Gottenberg JE, Brocq O, Perdriger A, et al. Non-TNF-targeted biologic vs a second anti-TNF drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: a randomized clinical trial. JAMA 2016;316:1172–80.
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Objective. To determine whether a non–tumor necrosis factor (TNF)-targeted drug is more effective than a second anti-TNF drug in rheumatoid arthritis (RA) patients who have had an inadequate response to a first anti-TNF drug.
Design. 52-week pragmatic, multicenter, open-label, parallel-group, randomized clinical trial (the “Rotation or Change” trial).
Setting and participants. 300 patients who were at least 18 years old were recruited from December 2009 to August 2012 from 47 French clinical centers. These patients had to have a diagnosis of RA according to the 1987 American College of Rheumatology criteria, presence of erosions, a DAS28-ESR (a measure of disease burden using patient global health, tender and swollen joint counts, and the erythrocyte sedimentation rate) of 3.2 or more, and insufficient response to an anti-TNF according to the physician (based on 1 or more of: persistent tender and swollen joints, persistent disease activity according to patient global assessment, elevated levels of acute-phase reactants, and dependence on analgesics, nonsteroidal anti-inflammatory drugs, or corticosteroids). In addition, patients had to have a stable dose of oral corticosteroids of 15 mg/d or less of equivalent prednisone within 4 weeks before enrollment, a stable dose of synthetic disease-modifying antirheumatic drugs (DMARDs) within 4 weeks of enrollment, and informed written consent. Exclusion criteria included cessation of the first anti-TNF agent due only to an adverse event, previous treatment with 2 or more anti-TNF agents, previous treatment with abatacept, rituximab, or tocilizumab, a contraindication to all anti-TNF agents and other biologics such as an infection or cancer, pregnancy and breastfeeding.
Intervention. Patients were randomly assigned in equal proportions to receive either a non-TNF biologic (abatacept, rituximab, or tocilizumab) or a second anti-TNF agent (adalimumab, certolizumab, etanercept, infliximab, or golimumab); the choice of agent after randomization was decided by the physician. The starting dose and frequency of treatment was predetermined. Golimumab was not available for use at the time of this study. The choice of future dosing and frequency of the treatment was left up to the treating physician in both groups. The assigned drug treatments continued for 12 months but were allowed to be discontinued for adverse events, patient choice, or inefficacy. Treatment and dose adjustments for oral corticosteroids and glucocorticoid intra-articular injections were allowed for both treatment groups.
Main outcome measures. The primary outcome was the proportion of patients at week 24 with a good or moderate European League Against Rheumatism (EULAR) response. A good EULAR response is defined as a decrease in DAS28-ESR of more than 1.2 points leading to a score of 3.2 or lower while a moderate EULAR response is defined as a decrease of more than 0.6 and resulting in a score of 5.1 points or lower. Secondary end points were EULAR response at weeks 12 and 52, DAS28-ESR at weeks 12, 24, and 52, low disease activity (DAS28-ESR < 3.2) and remission (DAS28-ESR < 2.6) at weeks 12, 24, and 52, mean oral corticosteroid use at weeks 24 and 52, therapeutic maintenance (defined as the proportion of patients who did not discontinue the assigned biologic treatment) at weeks 24 and 52, and health assessment questionnaire (HAQ) score (range, 0–3 with 0 representing the best and 3 the worst outcomes) at weeks 12, 24, and 52. Safety including serious adverse events as well as serious infections was also evaluated throughout the study.
Main results. 300 patients were randomized. The 2 groups were not different with regard to demographic and disease characteristics. In the non-TNF group of 150 patients, 33 of 146 patients (23%) received abatacept, 41 (28%) rituximab, and 70 (48%) tocilizumab; 2 patients (1%) did not receive the intervention as planned, 1 patient received adalimumab and 1 patient received no treatment. For the anti-TNF group, 57 of 146 patients (39%) received adalimumab, 23 (16%) certolizumab, 53 (36%) etanercept, and 8 (5%) infliximab. Five patients (3%) did not receive the intervention assigned as 2 patients received rituximab, 1 patient received tocilizumab, and 2 patients received no treatment. About two-thirds of patients in each group received concomitant methotrexate and about half in each group received oral corticosteroids.
With regard to the primary outcome, at week 24 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response, with 39% with a good response and 30% with a moderate response in the non-TNF group and 21% with a good response and 31% with a moderate response in the second anti-TNF group (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27 to 3.37; P = 0.004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = 0.004). More patients in the non-TNF group vs the second anti-TNF group showed low disease activity at week 24 (45% vs 28%; OR, 2.09; 95% CI, 1.27 to 3.43; P = 0.004) and at week 52 (41% vs 23%; OR, 2.26; 95% CI, 1.33 to 3.86; P = 0.003).
The mean DAS28-ESR change from baseline was greater for patients in the non-TNF group than for patients in the second anti-TNF group with a 24-week mean difference of −0.43 (95% CI,−0.72 to −0.14; P = 0.004) and 52-week mean difference of −0.38 (95% CI, −0.69 to −0.08; P = 0.01).
The proportion of EULAR good and moderate responders at week 24 did not significantly differ with abatacept, rituximab, and tocilizumab treatment. The therapeutic maintenance rate, defined as the proportion of patients who continued the biologic treatment, was found to be significantly higher at weeks 24 and 52 in the non-TNF group than in the second anti-TNF group. The mean change from baseline to weeks 24 and 52 in the level of prednisone doses was not significantly different between patients between treatment groups.
With respect to safety, 16 patients (11%) in the non-TNF group experienced 18 serious adverse events and 8 patients (5%) in the second anti-TNF group experienced 13 events (P = 0.10) with 7 patients (5%) in each group developing serious infections.
Conclusion. In patients with RA previously treated with an anti-TNF drug with an inadequate response, the use of a non-TNF biologic agent was found to be more effective in achieving a good or moderate disease activity response at 24 weeks compared with a second anti-TNF medication.
In patients with RA who have shown an inadequate response to methotrexate, TNF-α inhibitors have been shown to improve quality of life. However, it has been shown that almost one-third of patients have an insufficient and inadequate response to anti-TNF agents and continue to have persistent disease activity [1–3].Alternative treatments are therefore needed, but there is currently little guidance available for choosing the next treatment.
There are 3 placebo-controlled trials that have shown that switching to a non–TNF-targeted therapy may be appropriate [4–6]. The most commonly used non-TNF agents are abatacept, rituximab, and tocilizumab. However, there is evidence that switching to another anti-TNF agent after failure of a first can also be a good choice, as the molecular structure of TNF-inhibitors and their affinity for membrane and TNF-α vary. There were 2 randomized placebo-controlled trials that reported that approximately half of patients with RA with insufficient response to a TNF-α inhibitor responded to a second anti-TNF drug [7,8].
Although there have been observational studies addressing this question, this is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic compared to a second anti-TNF drug to treat RA in patients with an insufficient response to a first anti-TNF drug. Data showed that at week 24, 69% in the non-TNF group and 52% in the anti-TNF group achieved a good or moderate EULAR response. The non-TNF treatment was also associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52. The DAS28-ESR and the number of patients achieving low disease activity status were found to be greater at months 6 and 12 in the non-TNF group than in the second anti-TNF group. One strength of the study is its pragmatic design—the study evaluated the effectiveness of interventions under real-life, routine practice conditions where physicians often choose one drug over another for reasons based on the habits or characteristics of the patient. The comparison of strategies and not individual drugs more appropriately addresses the questions that physicians face in daily practice. However, there were some limitations including the lack of blinding by participants, the exclusion of some biologic agents such as golimunab, the lack of assessment of individual drug efficacy, and the fact that approximately 40% of patients in each group did not have concomitant treatment with methotrexate, an agent known to improve the efficacy of most biologic agents.
Applications for Clinical Practice
This is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic vs. a second anti-TNF in patients with RA who have an insufficient response to a first anti-TNF drug. Further studies addressing the limitations identified in this study are needed before physicians can employ these findings in clinical practice.
—Anita Laloo, MD
1. Hyrich KL, Lunt M, Watson KD, et al; British Society for Rheumatology Biologics Register. Outcomes after switching from one antitumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:13–20.
2. Hetland ML, Christensen IJ, Tarp U, et al; All Departments of Rheumatology in Denmark. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010;62:22–32.
3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964–75.
4. Cohen SB, Emery P, Greenwald MW, et al; REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793–806.
5. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67:1516–23.
6. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114–23.
7. Smolen JS, Kay J, Doyle MK, et al; GO-AFTER study investigators. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009;374:210–21.
8. Schiff MH, von Kempis J, Goldblum R, et al. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann Rheum Dis 2014;73:2174–7.
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