increased over time until disease onset. Following onset of disease no further avidity maturation was observed. CONCLUSIONS: Avidity maturation of the ACPA response takes place prior to disease onset. Show less
Broek, M. van den; Klarenbeek, N.B.; Dirven, L.; Schaardenburg, D. van; Hulsmans, H.M.J.; Kerstens, P.J.S.M.; ... ; Allaart, C.F. 2011
Objective To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of... Show moreObjective To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity. Methods In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS = 2.4) for 6 months. Predictors were identified using Cox regression analysis. Results 104 patients discontinued infl iximab, of whom 77 had received infl iximab plus methotrexate as initial treatment. Mean DAS at the time of infl iximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infl iximab, 84% of these patients again achieved a DAS = 2.4. In the multivariable model, smoking, infl iximab treatment duration = 18 months and shared epitope (SE) were independently associated with the re-introduction of infl iximab: 6% of the non-smoking, SE-negative patients treated < 18 months needed infl iximab re-introduction. Conclusion Cessation of infl iximab was successful in 52%, with numerically higher success rates in patients initially treated with infl iximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infl iximab treatment duration and SE were independently associated with re-introduction of infl iximab. Show less
Guler-Yuksel, M.; Allaart, C.F.; Watt, I.; Goekoop-Ruiterman, Y.P.M.; Vries-Bouwstra, J.K. de; Schaardenburg, D. van; ... ; Kloppenburg, M. 2010
OBJECTIVES To investigate the association between systemic and local inflammation and incident and progressive radiographic secondary osteoarthritis (OA) in interphalangeal joints (IPJs) over 3... Show moreOBJECTIVES To investigate the association between systemic and local inflammation and incident and progressive radiographic secondary osteoarthritis (OA) in interphalangeal joints (IPJs) over 3 years in rheumatoid arthritis (RA) patients and the effect of tumor necrosis factor alpha (TNF-α) inhibitor infliximab on secondary OA in IPJs. METHODS In the present observational longitudinal study baseline and 3-year hand X-rays of 416 recent-onset RA patients were scored for osteophytes and erosions in IPJs, blinded for time, using Osteoarthritis Research Society International atlas and Sharp-van der Heijde score. The associations between inflammatory factors and incident and progressive secondary OA in distal IPJs (DIPJs) and proximal IPJs (PIPJs) and the effect of infliximab compared to disease-modifying anti-rheumatic drug treatment on secondary OA were analyzed by multivariable regression and generalised estimating equations analyses. RESULTS Sixty-seven percent of the patients were female with, at baseline, a mean age of 54 years and OA present in DIPJs and PIPJs in 37% and 13%. Three years later, new secondary OA in DIPJs and PIPJs was seen in 11% and 10%, and progressive secondary OA in 36% and 35%. High erythrocyte sedimentation rate over 3 years and progressive erosive damage were risk factors for incident secondary OA in DIPJs, but not in PIPJs. At joint level, progression of erosions was associated with both incident and progressive secondary OA, only in DIPJs. Infliximab treatment was associated with lower incident secondary OA in PIPJs [relative risk 0.5 (95% confidence interval 0.2, 1.0)], independent of decrease in inflammation. CONCLUSION Incident and progressive secondary OA in DIPJs over 3 years was associated with high inflammatory activity in RA. Infliximab treatment reduced incident secondary OA in PIPJs independent of decrease in inflammation, suggesting that anti-TNF-α therapy might be effective against secondary hand OA via other pathways than suppression of inflammation. Further studies in populations of primary hand OA are necessary to determine the role of anti-TNF-α in treatment of primary hand OA. Show less
