Monika Ronneberger

Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study

Objective To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial. Methods Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months. Results In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003). Conclusions This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA. Trial registration number 2009-015740-42.

Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade

Adult-onset Stills disease (AOSD) is a systemic inflammatory disorder of unknown aetiology.1 Based on the substantial acute phase responses observed in AOSD, we hypothesised that blockade of the interleukin 6R (IL-6R), neutralising the induction of the acute phase response by IL-6, could be a useful treatment in multidrug-resistant AOSD. We here report on three patients with AOSD who were refractory to standard treatment and cytokine blockade with anakinra and tumour necrosis factor (TNF) blockers and were subjected to treatment with tocilizumab. The characteristics of these three patients are summarised in table 1. View this table: Table 1 Characteristics of patients A 19-year-old woman was first diagnosed with AOSD in July 2006. Prednisone therapy was started, but multiple relapses occurred during the following 2 years requiring …

Standardization of joint examination technique leads to a significant decrease in variability among different examiners.

Objective. To reduce the amount of variability among assessors, we conducted joint examination standardization seminars in conjunction with multicenter clinical trials for patients with rheumatoid arthritis (RA). The examination techniques used were based on the recommendations of the European League Against Rheumatism (EULAR). Methods. To evaluate the effect of standardization, participants at the seminars examined a given patient with RA before and after they were made familiar with the EULAR examination technique. The number of tender and swollen joints as well as the variance among the examiners before and after the training were compared. Joints were rated positive or negative for tenderness and swelling without grading. Results. Overall, 553 individuals from a variety of countries in Europe, North America, Asia, and Australia participated. Examiners included different kinds of health professionals, mainly physicians and nurses. We found a substantial variance among examiners before the training in the standardized method. This variance could be significantly reduced by the training. We also found that the number of joints considered active was markedly reduced after the training. Conclusion. Standardized joint examination training significantly reduces variability among different assessors.

Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment

Objective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1–100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA−/ACPA−, moderate in patients who were MBDA+/ACPA− (33.3%) and MBDA−ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. Trial registration number EudraCT 2009-015740-42.

Can MRI substitute for biopsy in eosinophilic fasciitis

In the April 2008 issue of Annals of the Rheumatic Diseases , Dybowski et al reported a patient with eosinophilic fasciitis (EF), for whom ultrasound and MRI provided seminal findings in the diagnostic procedure, whereas laboratory tests could not sufficiently confirm the diagnosis.1 Here, we report two cases where MRI generated results equal or even superior to biopsy. Patient 1 was a 35-year-old woman with severe pain and symmetric swelling of lower legs and forearms. In addition to 3 months of increasing tenderness in those areas, she had general myalgias and morning stiffness in the wrists and ankles of short duration. Clinical examination revealed the typical “groove sign”, characterised by marked retractions of the subcutaneous tissue above the superficial veins upon elevation of the limbs (fig 1A). Forearms and lower legs …

Measuring joint involvement in polyarticular psoriatic arthritis: An introduction of alternatives†

To compare the reliability of 3 different simplified joint counts with the gold standard 66 swollen/68 tender joint count (JC66/68) for assessing clinical response in patients with polyarticular psoriatic arthritis (PsA).

Pathophysiology of Spondyloarthritis

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation in the spine and entheses. The disease is the result of a complex interplay among susceptibility genes, microbial triggers, inflammation of bone marrow, and the enthesial structures and new bone formation. This article gives a conceptual overview of the major insights into the pathophysiology of SpA and discusses the main genes associated with SpA, as well as other factors that are involved in the onset of inflammation. It also addresses the nature of inflammation in SpA and the mechanisms of ankylosis.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs

Objective To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. Methods Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0–1/10, 2–5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0–3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. Results Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0–1/10 reactivities) to 34% (2–5/10) and 55% (>5/10). With respect to specificity groups (0–3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. Conclusions The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. Trial registration number 2009-015740-42; Results.

Use of the 28-Joint Count Yields Significantly Higher Concordance Between Different Examiners Than the 66/68-Joint Count

Objective. Joint counts are the key outcome measure in rheumatoid arthritis (RA). There is a great variability between different assessors of the same patient; this variability can be reduced by standardized training. The training effect is far less pronounced for the 66/68-joint count compared to the 28-joint count. We evaluated the reason for the higher interrater disagreement in the 66/68 compared to the 28-joint count. Methods. Participants in joint examination seminars evaluated a patient with RA before and after training in the European League Against Rheumatism technique. Joints were rated positive or negative for tenderness and swelling. The number of positive joints and the variability between examiners before and after the training were compared. Concordance was calculated for every single joint using the Fleiss-Kappa test. Results. In total, 256 health professionals were instructed in the 66/68-joint count and 84 in the 28-joint count. The disagreement between examiners was higher for swelling than for tenderness. After the training, there was a significant reduction of interrater variability, which was more pronounced in the 28 than in the 66/68-joint count. Comparisons between joint counts revealed that the joints of the feet were more likely to be rated negative, yet interrater disagreement was still high. Conclusion. Standardization of joint examination significantly reduces variability between assessors. The better performance of the 28-joint count is due to the lower number of joints examined, especially the foot joints, which remain difficult to assess reliably even after training.

FRI0098 Elevated multi-biomarker disease activity (MBDA) predicts relapses in ra patients in sustained remission tapering tumour necrosis factor inhibitor therapy- results from the randomized controlled retro study

Background Tumor necrosis factor inhibitors (TNFi) are the most frequently used bDMARDs in RA patients. TNFi induces remission in a substantial numbers of patients. Once remission, particularly sustained remission is achieved the question arises whether TNFi can be successfully tapered. To date biomarkers, which can help to predict if TNFi can be tapered or stopped, remain to be developed. Objectives To test whether residual subclinical inflammation assessed by multi-biomarker disease activity (MBDA) predicts the risk of disease relapse after tapering or stopping TNFi treatment in RA patients in sustained remission. Methods Sub-analysis of TNFi treated patients of the RETRO study, a randomized-controlled study in RA patients in sustained (>6 month) DAS28 remission comparing 3 different DMARD treatment strategies (continuation of full dose, 50% dose tapering, stopping after 50% dose tapering). Patients were followed over one year for the occurrence of relapses as defined by leaving DAS28-ESR remission (>2.6 units) (1). Vectra-DA tests were done in the baseline samples of all patients included into the RETRO study. MBDA score was calculated according to previously defined algorithms with low MDBA score defined as <30 units and moderate to high scores as ≥30 units (2). Results Of the 151 patients included in the RETRO study, 42 received TNFi treatment (mean age: 56 ys, 25 (60%) females, 78% concomitant csDMARDs; 69% ACPA/RF positive. Baseline demographic and disease specific characteristics of these patients were comparable to the non-TNFi treated patients of the RETRO study. 26/42 patients (62%) had low MBDA scores at baseline, while 16/42 (38%) had moderate/high scores. Relapse rates were significantly (chi square p=0.016) lower in RA patients with low MBDA scores (N=8 of 26; 31%) than in those with moderate/high scores (N=11 of 16; 69%) (Figure; left graph). When separately analyzing only patients tapering TNFi (N=29), relapse rates were moderate in RA patients with low MBDA scores (N=6 of 16; 37%) but high in those with moderate/high scores (N=10 of 13; 77%) (chi square p=0.015) (Figure; right graph). Conclusions These data show that the majority of RA patients in sustained clinical remission with low MBDA scores can successfully taper TNFi. In contrast tapering cannot be recommended in patients with moderate to high MBDA scores, as relapse rates are high in these patients. References Haschka J et al. Ann Rheum Dis 2016,75;45–51. Curtis JR et al. Arthritis Care Res 2012;64:1794–803. Disclosure of Interest None declared