Almut Scherer

Tumor Necrosis Factor α Inhibition in Radiographic and Nonradiographic Axial Spondyloarthritis: Results From a Large Observational Cohort

OBJECTIVE To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. METHODS We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. RESULTS We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). CONCLUSION The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA.

Differential drug retention between anti-TNF agents and alternative biological agents after inadequate response to an anti-TNF agent in rheumatoid arthritis patients

Background After inadequate response to an antitumour necrosis factor (aTNF) agent for treatment of rheumatoid arthritis (RA), rheumatologists can choose an alternative aTNF or a biological agent with another mode of action (non-aTNF biological (non-aTNF-Bio)). Objective To compare drug retention rates of non-aTNF-Bio with alternative aTNF. Methods All patients within the Swiss RA cohort (SCQM-RA) treated with an alternative biotherapy after a prior inadequate response to aTNF were analysed. The drug retention of alternative aTNF was compared with non-aTNF-Bio using Cox proportional hazards models, adjusted for potential confounders. Results 1485 treatment courses after aTNF failure were available for analysis, 853 with alternative aTNF and 632 with non-aTNF-Bio. The median drug retention was 32 months (IQR 14–54) on non-aTNF-Bio versus 21 months (IQR 8–53) on alternative aTNF, or a 50% reduction drug discontinuation risk in favour of non-aTNF-Bio (adjusted hazard ratio (HR) for non-aTNF-Bio: 0.50 (95% CI 0.41 to 0.62)). This effect appears to be modified by the type of prior aTNF failure, with a larger difference in favour of non-aTNF-Bio in patients having experienced a primary failure with a previous aTNF (HR: 0.33 (95% CI 0.24 to 0.47), p<0.001). Conclusion After inadequate response to aTNF, and particularly after primary failure, patients on a non-aTNF-Bio agent have significantly higher drug retention rates.

Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study

Objectives Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. Methods Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 ‘NSAID users’ were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were ‘NSAID naive’. Primary outcome was the estimated glomerular filtration rate according to the Cockroft–Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. Findings In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between ‘NSAID users’ (mean change in eGFRCG −0.87 mL/min/year, 95% CI −1.15 to −0.59) and ‘NSAID naive’ (−0.67 mL/min/year, 95% CI −1.26 to −0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. Conclusions NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.

Impaired response to treatment with tumour necrosis factor α inhibitors in smokers with axial spondyloarthritis

Objectives To investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort. Methods Patients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses. Results A first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively). Conclusions Current smoking is associated with an impaired response to TNFi in axSpA.

Ultrasound evaluation of synovitis in RA: Correlation with clinical disease activity and sensitivity to change in an observational cohort study

OBJECTIVE To evaluate the correlation between clinical measures of disease activity and a ultrasound (US) scoring system for synovitis applied by many different ultrasonographers in a daily routine care setting within the Swiss registry for RA (SCQM) and further to determine the sensitivity to change of this US Score. METHODS One hundred and eight Swiss rheumatologists were trained in performing the Swiss Sonography in Arthritis and Rheumatism (SONAR) score. US B-mode and Power Doppler (PwD) scores were correlated with DAS28 and compared between the clinical categories in a cross-sectional cohort of patients. In patients with a second US (longitudinal cohort), we investigated if change in US score correlated with change in DAS and evaluated the responsiveness of both methods. RESULTS In the cross-sectional cohort with 536 patients, correlation between the B-mode score and DAS28 was significant but modest (Pearson coefficient r = 0.41, P < 0.0001). The same was true for the PwD score (r = 0.41, P < 0.0001). In the longitudinal cohort with 183 patients we also found a significant correlation between change in B-mode and in PwD score with change in DAS28 (r = 0.54, P < 0.0001 and r = 0.46, P < 0.0001, respectively). Both methods of evaluation (DAS and US) showed similar responsiveness according to standardized response mean (SRM). CONCLUSIONS The SONAR Score is practicable and was applied by many rheumatologists in daily routine care after initial training. It demonstrates significant correlations with the degree of as well as change in disease activity as measured by DAS. On the level of the individual, the US score shows many discrepancies and overlapping results exist.

Effectiveness of biologic DMARDs in monotherapy versus in combination with synthetic DMARDs in rheumatoid arthritis: data from the Swiss Clinical Quality Management Registry

OBJECTIVES To determine the frequency of use of biologic DMARDs (bDMARDs) in monotherapy, to describe the baseline characteristics of patients treated with bDMARDs in monotherapy and to compare the effectiveness of bDMARDs in monotherapy with that of bDMARDs in combination with synthetic DMARDs (sDMARDs). METHODS Using data from the Swiss RA (SCQM-RA) registry, bDMARD treatment courses (TCs) were classified either as monotherapy or as combination therapy, depending on the presence of concomitant sDMARDs. Prescription of bDMARD monotherapy was analysed using logistic regression. bDMARD retention was analysed using Kaplan-Meier and Cox models with the addition of time-varying covariate effects. Evolution of the DAS28 over time was analysed with mixed-effects models for longitudinal data. RESULTS A total of 4218 TCs on bDMARDs from 3111 patients were included, of which 1136 TCs (27%) were initiated as monotherapy. bDMARD monotherapy was preferentially prescribed to older, co-morbid patients with longer disease duration, lower BMI, more active disease and more previous bDMARDs. After adjusting for potential confounding factors, drug retention was significantly lower in monotherapy [hazard ratio 1.15 (95% CI: 1.03, 1.30)]. Other factors such as type of bDMARD and calendar year of prescription were associated with a stronger effect on drug retention. Response to treatment in terms of DAS28 evolution was also slightly but significantly less favourable in monotherapy (P = 0.04). CONCLUSION Our data suggest that bDMARD monotherapy is prescribed to more complex cases and is significantly less effective than bDMARD therapy in combination with sDMARDs, but to an extent that is clinically only marginally relevant.

TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort

Objectives To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS). Methods Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis. Results A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97). Conclusion TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity.

Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis: a prospective cohort study

Objective Anaemia in rheumatoid arthritis (RA) is prototypical of the chronic disease type and is often neglected in clinical practice. We studied anaemia in relation to disease activity, medications and radiographic progression. Methods Data were collected between 1996 and 2007 over a mean follow-up of 2.2 years. Anaemia was defined according to WHO (♀ haemoglobin<12 g/dl, ♂: haemoglobin<13 g/dl), or alternative criteria. Anaemia prevalence was studied in relation to disease parameters and pharmacological therapy. Radiographic progression was analysed in 9731 radiograph sets from 2681 patients in crude longitudinal regression models and after adjusting for potential confounding factors, including the clinical disease activity score with the 28-joint count for tender and swollen joints and erythrocyte sedimentation rate (DAS28ESR) or the clinical disease activity index (cDAI), synthetic antirheumatic drugs and antitumour necrosis factor (TNF) therapy. Results Anaemia prevalence decreased from more than 24% in years before 2001 to 15% in 2007. Erosions progressed significantly faster in patients with anaemia (p<0.001). Adjusted models showed these effects independently of clinical disease activity and other indicators of disease severity. Radiographic damage progression rates were increasing with severity of anaemia, suggesting a ‘dose-response effect’. The effect of anaemia on damage progression was maintained in subgroups of patients treated with TNF blockade or corticosteroids, and without non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). Conclusions Anaemia in RA appears to capture disease processes that remain unmeasured by established disease activity measures in patients with or without TNF blockade, and may help to identify patients with more rapid erosive disease.

Age at symptom onset in ankylosing spondylitis: is there a gender difference?

The impact of human leukocyte antigen (HLA)-B27 on the age at disease onset in patients with ankylosing spondylitis (AS) has consistently been shown in several cohorts.1–4 A potential gender difference with respect to age at symptom onset remains, however, controversial5–8 as the distribution of HLA-B27 within these populations is not known in all studies. While no sex differences with regard to disease onset were found in several cohorts from Europe,5 ,6 a later disease onset in men was reported in a North American investigation.7 We analysed this issue within the ongoing Swiss Clinical Quality Management cohort of patients with axial spondyloarthritis (axSpA).9 Ethics approval was given by the regional review boards. Informed consent was obtained from all patients. From a total of 3046 spondyloarthritis patients recruited until June 2014, 2098 (1294 men, 804 women) were included in this analysis, as they fulfilled the Assessment in SpondyloArthritis International Society (ASAS) classification criteria, with the following minor modifications, as the cohort was initiated before the publication of these criteria.9 First, …

OP0275 Persistence of ultrasound synovitis in the patients fullfiling the DAS and/or the new ACR/EULAR RA remission definitions: Results of the sonar score applied to the patients of the SCQM cohort

Background Remission is nowadays the primary goal of RA treatment, As the traditional remission criterion of DAS28 <2.6 seemed to be not stringent enough, the EULAR and ACR have proposed a new definition. Since 2008, the Swiss Sonography in Arthritis and Rheumatism (SONAR) group has developed a standardized semi-quantitative US score for RA using OMERACT criteria for synovitis. The score has been learned by 70 rheumatologists and since 2009 included as a routine evaluation tool in the Swiss SCQM RA cohort. Objectives The aims of the present study were: to evaluate whether this SONAR score applied to patients of the Swiss RA registry could differentiate the two clinical scores of remission and to compare them with ultrasound remission definition. Methods The first available visit with SONAR data in DAS28 (ESR) and or the new ACR/EULAR remission was selected. The SONAR score includes a semi-quantitative B mode and Doppler evaluation (22 joints, grade: 0 to 3, maximum of 66 points each). In order to establish ultrasound remission definition, the score was also applied to 40 matched controls (age and sex) recruited like the patients in different centers. Results 362 RA patients had, at the time of US examination, complete data for calculation of DAS28ESR and 177 for ACR/EULAR remission criteria. 121 patients fulfilled the DAS remission (33%) and only 29 the new ACR/EULAR definition (17%). Both groups were similar as for the age, sex, RF and duration of RA. RA patients in remission according to the DAS28 only or the ACR/EULAR criterion did not significantly differ in terms of B mode or Doppler score. In B mode, the mean total score (±SD) was higher but insignificantly in RA patients by either definition (mean ± SD: 8.2±6.5, p: 0.06 for DAS criteria) and (7.7±5.6, p: 0.16, for ACR/EULAR) as compared to the controls (5.5±2.4). The cut-off in B mode for significant ultrasound synovitis was defined by a total score >8, as 90% of the controls were below these values. When considering this cut-off, remaining synovitis were present among more than a third of RA patients in remission according to DAS28 (38.6%, 95% Wilson CI 30% – 48%) or the ACR/EULAR criteria (37.9%, IC 23% – 56%). Furthermore, the mean number of joints with b-mode synovitis of at least grade 2 was significantly higher in RA patients in clinical remission (6.7 for DAS, and 6.3 for ACR/EULAR p=0.0001 for both) compared to the controls (0.3). Finally, the mean Doppler score was very similar between the two remission kinds (p=0.45) but significantly higher in RA patients in clinical remission by either definition (0.8, for DAS, p=0.001) and (0.6, for ACR/EULAR, p=0.02) as compared to controls (0.1). Conclusions This study shows that the SONAR score applied by different examinators to RA patients is not different in those fulfilling the DAS remission and the new ACR/EULAR criteria. More than a third of all RA patients in clinical remission (either DAS or ACR/EULAR) still present signs of ultrasound synovitis suggesting that they have reached a low activity instead of a true remission state. Disclosure of Interest None Declared