If the first anti-TNF fails in RA, what's next?


When methotrexate fails in rheumatoid arthritis, the next-line treatment is usually a TNF-α inhibitor. But if this treatment fails as well, what's next?

When methotrexate fails in rheumatoid arthritis, the next-line treatment is usually a Tumor necrosis factor α (TNF-α) inhibitor. But if this treatment fails as well, what's next? Both a second anti-TNF and a non-TNF targeting biologic have been shown to work for some patients. Now, a new randomized clinical trial pits these two options head-to-head and finds that non-TNF targeting biologics prompt a response in a greater proportion of patients than a second anti-TNF(1). However, a second anti-TNF will work for about half of patients.

Inadequate response

Approximately one-third of patients show an inadequate response to the first TNF-α inhibitor prescribed. A 2010 study published in Arthritis & Rheumatology(2) found that low functional status (as measured by the Health Assessment Questionnaire score), older age and prednisolone treatment were associated with a lower chance of clinical response to a first-line anti-TNF. A 2006 study published in Rheumatology analyzed patients taking etanercept or infliximab and found, in contrast, that higher Health Assessment Questionnaire scores predicted lower response rates(3). Smoking was also predictive of lower response rates, but age was not associated with response rate in that analysis. Combination therapy with methotrexate was linked to a better response rate. The fact that few baseline characteristics were predictive of response indicates that less measurable factors like genetic difference might play a role in determining what works for individual patients, the authors wrote.  

There are also few guideposts after a patient does try an anti-TNF drug and that drug fails. The 2015 American College of Rheumatology recommendations for the treatment of rheumatoid arthritis call suggest either switching to another anti-TNF or trying a non-TNF biologic. The ACR committee ranked the level of evidence for these suggestions as "low to very low." (4)

Anti-TNF drugs are structurally and functionally different, and patients may not respond to one particular formulation because of anti-drug antibodies. Thus, changing TNF inhibitors may be a successful strategy, wrote Jacques-Eric Gottenberg, M.D, Ph.D, of Strasbourg University Hospital in France and colleagues in their new study published Sept. 20 in JAMA. 

Selecting a second drug

The researchers recruited patients with insufficient anti-TNF response from 47 clinical centers in France. These patients were randomly assigned to receive a non-TNF biologic (abatacept, rituximab or tocilizumab) or an anti-TNF agent (adalimumab, certolizumab, etanercept, or infliximab - golimumab was not available during the study period). The treating physician chose the specific drug used in each category. Each anti-TNF agent has a similar safety and effectiveness profile, so the choice between them is often a matter of clinical judgement, physician habit and patient preference as to method of dosing.

"We chose to compare strategies instead of individual drug prescriptions because this issue corresponds to the therapeutic question clinicians face in daily practice," the researchers wrote. "Therefore, the choice of the biologic within each randomized group and the concomitant synthetic DMARDs was left to the clinicians."

Ultimately, 300 patients were enrolled in the study, 285 of whom were included in the final analysis. Of those, 144 had been randomly assigned to receive a non-TNF biologic and 141 received a second anti-TNF biologic. Twenty-three percent of the non-TNF patients were prescribed abatacept, 28 percent rituximab and 48 percent tocilizumab.

Thirty-nine percent of the anti-TNF group received adalimumab, 16 percent certolizumab, 36 percent etanercept and 5 percent infliximab. At week 24 of the 52-week study, two-thirds of patients in each group also received methotrexate, and about half received oral corticosteroids. The primary endpoint of the trial was a good or moderate EULAR response as measured at 24 weeks.

Patient Outcomes 

The major finding of this head-to-head trial was that the non-TNF group responded at a higher rate than the second anti-TNF group. At week 24, the researchers reported, 69 percent of the non-TNF patients achieved a good or moderate EULAR response, compared with 52 percent in the anti-TNF group.

Thirty-nine percent of the non-TNF group had a good response, and 30 percent had a moderate response; 21 percent of the anti-TNF group had a good response, and 30 percent had a moderate response (O.R. 2.12, 95 percent C.I., 1.31-3.46, P=0.003).

At week 52 of the study, 38 percent of the non-TNF group had a good response, and 22 percent had a moderate response. In the anti-TNF group, 21 percent had a good response, and 22 percent had a moderate response.

Patients in the non-TNF group also saw greater improvements in their DAS28-ESR scores than those in the anti-TNF group, with a mean difference of -0.43 at 24 weeks (95 percent C.I., -0.72 to -0.14, p=0.04). Forty-five percent of those in the non-TNF group had a DAS28-ESR score of less than 3.2, indicating low disease activity, at week 24, compared with 28 percent prescribed a second anti-TNF drug. Twice the proportion of patients prescribed a non-TNF biologic achieved remission by week 12 than patients prescribed a second anti-TNF (20 percent versus 10 percent, OR 2.41, 95 percent C.I., 1.19; 4.89, p=0.02). Likewise, at week 52, 27 percent of the non-TNF patients had achieved remission compared with 14 percent of the anti-TNF patients (OR 2.36, 95 percent C.I., 1.25-4.43, p=0.008).

There was no difference in health assessment questionnaire scores between the two groups, and the researchers found no evidence of differences based on which non-TNF treatment patients received. At 24 weeks, patients treated with abatacept, rituximab or tocilizumab did not differ in the rate of good or moderate EULAR responses.

Eighteen percent (27 patients) of the non-TNF patients and 33 percent (48 patients) of the anti-TNF patients switched biologics during the course of the study. Of the 27 non-TNF patients who switched to a second non-TNF drug, 14 did so because the first drug was ineffective, 12 did so because of adverse events, and one for unknown reasons, the researchers reported. Of the 48 anti-TNF patients who switched to another TNF inhibitor, 40 did so because the original anti-TNF agent was ineffective, six because of adverse events, one because of trying to become pregnant, and one for unknown reasons.

The therapeutic maintenance rate was higher at weeks 24 and 52 in the group prescribed non-TNF biologics. Eleven percent (16 patients) in that group experienced at least one serious adverse event, compared with 5 percent (8 patients) in the anti-TNF group. Seven in each group were cases of serious infection, the researchers reported. In the non-TNF group, there were six serious cardiovascular events as well as a death from aortic aneurysm. In the anti-TNF group, there was one case of tuberculosis and one hypertensive crisis. 

Takeaways for the Clinical Practice

One placebo-controlled study found that trying a second anti-TNF (in this case, golimumab) in patients who had an insufficient response to another anti-TNF was successful in half of patients(5). The new head-to-head study found a similar rate of success for a second anti-TNF treatment when doctors were able to pick from multiple options.

The rate of success in the non-TNF biologic was also similar to that seen in previous placebo-controlled studies, Gottenberg and his colleagues found. Rituximab and tocilizumab after the failure of an anti-TNF were successful about 66 percent of the time in previous placebo-controlled studies(6,7).  

All biologic treatments are expensive, but one study published in May 2016 found that costs were lower for patients switching to an alternative anti-TNF drug versus those who had switched to a non-TNF biologic in a large commercial database ($36,932 versus $44,566; adjusted difference $7,045, p<0.01)(8). Both medical costs and pharmacy costs were lower for the patients in the anti-TNF group. But that study was retrospective, and the anti-TNF cohort was younger with a lesser comorbidity burden than the non-TNF group.

The new JAMA study was not powered to differentiate between drugs or to compare the safety profiles of each option head-to-head. In addition, only about 60 percent of patients in each group were treated simultaneously with methotrexate, which typically boosts the efficacy of biologics, the researchers wrote.




1) Gottenberg J-E, 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 DrugJama. 2016;316(11):1172. doi:10.1001/jama.2016.13512.

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 (1):22-32. 4.

3) Hyrich KL, Watson KD, Silman AJ, Symmons DPM. Predictors of response to anti-TNF-  therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2006;45(12):1558-1565. doi:10.1093/rheumatology/kel149.

4) Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid ArthritisArthritis & Rheumatology. 2015;68(1):1-26. doi:10.1002/art.39480.

5) 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(9685):210-221.

6) 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(9): 2793-2806.

7) 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(11):1516-1523.

8) Zhou Z-Y, Griffith J, Du EX, Chin D, Betts KA, Ganguli A. Economic Burden of Switching to a Non-Tumor Necrosis Factor Inhibitor Versus a Tumor Necrosis Factor Inhibitor Biologic Therapy among Patients with Rheumatoid ArthritisAdvances in Therapy Adv Ther. 2016;33(5):807-823. doi:10.1007/s12325-016-0318-5.


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