The management of first-line biologic therapy failures in rheumatoid arthritis: Current practice and future perspectives.

The introduction of biologic disease-modifying anti-rheumatic drugs (bDMARDs) has dramatically changed the management of rheumatoid arthritis (RA). However, in a real-life setting about 30-40% of bDMARD treated patients experience drug discontinuation because of either inefficacy or adverse events. According to international recommendations, to date the best strategy for managing first-line bDMARD failures has not been defined yet and available data (especially on TNF inhibitors [TNFis]) seem to drive toward a personalized approach for the individual patient. Some TNFi partial responders may benefit from optimization of concomitant methotrexate therapy or from switching to a different concomitant sDMARD such as leflunomide. Conversely, apart from infliximab, TNFi dose escalation seems to be poor efficacious and poor cost-effective compared with alternative strategies. Albeit counterintuitive, the use of a second TNFi after the failure of the first-one (cycling strategy) is supported by clear evidences and has become widespread in the 2000s as the result of the limited alternative options till the introduction of bDMARDs with a mechanism of action other than TNF blockade. Nowadays, the use of abatacept, rituximab, tocilizumab, or JAK inhibitors as second-line agent (swapping strategy) is strongly supported by RCTs and real-life experiences. In the absence of head-to-head trials directly comparing these two strategies, meta-analyses of separated RCTs failed to find significant differences in favor of one or another choice. However, results from most observational studies, including well designed prospective pragmatic randomised analyses, demonstrated the superiority of swapping over cycling approach, whereas only few studies reported a comparable effectiveness. In this review, we aimed to critically analyze all the potential therapeutic options for the treatment of first-line bDMARD failures in order to provide a comprehensive overview of available strategies to be applied in clinical practice.

Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies.

OBJECTIVE: The aim of this study was to evaluate the survival on treatment with second-line biologic therapy in RA patient non-responders to TNF inhibitors (TNFis) by comparing treatments with a second anti-TNF (cycling strategy) or with agents with a different mechanism of action (MoA; swap strategy). METHODS: RA patients treated with biologics since 1999 who stopped a first-line TNFi and started a second-line biotherapy were included in this cohort study. After adjusting for propensity scores, drug retention rates were calculated using the Kaplan-Meier method. The log-rank test was used to compare survival curves and the Cox regression model was used to compare risk for discontinuation between the two groups. RESULTS: Two hundred and one patients discontinued the first TNFi, switching to a second anti-TNF [n = 119 (59.2%)] or to abatacept [n = 26 (31.7%)], rituximab [n = 40 (48.8%)] or tocilizumab [n = 15 (18.3%)]. Drug survival was significantly higher in the swap group than in the cycling group (P < 0.0001). After adjustment for propensity scores, probability of treatment retention in the swap group was significantly higher (hazard ratio = 2.258, 95% CI 1.507, 3.385), even after stratification according to the reason for the first TNFi discontinuation (P = 0.005). No significant differences emerged when comparing the retention rates of different MoAs (P = 0.51) in the swap group. CONCLUSION: In the clinical practice setting, the best option for managing TNFi non-responders seems to be swapping to a different MoA, with no differences between abatacept, rituximab and tocilizumab, irrespective of the reason for first TNFi discontinuation.

Standardization of autoantibody testing: a paradigm for serology in rheumatic diseases.

Autoantibody measurement is an excellent tool to confirm the diagnosis of rheumatic autoimmune diseases. Hence, reliability and harmonization of autoantibody testing are essential, but these issues are still a matter of debate. Intrinsic variability in analytes and reagents as well as heterogeneity of the techniques are the main reasons for discrepancies in inter-laboratory variations and reporting of test results. This lack of reliability might be responsible for wrong or missed diagnoses, as well as additional costs due to assay repetition, unnecessary use of confirmatory tests and/or consequent diagnostic investigations. To overcome such issues, the standardization of autoantibody testing requires efforts on all aspects of the assays, including the definition of the analyte, the pre-analytical stages, the calibration method and the reporting of results. As part of such efforts, the availability of suitable reference materials for calibration and quality control would enable the development of a reliable reference system. Strong-positive sera from patients have been used as reference materials in most of the autoantibody assays for rheumatic diseases; however, antigen-affinity-purified immunoglobulin fractions or in some cases reliable monoclonal antibody preparations offer more adequate tools for standardization. Systematic assessments of reference materials are currently underway, and preliminary results appear to be encouraging.