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

In clinical trials and observational studies, leflunomide, sulfasalazine, and hydroxychloroquine have been used as alternate csDMARDs added to the treatment regimen.^59-62 There are, however, only 2 trials comparing the efficacy of methotrexate with that of other csDMARDs as concomitant treatment in patients with inadequate response to TNFi therapy. The RABBIT trial found a slight decrease in effectiveness with concomitant TNFi and leflunomide compared to TNFi/methotrexate, but overall each group had similar EULAR responses at 24 months.⁶³ A study by De Stefano et al found comparable ACR20 and DAS28 responses among individuals receiving TNFis with methotrexate or leflunomide.⁶¹

The “Swapping” Strategy

The efficacy of the swapping strategy has been shown in 3 randomized clinical trials demonstrating the superiority of abatacept, tocilizumab, and rituximab in the treatment of individuals with RA refractory to TNFis. Tocilizumab was studied in the RADIATE⁶⁴ trial, which involved 499 patients with inadequate response to 1 or more TNFi agents. The primary endpoint (24-week ACR20) was achieved by 50.0%, 30.4%, and 10.1% of patients in the 8 mg/kg, 4 mg/kg, and control groups, respectively (P < 0.001 for both tocilizumab groups versus placebo). The utility of abatacept as second-line therapy after initial TNF failure was evaluated in the ATTAIN⁶⁵ study. Participants with an inadequate response to etanercept or infliximab were randomly assigned to receive either abatacept or placebo. ACR50 response rates after 6 months of treatment were 20.3% with abatacept and 3.8% with placebo (P < 0.001). The SWITCH-RA study,⁶⁶ an observational study, compared rituximab to TNFis in 1112 participants with inadequate response to initial anti-TNF therapy. At 6 months, mean change in DAS28 was small but significantly greater for the rituximab group (–1.5 vs –1.1; P = 0.007). The difference in response rates was greatest among seropositive patients. These data suggest that rituximab has efficacy following TNFi failure, particularly for seropositive patients. Additionally, REFLEX⁶⁷ is the sole randomized controlled trial in patients with insufficient response to TNFis that showed significant prevention of radiographic progression at week 56 in patients on rituximab compared to placebo (mean change from baseline in total Genant-modified Sharp score, 1.00 vs 2.31, respectively; P = 0.005).

One study randomly assigned 399 patients with active RA who had inadequate response to prior TNFi therapy to tofacitinib⁶⁸ (5 mg twice daily or 10 mg twice daily) or placebo, both with methotrexate.⁶ After 3 months of treatment, ACR20 response rates (41.7% for 5 mg, 28.1% for 10 mg, 24.4% for placebo) and DAS28 remission rates (6.7% for 5 mg, 8.8% for 10 mg, 1.7% for placebo) were significantly greater among patients treated with tofacitinib compared to those treated with placebo. More recently, the RA-BEACON trial⁶⁹ demonstrated a consistent, beneficial treatment effect of baricitinib in patients with insufficient response to 1 or more TNFis. In this trial, 527 patients with an inadequate response to bDMARDs were randomly assigned to receive baricitinib 2 mg or 4 mg daily or placebo for 24 weeks. A higher proportion of patients receiving baricitinib 4 mg had an ACR20 response at week 12 compared with those treated with placebo (55% vs 27%, P < 0.001), and patients receiving the 4-mg dose had significant improvements from baseline in DAS28 and Health Assessment Questionnaire–Disability Index scores (P < 0.001 for both comparisons).

To Cycle or to Swap?

Several observational studies (SCQM-RA,⁷⁰ STURE,⁷¹ BSRBR,⁷² Favalli,⁴³ MIRAR,⁷³ SWITCH-RA,⁷⁴ ROC⁷²) have clearly demonstrated that the swapping strategy is favored over the cycling strategy. In the ROC study,⁷² patients were randomly assigned (based on physician discretion) to receive a non-TNF biologic or a TNFi. More patients in the non-TNF group than in the TNFi group showed low disease activity at week 24 (45% vs 28%; odds ratio [OR], 2.09; 95% confidence interval [CI], 1.27-3.43; P = 0.004) and at week 52 (41% vs 23%; OR, 2.26; 95% CI, 1.33-3.86; P = 0.003). The authors concluded that in patients having an insufficient response to TNFi therapy, a non-TNF biologic agent may be more effective than a second TNFi drug. Only a few studies^75-77 have demonstrated similar results between the 2 strategies. Overall, the available evidence seems to suggest the superiority of the swapping over the cycling strategy.

An important clinical pearl to keep in mind is that both swapping and cycling strategies might theoretically increase the risk of infection; however, limited evidence is reported in the literature. In a large retrospective analysis⁷⁸ of data on 4332 RA patients from a large US claims database, patients who had cycled between TNFi agents had a 30% to 40% increased risk of infection compared to patients treated with rituximab. Patients on infliximab had a 62% higher hazard of severe infections, and this has also been reported in an observational study.⁷⁹ In another study,⁷⁰ 41% of 201 patients with RA followed between 1999 and 2013 who swapped to abatacept/rituximab or tocilizumab developed adverse events, as compared to 59% of those who switched to a second TNFi.