J. Callhoff

Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS)

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 MRI as 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-of-concept clinical trial, ustekinumab treatment was associated with a reduction of signs and symptoms in active AS and was well tolerated.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography

Objective To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). Methods CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. Results In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. Conclusions Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence ‘inflammation–FD–new bone formation’ was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis

Objectives This meta-analysis investigates the efficacy of tumour necrosis factor α (TNFα) blockers versus placebo for the treatment of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). Methods A systematic literature search was conducted independently by two reviewers. Double-blind randomised controlled trials (RCTs) investigating the efficacy of adalimumab, certolizumab, etanercept, golimumab or infliximab in approved dosages in comparison with placebo were included. The use of concomitant non-steroidal antirheumatic drugs was allowed. The outcome parameters were improvement in disease activity and function measured by the Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI) and ASAS40 response. The effect sizes of the changes in BASDAI/BASFI between TNFα blocker and placebo comparator groups were calculated. Mixed effect models were applied separately for RCTs with AS and nr-axSpA patients and differences between those groups were evaluated in a joint model. Results 20 studies with data from 3096 patients were included in the analysis: 15 studies with AS patients, four with nr-axSpA patients and one with both. For AS patients, TNFα blockers showed better efficacy than placebo for BASDAI (effect size 1.00), BASFI (effect size 0.67) and ASAS40 response (OR 4.7). For nr-axSpA patients, the differences were smaller (effect sizes 0.73, 0.57; OR 3.6). However, after adjustment for the year of publication as a proxy for disease severity, no differences in the effect sizes between the AS and nr-axSpA trials were observed. Conclusions Compared with placebo, TNFα blockers improve disease activity and functional capacity clinically meaningful for both AS and nr-axSpA patients.

Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS)

Background To date, only a single controlled trial provided evidence that non-steroidal anti-inflammatory drugs (NSAIDs) given continuously reduce radiographic progression compared with an on-demand therapy over 2 years in patients with ankylosing spondylitis (AS). In the current study, we tested whether such an effect of NSAIDs could be confirmed in another randomised trial. Methods Patients with AS were randomised for treatment with either continuous (150 mg/day) or on-demand diclofenac for 2 years. Tumour necrosis factor-blocker treatment was not allowed during the entire study period. The primary outcome was the difference in radiographic progression in the spine as measured by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) scored by two readers blinded to treatment arm and time point. Results 62 of 85 patients enrolled in the continuous arm and 60 of 82 enrolled in the on-demand arm completed the study. The mSASSS progression was numerically higher in the continuous group (1.28 (0.7 to 1.9) vs 0.79 (0.2 to 1.4)) (p=0.39). If only patients were analysed who were either C reactive protein positive or had syndesmophytes at baseline, there was again a higher radiographic progression in the continuous versus the on-demand group: 1.68 (0.7 to 2.6) vs 0.96 (0.0 to 1.9) and 2.11 (1.1 to 3.1) vs 0.95 (0.0 to 1.9), respectively. There was no difference between the two treatment groups regarding adverse events. Conclusions In our study, continuous treatment with diclofenac over 2 years did not reduce radiographic progression compared with on-demand treatment in AS. Trial registration numbers EudraCt-no 2007-007637-39; ClinicalTrials.gov NCT00715091.

Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial

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. ClinicalTrials.gov Identifier NCT00244166

Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression.

Adipokines have metabolic and inflammatory functions but can also affect bone metabolism. The purpose of this study was to determine the relationship between serum levels of adiponectin, resistin, and visfatin and markers of inflammation, disease activity, and radiographic spinal progression in patients with ankylosing spondylitis (AS).

Impact of biologic therapy on functional status in patients with rheumatoid arthritis—a meta-analysis

OBJECTIVE Using meta-analysis methods, this study aimed to estimate the impact of biologic agents on physical function in patients with RA. METHODS A systematic literature search was conducted independently by two investigators. Double-blind randomized controlled trials (RCTs) investigating the efficacy of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab or rituximab in approved dosages in comparison with treatment with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) and placebo were included. The outcome parameter was improvement in function measured by the standardized mean difference (SMD) of HAQ scores. The SMD is the difference of the change in HAQ between biologic and DMARD comparator groups divided by the pooled standard deviation. Mixed effect models were applied separately for RCTs with DMARD-naive patients and those with DMARD inadequate responders (IRs). RESULTS Thirty-five RCTs were included in the analysis, 10 with DMARD-naive patients and 25 with DMARD IRs. Overall, biologics led to a greater improvement of physical function than nbDMARDs, with an SMD of the HAQ of 0.44 (95% CI 0.38, 0.50). The improvement was greater for DMARD IRs (SMD 0.48, 95% CI 0.41, 0.56) than for DMARD-naïve patients (SMD 0.32, 95% CI 0.23, 0.41). There were no significant differences between individual biologics in both groups. CONCLUSION Treatment with biologics led to a clinically relevant greater improvement in physical function than treatment with nbDMARDs. Our results suggest that the improvement found on the group level was caused by a clinically relevant improvement on the patient level in more than 50% of the patients.

Erosions and fatty lesions of sacroiliac joints in patients with axial spondyloarthritis: evaluation of different MRI techniques and two scoring methods.

Objective. Assessment of structural damage of sacroiliac joints (SIJ) in patients with axial spondyloarthritides (axSpA) has been discussed as a useful outcome measure in clinical trials. The aim of our study was to evaluate different magnetic resonance imaging (MRI) scoring methods and pulse sequences with a focus on fatty lesions and bony erosions. Methods. Seventy-five patients with the diagnosis of axSpA underwent MRI at 3 timepoints as part of the ESTHER trial, which compared 2 groups of patients treated with etanercept or sulfasalazine. Two MRI sequences [unenhanced T1-weighted (T1w) turbo spin-echo (TSE) and unenhanced T1w opposed-phase gradient-echo sequences (opGRE)] and 2 different scoring systems (simple and comprehensive Berlin method) were used for the evaluation of fatty lesions and erosions of the SIJ. Differences between techniques and methods were evaluated by intraclass correlation coefficients (ICC) and standardized response means (SRM). Results. Applying the simple Berlin method, mean fatty lesion scores for etanercept-treated patients were 4.59 and 5.19 at baseline and Week 48, respectively, while the comprehensive Berlin method revealed mean fatty lesion scores of 6.59 and 7.64, respectively. Corresponding SRM were 0.59 and 0.86 for simple and comprehensive methods, respectively, while ICC dropped from 0.76–0.77 to 0.59–0.62. Scoring of erosions on T1w opGRE images resulted in a higher interreader agreement (ICC of 0.65) compared to T1w TSE sequences (ICC of 0.18). Conclusion. Better characterization of fatty lesion changes within 1 year was achieved by the comprehensive Berlin scoring method; however, more reader variation has to be taken into account. The delineation of erosions is markedly improved when using T1w opGRE pulse sequences.

Prävalenz der rheumatoiden Arthritis in Deutschland auf Basis von Kassendaten

BACKGROUND Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease with a prevalence of up to 1 % in the adult population. OBJECTIVE This study describes the prevalence of RA diagnoses in outpatient health insurance claims data, based on different case definitions and stratified by age, sex and region of residence. METHODS Based on data from a nationwide statutory health insurance fund (BARMER GEK) from the year 2013, a cross-sectional study of insurants aged 18 years or older was conducted. The following case definitions were applied: A) a diagnosis of seropositive rheumatoid arthritis (M05) or other rheumatoid arthritis (M06) according to the international classification of diseases 10 German modification (ICD-10-GM) in at least two quarterly periods of the year 2013, B) case definition A plus determination of C‑reactive protein (CRP) or erythrocyte sedimentation rate (ESR) at least once, C) case definition B plus specific drug therapy and D) case definition A plus treatment by a rheumatologist. Raw as well as age and sex-standardized prevalences were calculated and stratified according to the federal state. RESULTS The study population consisted of 7,155,315 insurants of whom 60.2 % were female. Overall, RA prevalences for the respective case definitions were 1.62 % (A), 1.11 % (B), 0.94 % (C) and 0.64 % (D). When standardized to the German population the prevalences were 1.38 % (A), 0.95 % (B), 0.81 % (C) and 0.55 % (D). The proportion of women was approximately 80 % for all case definitions. Prevalences increased with age, peaking in the age group 70-79 years old and showing the highest values in eastern and the lowest in southern Germany for raw as well as standardized measures. CONCLUSION Regional differences in the prevalence of RA diagnoses in health insurance claims data were observed independent of age, sex and case definition. The expected prevalence according to the results of international studies was best achieved when case definitions with CRP or ESR were considered.

Depression is a stronger predictor of the risk to consider work disability in early arthritis than disease activity or response to therapy

Objectives To evaluate the factors that influence patients with early inflammatory arthritis to consider a disability pension. Methods A total of 528 patients aged 63 or younger from an early arthritis cohort with a mean symptom duration of 3 months at inclusion were asked at 12 and 24 months whether they were considering applying for, had applied for or were receiving a disability pension because of arthritis. Possible predictors were analysed with univariate and multivariate logistic regression. Results 69 patients (13%) were considering, had applied for or were receiving a disability pension. Univariate predictors were older age, disease activity, several patient-reported outcomes and depression. In a multivariate analysis, age, days on sick leave, impairment of physical function and depression were predictive for considering a disability pension (OR for severe vs no depression: 3.85, 95% CI 1.43 to 10.4). Conclusions In patients with early arthritis, depression appears to be a stronger predictor of the risk to consider applying for work disability pension than the features of disease activity. Patients at risk could be identified with one single depression statement. This finding should prompt physicians to react early to signs and symptoms of depression to help patients to maintain their ability to work.