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

What are the alternative treatment options after first biologic failure?

In patients who have failed treatment with an initial biologic, usually a TNFi, the treating rheumatologist has the following options (Figure), with the best treatment strategy being driven by individualized patient and disease-related factors (Table 1 and Table 2):

• TNFi dose escalation
• Trial of an alternate TNFi agent (the “cycling” strategy)
• Optimization of therapy conjoined with a conventional synthetic DMARD (csDMARD)
• Use of a non-TNF biologic or targeted synthetic DMARD (the “swapping” strategy)

If all the listed strategies fail, the next step can be the addition of short-term, low-dose glucocorticoid therapy.

TNFi Dose Escalation

The available data have demonstrated the safety, efficacy, and cost-effectiveness of dose escalation in patients with RA receiving infliximab.^16-18 The ATTRACT trial first demonstrated this, with greater clinical and radiographic improvements in those with higher trough serum concentrations, suggesting that doses higher than 3 mg/kg or more frequent than every 8 weeks may be needed for full response in some patients.¹⁹

There is a lack of studies in RA patients to determine the most effective dose escalation strategy. A study in patients with Crohn disease showed that intensification to 10 mg/kg every 8 weeks (dose doubling) was at least as effective as 5 mg/kg every 4 weeks (halving interval) at 12 months.¹⁶ Due to greater patient and administration convenience of dose-doubling, this strategy may be preferred.¹⁷ A starting dose of 10 mg/kg every 8 weeks is not routinely recommended due to an increased risk of serious infection; these adverse events were not found when the dose was gradually increased, as clinically indicated, starting at 3 mg/kg.^19,20 Further studies are needed to explore this approach in RA patients.

These results, however, have not been replicated with other TNFi agents. No significant clinical improvements were identified with etanercept 50 mg twice weekly,²¹ adalimumab 40 mg every week in the PREMIER trial,¹⁸ or certolizumab 400 mg every other week in an open-label extension phase of the RAPID 1 study.²² A Japanese study found significantly worse clinical outcomes with dose escalation of golimumab.²³ Conversely, 2 studies found clinical benefits after escalating the tocilizumab dose, the first a real-world review from the Consortium of Rheumatology Researchers of North America (CORRONA) registry using the intravenous formulation,²⁴ and the other the BREVACTA study utilizing subcutaneous tocilizumab.²⁵ No studies to date have been published on dose escalation of abatacept in patients with RA who respond poorly. Overall, previous studies support dose escalation in individuals being treated with infliximab to improve clinical outcomes, but additional studies are needed for other bDMARDs.