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.

Factors influencing the choice of first- and second-line biologic therapy for the treatment of rheumatoid arthritis: real-life data from the Italian LORHEN Registry.

According to international recommendations, the selection of the biologic disease modifying anti-rheumatic drug (bDMARD) for rheumatoid arthritis (RA) is mainly left to the clinician's preference. We analyzed the real-life factors influencing the first-line choice or the switching strategy, focusing on the prescription of abatacept (ABA) or tocilizumab (TCZ) compared to TNFα inhibitors (TNFi). Patients enrolled in the Lombardy Rheumatology Network (LORHEN) Registry after January 1, 2010, when all considered bDMARD agents were available, were included. The population was divided into "first-" and "second-line" bDMARD. We included 1910 patients (first line n = 1264, second line n = 646). Age was higher in ABA or TCZ vs TNFi treated patients (p < 0.0001). Positive latent tuberculosis screening was associated with first-line ABA (p = 0.002). Methotrexate (MTX) combination therapy was lower in the TCZ group (p = 0.02). The type (dyslipidemia, hypertension, pulmonary disease) and the number of comorbidities influenced the choice towards ABA (p = 0.01). Multinomial logistic regression demonstrated that a second-line treatment, higher age, dyslipidemia, pulmonary disease, other comorbidities, and extra-articular RA manifestations were associated with ABA compared to TNFi. TCZ was associated with a second-line treatment, higher age, and more severe disease activity. Stopping the first bDMARD due to adverse events (AE) influenced the choice towards ABA. In real life, higher age and comorbidities influence the choice towards ABA and TCZ compared to TNFi. ABA was preferred in case of suspension of previous treatments due to AE. After failing a first-line TNFi, swapping to a different mechanism of action is more common.

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.

Novel mechanisms of action of the biologicals in rheumatic diseases.

Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.