German Rheumatism Research Center

Berlin, Germany

German Rheumatism Research Center

Berlin, Germany
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Song I.-H.,Charité - Medical University of Berlin | Rudwaleit M.,Charité - Medical University of Berlin | Listing J.,German Rheumatism Research Center | Appel H.,Charité - Medical University of Berlin | Sieper J.,Charité - Medical University of Berlin
Arthritis and Rheumatism | Year: 2010

Objective. Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor α (TNFα) blockers either had not been tried or had failed. Methods. In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). Results. Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BAS-DAI) score ≥4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). Conclusion. Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future. © 2010, American College of Rheumatology.


Song I.-H.,Charité - Medical University of Berlin | Rudwaleit M.,Charité - Medical University of Berlin | Haibel H.,Charité - Medical University of Berlin | Weiss A.,German Rheumatism Research Center | Sieper J.,Charité - Medical University of Berlin
Annals of the Rheumatic Diseases | Year: 2011

Objective To prospectively explore the short-term efficacy and safety of abatacept in patients with ankylosing spondylitis (AS). Methods In this prospective open-label pilot study, abatacept (10 mg/kg) was administered intravenously on days 1, 15, 29 and every 28 days thereafter up to week 24 in 15 tumour necrosis factor a (TNFa)-inhibitor naive patients (group 1) and 15 patients with inadequate response to TNFa inhibitors (group 2) with active AS. The primary end point was the proportion of patients with 40% improvement according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) in both groups at week 24. Results At week 24, ASAS40 was reached by 13% of group 1 and 0% of group 2; 20% improvement (ASAS20) was reached by 27% and 20%, respectively. There was no significant change of Bath Ankylosing Spondylitis Disease Activity Index score, patient global assessment or C reactive protein. Overall, abatacept was well tolerated. Conclusions In this pilot open-label AS study a major response was not observed.


Haibel H.,Campus Benjamin Franklin Hospital | Listing J.,German Rheumatism Research Center | Callhoff J.,German Rheumatism Research Center | Sieper J.,Campus Benjamin Franklin Hospital | Sieper J.,German Rheumatism Research Center
Annals of the Rheumatic Diseases | Year: 2014

Background The efficacy of oral prednisolone in patients with active ankylosing spondylitis (AS) has not been studied to date. Methods In this double-blind, randomised, placebo-controlled trial, patients with AS with active disease despite taking non-steroidal antirheumatic drugs were randomised to three groups in which they were either treated with 20 mg (n=13) or 50 mg (n=12) of prednisolone, or placebo (n=14), administered orally every day for a total of 2 weeks. The primary endpoint was defined as a 50% improvement of the Bath AS Disease Activity Index (BASDAI) at week 2. Results The primary endpoint was reached in 33% and 27% of the patients treated with 50 and 20 mg of prednisolone, respectively, versus only 8% on placebo (p=0.16 and p=0.30). However, the mean improvement of BASDAI score was significantly higher in the 50 mg prednisolone compared to the placebo group (2.39±0.5 vs 0.66±0.49, p=0.03), while there was only a small change in the 20 mg group (1.19±0.53; p=0.41). The results for other outcome parameters were similar. Conclusions Oral prednisolone 50 mg per day, but not low dose prednisolone, showed a short-term response that was significantly higher than placebo. The clinical significance and the duration of this effect warrant further study.


Poddubnyy D.,Charite Campus Benjamin Franklin | Rudwaleit M.,Evangelisches Krankenhaus Hagen Haspe | Haibel H.,Charite Campus Benjamin Franklin | Listing J.,German Rheumatism Research Center | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To assess the progression of radiographic sacroiliitis in a cohort of patients with early axial spondyloarthritis over a period of 2 years and to explore predictors of progression. Methods: 210 patients with axial spondyloarthritis from the German Spondyloarthritis Inception Cohort have been selected for this analysis based on availability of radiographs at baseline and after 2 years of follow-up. Radiographs were centrally digitised and the sacroiliac joints were scored independently according to the grading system of the modified New York criteria for ankylosing spondylitis (AS) by two trained readers. The readers scored both time points simultaneously but were blinded for the time point and for all clinical data. Results: 115 patients (54.8%) fulfilled the modified New York criteria for AS in their radiographic part in the opinion of both readers at baseline, while 95 patients (45.2%) were classified as non-radiographic axial spondyloarthritis. More patients with non-radiographic spondyloarthritis (10.5%) compared with AS (4.4%) showed an estimated 'true' progression by at least one grade according to both readers, although the difference between the two groups was statistically non-significant. The rate of progression from non-radiographic axial spondyloarthritis to AS was 11.6% over 2 years. An elevated level of C-reactive protein (CRP) at baseline was a strong positive predictor of radiographic sacroiliitis progression in non-radiographic axial spondyloarthritis and AS (OR 3.65 and 5.08, respectively, p<0.05). Conclusion: Progression of radiographic sacroiliitis by at least one grade after 2 years occurs only in a small percentage of patients with early axial spondyloarthritis. An elevated level of CRP was found to be a strong positive predictor of sacroiliitis progression.


Poddubnyy D.,Charité - Medical University of Berlin | Rudwaleit M.,Endokrinologikum | Haibel H.,Charité - Medical University of Berlin | Listing J.,German Rheumatism Research Center | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objective: To investigate the influence of non-steroidal anti-inflammatory drugs (NSAIDs) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (SpA). Methods: 164 patients with axial SpA (88 with AS and 76 with non-radiographic axial SpA) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake. Spinal radiographs were scored by two trained readers in a concealed randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system. An index of the NSAID intake counting both dose and duration of drug intake was calculated. Results: High NSAIDs intake (NSAID index≥50) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units: OR=0.15, 95% CI 0.02 to 0.96, p=0.045 (adjusted for baseline structural damage, elevated C reactive protein (CRP) and smoking status) in comparison with patients with low NSAIDs intake (NSAID index<50). This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP: mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake, p=0.02. In non-radiographic axial SpA, no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found. Conclusion: A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS. In non-radiographic axial SpA this effect is less evident, probably due to a low grade of new bone formation in the spine at this stage..


Mei H.E.,German Rheumatism Research Center | Mei H.E.,Charité - Medical University of Berlin | Schmidt S.,German Rheumatism Research Center | Schmidt S.,Charité - Medical University of Berlin | And 2 more authors.
Arthritis Research and Therapy | Year: 2012

Anti-CD20 therapy using rituximab directly targeting B cells has been approved for treatment of non-Hodgkin lymphoma, rheumatoid arthritis and anti-neutrophil cytoplasmic antibody-associated vasculitides and has led to reappreciation of B-lineage cells for anti-rheumatic treatment strategies. Moreover, blocking B-cell activating factor with belimumab, a drug that is licensed for treatment of active, seropositive systemic lupus erythematosus (SLE), represents an alternative, indirect anti-B-cell approach interfering with proper B-cell development. While these approaches apparently have no substantial impact on antibody-secreting plasma cells, challenges to improve the treatment of difficult-to-treat patients with SLE remain. In this context, anti-CD19 antibodies have the promise to directly target autoantibody-secreting plasmablasts and plasma cells as well as early B-cell differentiation stages not covered by anti-CD20 therapy. Currently known distinct expression profiles of CD19 by human plasma cell subsets, experiences with anti-CD19 therapies in malignant conditions as well as the rationale of targeting autoreactive plasma cells in patients with SLE are discussed in this review. © 2012 BioMed Central Ltd.


Poddubnyy D.,Charité - Medical University of Berlin | Haibel H.,Charité - Medical University of Berlin | Listing J.,German Rheumatism Research Center | Marker-Hermann E.,Horst Schmidt Kliniken | And 4 more authors.
Arthritis and Rheumatism | Year: 2012

Objective To assess prospectively the rates and to explore predictors of spinal radiographic progression over 2 years in a cohort of patients with early axial spondylarthritis (SpA). Methods Two hundred ten patients with axial SpA from the German Spondyloarthritis Inception Cohort were selected for this analysis based on the availability of radiographs at baseline and after 2 years of followup. Spinal radiographs were scored by 2 trained readers in a blinded, randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Spinal radiographic progression was defined as worsening of the mean mSASSS by ≥2 units over 2 years. Results Among the patients with axial SpA, 14.3% showed spinal radiographic progression after 2 years (20% of those with AS and 7.4% of those with nonradiographic axial SpA). The following parameters were independently associated with spinal radiographic progression: presence of syndesmophytes at baseline (odds ratio [OR] 6.29, P < 0.001), elevated levels of markers of systemic inflammation (for the erythrocyte sedimentation rate, OR 4.04, P = 0.001; for C-reactive protein level time-averaged over 2 years, OR 3.81, P = 0.001), and cigarette smoking (OR 2.75, P = 0.012). These associations were confirmed by multivariate logistic regression analysis. No clear association with spinal radiographic progression was observed for HLA-B27 status, sex, age, disease duration, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, presence of peripheral arthritis, enthesitis, psoriasis, treatment with nonsteroidal antiinflammatory drugs, or treatment with disease-modifying antirheumatic drugs at baseline. Conclusion The presence of radiographic damage at baseline (syndesmophytes), elevated levels of acute-phase reactants, and cigarette smoking were all independently associated with spinal radiographic progression in patients with early axial SpA. Copyright © 2012 by the American College of Rheumatology.


Poddubnyy D.,Charité - Medical University of Berlin | Hermann K.-G.A.,Charité - Medical University of Berlin | Callhoff J.,German Rheumatism Research Center | Listing J.,German Rheumatism Research Center | Sieper J.,Charité - Medical University of Berlin
Annals of the Rheumatic Diseases | Year: 2014

Objective To evaluate efficacy and safety of ustekinumab in patients with ankylosing spondylitis (AS). Methods In this prospective, open-label, single-arm, proof-of-concept clinical trial (ClinicalTrials.gov identifier NCT01330901), ustekinumab in a dose of 90 mg was administered subcutaneously at baseline, week 4 and week 16 in 20 patients with active AS. Eligible patients were required to have a diagnosis of AS according to the modified New York criteria and an active disease defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4 despite previous non-steroidal anti-inflammatory drug (NSAID) treatment. The primary study endpoint was the proportion of patients reached the Assessment of SpondyloArthritis International Society 40 (ASAS40) response at week 24. Results At week 24, ASAS40 response was reached by 65% of the patients. ASAS20, ASAS5/6 and ASAS partial remission were observed in 75%, 50% and 30% of the patients, respectively. A ≥50% improvement of the BASDAI (BASDAI50) occurred in 55% of the patients. A total of 50% and 20% of the patients achieved the AS Disease Activity Score (ASDAS) clinically important improvement and major improvement, respectively. At week 24, 35% of the patients had an ASDAS inactive disease (ASDAS <1.3). Significant improvement of other patient-reported outcome parameters and active inflammation as detected by MRIas well as significant reduction of NSAIDs intake occurred during the treatment. Clinical response correlated with reduction of active inflammation on MRI and of serum C reactive protein level. Overall, ustekinumab was well tolerated. Conclusions In this prospective, open-label, proof-ofconcept clinical trial, ustekinumab treatment was associated with a reduction of signs and symptoms in active AS and was well tolerated.


Poddubnyy D.A.,Charite Campus Benjamin Franklin | Rudwaleit M.,Charite Campus Benjamin Franklin | Listing J.,German Rheumatism Research Center | Braun J.,Ruhr University Bochum | Sieper J.,Charite Campus Benjamin Franklin
Annals of the Rheumatic Diseases | Year: 2010

Objective: This study was aimed at comparing high sensitivity C reactive protein (hsCRP) measurement with routine C reactive protein (CRP) evaluation as disease activity parameters in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nrSpA). Methods: A total of 269 patients (153 with AS and 116 with nrSpA) were included. Level of hsCRP was measured using particle-enhanced immunoturbidimetric method with the lowest detected level of 0.1 mg/litre. The hsCRP values were compared to results of routine turbidimetric CRP test with the lowest detected level of 6 mg/litre. Results: In the whole group of patients with AS, hsCRP showed a better than routine CRP correlation with clinical parameters. In the whole group of patients with nrSpA, hsCRP correlated with the level of enthesitis-related tenderness only. In the AS subgroup with a negative routine CRP (<6 mg/litre) there was a clear trend for an increased level of pain, stiffness and functional impairment in patients with higher hsCRP concentration. Such a trend was less pronounced in patients with nrSpA. Conclusions: hsCRP correlates better than routine CRP with clinical disease activity parameters in patients with axial SpA, especially in AS. Therefore, hsCRP could be superior to standard CRP in assessing disease activity in axial SpA.


Ziegler S.,German Rheumatism Research Center | Huscher D.,German Rheumatism Research Center | Krause A.,Immanuel Krankenhaus | Wassenberg S.,Evangelisches Fachkrankenhaus | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background: New strategies and options for the treatment of rheumatoid arthritis (RA) have evolved during the past decade. A study was undertaken to investigate to what extent this influenced daily rheumatological care and how this translates into clinical and patient-reported outcomes. Methods: Data from a total of 38 723 outpatients with RA enrolled in the National Database of the German Collaborative Arthritis Centres in the years 1997-2007 were analysed. The cross-sectional annual data were compared to detect time trends. Results: Between 1997 and 2007 the prescription of combinations of traditional disease-modifying antirheumatic drugs (DMARDs) increased from 8% of all patients to 23%; biological agents were prescribed to 16% of patients with RA in 2007. The mean disease activity (DAS28) fell from 4.5 to 3.4 (median 4.5-3.2). The percentage of patients with low disease activity (DAS28 <3.2) increased significantly from 23% to 49%. The proportion of patients with ≥6 swollen joints fell from 43.1% in 1997 to 8.1% in 2007 and, in those with ≤6 tender joints, from 46.3% to 15.8%. There was a large decrease in the total annual number of days of sick leave due to the rheumatic condition from 27.2 to 8.8 days per gainfully employed person. This reduction is far beyond the decline in the general population. There was also a tendency to higher participation in the work force, specifically in older patients, reflecting the trend seen in the general population. Conclusions: The intensity of drug treatment in patients with RA has increased during the past 7 years. This has been accompanied by not only a decrease in disease activity but also a considerable reduction of economic losses due to sick leave and permanent work disability.

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