[RABBIT-SpA: a new disease register for axial spondyloarthritis and psoriatic arthritis]. / RABBIT-SpA: ein neues Krankheitsregister für axiale Spondyloarthritis und Psoriasisarthritis.

BACKGROUND: The treatment of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) has changed enormously in recent years due to market authorization of a number of new biologicals with different modes of action and the increasing use of biosimilars. Real-world data on long-term safety and efficacy under routine daily conditions is not yet sufficient. Therefore, the German Rheumatism Research Center has initiated a new cohort study covering axSpA and PsA. OBJECTIVE: Presentation of initial results from the new register RABBIT-SpA, which was started in May 2017. MATERIAL AND METHODS: This is a prospective longitudinal cohort study with a similar study design to the German biologics register RABBIT. Patients can be included at the start of a new treatment either in the so-called index drug group or in the comparison group (conventional systemic treatment, including non-steroidal anti-inflammatory drugs, NSAID). Follow-up per patient should be at least 5 years and preferably 10 years. The RABBIT-SpA uses a web-based documentation system. RESULTS: Up to mid-December 2018 a total of 514 axSpA patients had been documented in RABBIT-SpA, 410 with an index drug and 104 with conventional treatment. There are differences between these treatment groups, e. g. in the duration of the disease and in parameters of disease activity. It is also noticeable that in axSpA patients, approximately 5 years lie between the onset of the symptoms and confirmation of the diagnosis. Of the 355 PsA patients, 265 were included with an index drug and 90 with conventional treatment. Of the PsA patients 86% have a dominant peripheral manifestation. The average number of pressure tender joints is 8 and the average number of swollen joints is 4. CONCLUSION: The online register RABBIT-SpA is well-received by the participating rheumatological institutions. The electronic recording of patient data can be carried out in a reasonable time. Participation in the RABBIT-SpA is open to new rheumatological institutions at any time.

Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: results from the German RABBIT cohort.

OBJECTIVE: In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account. METHODS: Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case-control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model. RESULTS: During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)). In the case-control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)). CONCLUSIONS: Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis.

OBJECTIVE: This observational cohort study investigated the impact of biological (b) disease-modifying antirheumatic drugs (DMARDs) on the outcomes of serious infections (SIs) in patients with rheumatoid arthritis. METHODS: We investigated outcomes of SIs observed in 947 patients enrolled in the German biologics register RABBIT(Rheumatoid arthritis: observation of biologic therapy). Outcomes were (1) recovery without complication, (2) sepsis following SI (≤30 days), and (3) death after SI without known sepsis (≤90 days). We applied a multinomial generalised estimating equation model for longitudinal data to evaluate the risks of sepsis and death simultaneously. RESULTS: Sepsis within 30 days after SI was reported in 135 out of 947 patients, 85 of these had a fatal outcome. Fifty-three patients died within 90 days after SI without known sepsis. The adjusted risk of developing sepsis increased with age and was higher in patients with chronic renal disease. Compared with conventional synthetic (cs)DMARDs, the risk was significantly lower when patients were exposed to bDMARDs at the time of SI (OR: 0.56, 95% CI 0.38 to 0.81). Risk factors of fatal SI were higher age, use of glucocorticoids at higher doses and heart failure. Patients treated with bDMARDs and those with better physical function had a significantly lower mortality risk. CONCLUSIONS: These results suggest a beneficial effect of bDMARDs on the risk of sepsis after SI and the risk of a fatal outcome. Successful immunosuppression may prevent an unregulated host response to SI, that is, the escalation to sepsis. Further investigation is needed to validate these results.

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.

Evaluation of the RABBIT Risk Score for serious infections.

OBJECTIVE: To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA). METHODS: The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample. RESULTS: The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor α (TNFα) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk. CONCLUSIONS: The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.

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.

A comparison of new bone formation in patients with ankylosing spondylitis and patients with diffuse idiopathic skeletal hyperostosis: a retrospective cohort study over six years.

OBJECTIVE: Ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) are both characterized by new bone formation in the spine but presumably have a different pathogenesis. This study was undertaken to compare the natural course of new bone formation in AS and DISH. METHODS: Lateral radiographs of the cervical and lumbar spine from AS and DISH patients obtained at ≥2 time points within 6 years were analyzed to quantify osteophyte development. Radiographs were scored in a blinded manner by 2 readers using the modified Stoke AS Spine Score (mSASSS). Bone spurs were categorized as having an angle of <45° or >45°. RESULTS: AS patients (n = 146) were younger than DISH patients (n = 141) (mean ± SD 54.2 ± 12.3 years versus 60.3 ± 7.7 years). Symptom duration (mean ± SD) was 23.6 ± 11.2 years in AS patients and 21.6 ± 12.4 years in DISH patients. The mSASSS at baseline was lower in DISH patients (mean ± SD 14.3 ± 6.7) than in AS patients (20.5 ± 14.5) but had increased by a similar amount at followup (3.3 ± 4.2 versus 4.1 ± 9.5). The mean mSASSS progression rate per year (1.3 units) was also comparable. The mean ± SD number of syndesmophytes per patient was higher in AS (5.7 ± 5.5) than DISH (2.7 ± 2.8) patients (P < 0.001), while degenerative bone spurs (mean ± SD) were more frequent in DISH (1.4 ± 1.8) than AS (1.0 ± 1.4) patients. AS patients developed more new bone spurs with an angle of <45° than >45° per patient (mean ± SD 2.1 ± 2.7 versus 0.6 ± 0.9) (P < 0.001), while similar amounts of both types of bone formation were seen in DISH patients. CONCLUSION: Our findings indicate that the rates of new bone formation in AS and DISH are largely similar. Both groups show osteophyte development, but as expected, syndesmophytes are more frequent in AS patients while DISH patients have more degenerative bone spurs. The nature of the different mechanisms of bone formation needs further study.

[Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. / Biomarker in der Rheumatologie. Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually.

Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient?

OBJECTIVE: To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). METHODS: Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR(adj)) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. RESULTS: Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRR(adj) 2.1 (95% CI 1.4 to 3.2); ≥ 15 mg/day, IRR(adj) 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRR(adj) 1.8 (95% CI 1.2 to 2.7)). CONCLUSION: Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.

Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial.

PURPOSE: To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. METHODS: Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. RESULTS: In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. CONCLUSION: In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group.

Relationship between active inflammatory lesions in the spine and sacroiliac joints and new development of chronic lesions on whole-body MRI in early axial spondyloarthritis: results of the ESTHER trial at week 48.

AIM: To investigate the relationship between active inflammatory lesions on whole-body MRI (wb-MRI) and new development of chronic lesions on T1 MRI in patients with early axial spondyloarthritis (SpA) treated either with etanercept (ETA) or sulfasalazine (SSZ). METHODS: Wb-MRIs of 65 patients treated either with ETA (n=35) or SSZ (n=30) over 1 year were scored for active inflammation, fatty lesions, erosions and ankylosis in the 23 vertebral units (VUs) of the spine and in the sacroiliac joints (SI joints). Scoring was performed by two blinded radiologists. RESULTS: If there was no previous inflammation in the bone no new fatty lesions occurred in SI joint quadrants and only a few (0.6%) in spine VUs. There was a significant relationship between disappearance of inflammation and the appearance of fatty lesions: if baseline inflammation resolved fatty lesions occurred in 10.5% of SI joint quadrants and 17.9% of VUs. If inflammation did not resolve over 1 year, fatty lesions occurred less frequently: 2.4% (SI joint quadrants) and 7.2% (VUs). There was a significantly higher increase of the mean fatty lesion score between baseline and week 48 in the ETA (4.0 vs 4.8 for the SI joints and 1.9 vs 2.7 for the spine) compared to the SSZ (3.0 vs 3.2 for the SI joints and 1.1 vs 1.2 for the spine, respectively) group (p=0.001 and p=0.020 for the differences). No significant changes in the erosion or ankylosis score were observed in any of the two groups during this time. CONCLUSIONS: These data indicate that there is a close interaction between inflammation, tumour necrosis factor blockade and the development of fatty lesions in subchondral bone marrow of patients with axial SpA.

The European ankylosing spondylitis infliximab cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab.

OBJECTIVES: To study the long-term efficacy and safety of treatment with infliximab in patients with ankylosing spondylitis (AS) in a real life setting. METHODS: AS patients from 6 European countries who had finished the 2-year trial ASSERT were invited to participate in the open- label investigator-driven study EASIC. At baseline, 2 groups were formed: patients of group 1 had not been treated with infliximab after ASSERT, while those of group 2 had continuously received it. Patients of group 1 were further subdivided in group 1a: patients with a relapse and 1b: in remission. All patients of group 1a and 2 continuously received infliximab for 96 weeks, mean dose 5 mg/kg, intervals 6-8 weeks. Patients of group 1b were also treated in case of relapse. RESULTS: A total of 103/149 patients (69%) were included in EASIC, 1.3 ± 0.9 years after the end of ASSERT: 9 in group 1a, 5 in group 1b and 89 in group 2. Most patients were male (83%), mean age 44 years. Most patients of group 2 completed the trial (86%) vs. only 5 of group 1 (33%) - mostly due to allergic reactions after readministration of infliximab. In total, there were 22 drop-outs due to 6 adverse events, 4 lack of efficacy, 3 planned pregnancy. All standard assessments indicated beneficial values over time, at week 96 significantly better than at baseline of ASSERT. CONCLUSIONS: The majority of patients were continuously and successfully treated with infliximab for 5 years, whereas discontinuation and reintroduction of therapy was less satisfactory due to the frequent occurrence of hypersensitivity reactions. Anti-TNF therapy with infliximab proved to be effective and safe on a long-term basis.

Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial.

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 alpha (TNFalpha) 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 (BASDAI) score >or=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.

Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis.

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.

Different risk profiles of biologic agents for new-onset psoriasis in patients with rheumatoid arthritis.

OBJECTIVE: To investigate rates and risk factors for incident and recurrent psoriasis in rheumatoid arthritis (RA) patients treated with different biologic (b) and conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs). METHODS: RA patients enrolled in the German biologics register RABBIT without (n = 14,525) or with a history of psoriasis (n = 375) were analyzed separately. All first events of psoriasis reported until October 2017 were assigned to the treatments prescribed in the previous 3 months. Crude incidence rates (IR) of psoriasis were calculated per 1000 patient-years. To investigate risk factors for psoriasis, cox regressions with and without inverse probability weights were applied to adjust for confounding by indication. RESULTS: 117 incident and 37 recurrent psoriatic events were reported. Patients exposed to TNFi had a significantly higher incidence rate (IR = 3.04/1,000 PY) than those exposed to csDMARDs only (IR = 0.65), whereas IRs for abatacept, rituximab and tocilizumab did not differ significantly from csDMARDs. Adjusted Cox regression confirmed a higher risk for TNFi. Female sex (HR: 1.7) and smoking (HR: 2.1) were significantly associated with incident psoriasis while methotrexate decreased the risk (HR: 0.5). For recurrent psoriasis, IRs for TNFi, abatacept and rituximab were significantly higher than for csDMARDs. CONCLUSIONS: Our data confirm a previously observed increased risk of incident psoriasis in patients exposed to TNFi compared to csDMARDs. However, the overall risk is low and the event is usually non-serious. Comedication of TNFi with methotrexate seems to lower the risk of incident psoriasis. In patients with a history of psoriasis, recurrence as adverse event is rare.

Comparison of the Bath Ankylosing Spondylitis Disease Activity Index and a modified version of the index in assessing disease activity in patients with ankylosing spondylitis without peripheral manifestations.

OBJECTIVE: To compare the original Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) with a modified BASDAI without questions about peripheral arthritis (question 3) and enthesitis (question 4), here termed the mini-BASDAI, as an instrument to assess disease activity in patients with ankylosing spondylitis (AS) without peripheral manifestations. METHODS: The mini-BASDAI was calculated by omitting questions 3 and 4. The correlation of the original BASDAI and the mini-BASDAI with patient global and other disease parameters was assessed in a total of 692 patients from three AS cohorts including one observational AS cohort and two clinical trial populations treated with non-steroidal anti-inflammatory drugs and tumour necrosis factor alpha inhibitors. Sensitivity to change was assessed by calculating effect sizes. RESULTS: Up to 70% of AS patients did not have peripheral involvement. Patients with peripheral involvement had higher disease activity in all activity parameters. The mini-BASDAI had higher values compared with the original BASDAI, also in the subgroup with peripheral manifestations. However, the mini-BASDAI did not correlate better with other markers of disease activity compared with the original BASDAI. Furthermore, effect sizes of the original BASDAI and mini-BASDAI were comparable in the treatment trials. Interestingly, approximately 5% of active AS patients with pure axial disease manifestation were identified whose disease activity was underestimated by the original BASDAI. CONCLUSION: On a group level using the mini-BASDAI did not result in an advantage to assess disease activity or in the subgroup without peripheral involvement. In only approximately 5% of AS patients was the mini-BASDAI superior to the original BASDAI.

Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with either methotrexate or leflunomide.

OBJECTIVE: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor alpha (TNFalpha) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. METHODS: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFalpha inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n = 1375) or leflunomide (n = 394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. RESULTS: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. CONCLUSION: The current clinical practice is to use methotrexate as a first choice for the combination with TNFalpha antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis.

OBJECTIVES: To evaluate various validity aspects of four disease activity scores (ASDAS) for ankylosing spondylitis (AS) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), its individual components and physician and patient global assessment of disease activity. METHODS: The analyses were performed in two cohorts of patients with AS: (1) the NOR-DMARD database which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor (TNF) blocker and (2) patients participating in double-blind placebo controlled randomised clinical trials with TNF blockers in four centres. Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the standardised mean difference (difference in the group means divided by the pooled SD of the group means) and t score. RESULTS: The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change. The ASDAS scores outperformed the BASDAI and its single components in all settings: patient- or physician-based, reflecting status or change, with normal or raised C-reactive protein (CRP), in the presence or absence of peripheral arthritis. There were no major differences between the four ASDAS scores. Based on feasibility, the ASAS membership selected the ASDAS version which included back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints and CRP as the preferred version. CONCLUSIONS: The ASDAS is a validated, highly discriminatory instrument for assessing disease activity in AS, including patient-reported outcomes and CRP levels.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection.

OBJECTIVE: To validate and refine two sets of candidate criteria for the classification/diagnosis of axial spondyloarthritis (SpA). METHODS: All Assessment of SpondyloArthritis international Society (ASAS) members were invited to include consecutively new patients with chronic (> or =3 months) back pain of unknown origin that began before 45 years of age. The candidate criteria were first tested in the entire cohort of 649 patients from 25 centres, and then refined in a random selection of 40% of cases and thereafter validated in the remaining 60%. RESULTS: Upon diagnostic work-up, axial SpA was diagnosed in 60.2% of the cohort. Of these, 70% did not fulfil modified New York criteria and, therefore, were classified as having "non-radiographic" axial SpA. Refinement of the candidate criteria resulted in new ASAS classification criteria that are defined as: the presence of sacroiliitis by radiography or by magnetic resonance imaging (MRI) plus at least one SpA feature ("imaging arm") or the presence of HLA-B27 plus at least two SpA features ("clinical arm"). The sensitivity and specificity of the entire set of the new criteria were 82.9% and 84.4%, and for the imaging arm alone 66.2% and 97.3%, respectively. The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI (sensitivity 85.1%, specificity 65.1%) and slightly better than that of the modified Amor criteria (sensitivity 82.9, specificity 77.5%). CONCLUSION: The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain. TRIAL REGISTRATION NUMBER: NCT00328068.