Rheumatoid Arthritis: Therapeutic Strategies After Inadequate Response to Initial TNF Inhibitor Therapy

Trial of an Alternate TNF Agent: The “Cycling” Strategy

Per the ACR/EULAR^26,27 guidelines, all approved bDMARDs may be used without hierarchical positioning. However, after the failure of a TNFi agent, these guidelines do not provide specific advice about a preference between the “cycling” strategy (switching to an alternative TNFi) and “swapping” strategy (switching to a therapy with a different mode of action). Cycling might work for several reasons, including differences in the agents’ molecular structure, immunological mechanism of action, immunogenicity, and pharmacokinetics.^28-30 The cycling strategy is a well-established approach adopted by more than 94% of practicing rheumatologists, according to a national survey,³¹ and its efficacy is supported by trials and additional observational studies.^32-35

The greater clinical effectiveness of switching to infliximab compared with continuing with etanercept in patients with inadequate response to etanercept (n = 28) was suggested in the open-label OPPOSITE trial.³⁶ Data from the GO-AFTER trial³⁷ suggests that a greater proportion of patients with RA refractory to adalimumab, etanercept, or infliximab who were treated with golimumab achieved an ACR20 and ACR50 response compared with patients who received placebo, and this response persisted through 5 years.³⁸ More recently, certolizumab pegol and adalimumab were compared head-to-head in the EXXELERATE trial.³⁹ The results of this trial revealed the adequate efficacy of cycling to another TNFi after primary insufficient response to the first.

In studies from Finland and Sweden,^35,40 it has been observed that a better response is achieved in patients in whom TNF failure was initially due to secondary failure or intolerance rather than primary failure. A post-hoc analysis of the results of the GO-AFTER trial⁴¹ and from a few observational studies^35,40,42 revealed that switching from one TNFi to another, especially from a monoclonal antibody to a soluble receptor, was often more beneficial for RA patients than switching from a soluble receptor to a monoclonal antibody.

Optimization of Therapy Conjoined with csDMARDs

Methotrexate is one of the oldest and most effective csDMARDs available for the treatment of RA.⁴³ The 2016 EULAR guidelines recommend the addition of methotrexate and/or other csDMARDs to potentiate the effect of bDMARDs.²⁶ In the case of TNFi therapy, the observed synergistic effect between the monoclonal antibody and methotrexate may be explained by sustained suppression of ADA formation.⁴⁴ In the TEMPO,⁴⁵ PREMIER,¹⁸ and GO-BEFORE⁴⁶ trials, the addition of methotrexate led to improved clinical and radiological outcomes in patients treated with etanercept, adalimumab, and golimumab,⁴⁷ respectively. These findings were also demonstrated in several registries, where significant improvement in clinical response and retention rate of the TNFi agents was noted. Results have been replicated with non-TNFi bDMARDs, including abatacept^48,49 and rituximab.⁵⁰ Patients treated with interleukin (IL)-6 inhibitors in combination with methotrexate have shown significantly less radiographic progression compared to those treated with tocilizumab alone and those treated with monotherapy tocilizumab versus monotherapy methotrexate.^51,52 Results possibly favor the use of IL-6 inhibitors alone in those who cannot tolerate or have contraindications to methotrexate.

An open prospective study by Cohen et al added methotrexate to the treatment regimens of individuals on bDMARD monotherapy with a primary failure and found favorable changes in ACR20 and DAS28 scores at 3 and 12 months and therapeutic biological response (ESR, CRP) at 3 months.⁵³ Unlike monotherapy, in these situations methotrexate is known to be efficacious even at a lower dose, possibly at 7.5 mg to 10 mg per week. Some studies have shown that methotrexate administered parenterally may be more efficacious than when given orally.^54-58