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JAMA Study Finds Non-TNF Drugs Highly Effective for RA Patients

October 5, 2016
When patients suffering from rheumatoid arthritis are unresponsive to a tumor necrosis factor (TNF) inhibitor drug, doctors typically will switch patients onto a different TNF drug. However, new research suggests non-TNF biologics may be the superior alternative option.

Interview with Don L. Goldenberg, MD, FACP

A viable new class of medications--non-tumor necrosis factor-a--offer physicians an alternative to the currently preferred Tumor Necrosis Factor (TNF) -a drugs, according to findings reported in JAMA.1

TNF-a drugs were the first biologic medications found to be effective in rheumatoid arthritis (RA) patients who had not responded adequately to methotrexate or other non-biologic drugs. However, up to one third of patients have shown poor response to these medications.2,3

An inadequate response has led to clinicians switching patients to a second TNF-α inhibitor drug. However, during the past few years, a number of non-TNF biologic drugs have been found helpful in the treatment of RA. New research suggests these drugs even could offer better patient outcomes than a second TNF-α inhibitor drug.

In a prior open-label, randomized clinical trial, researchers found when patients were unresponsive to an anti-TNF therapy, they were better off subsequently receiving a non-TNF biologic, instead of an alternative anti-TNF medication.4

This new study is the first to suggest non-TNF biologics could be a better “plan B” option for patients unresponsive to TNF inhibitors, although certain barriers, like adverse effects and drug costs, may have to be taken into account.1

“Before this study was published in JAMA, it had not been clear whether the best course of action would be to switch to a different TNF inhibitor or to a different class of biologics,” Don L. Goldenberg, MD, FACP, a Professor of Medicine, Emeritus, at Tufts University School of Medicine in Boston, Massachusetts, told Practical Pain Management.

Finding the Path to Disease Regression

“During the past 2 decades, the treatment options for RA have exploded and dramatic improvement or even recovery is now the norm. This began with evidence that methotrexate was capable of inducing RA disease remission. The TNF inhibitors were then introduced and subsequently have demonstrated efficacy in patients not responding adequately to methotrexate,” said Dr. Goldenberg, who is a member of the Practical Pain Management editorial board.

However, if a patient shows an inadequate response to a TNF-α inhibitor drug, it poses a difficult problem to clinicians. Generally, doctors can choose from 2 different strategies: switch the patient onto a different TNF-α inhibitor drug or prescribe a non-TNF biologic, instead.

Both courses of action are considered good alternatives. However, the molecular structures of TNF-α inhibitor drugs differ, so about 50% of unresponsive RA patients do respond better to a TNF-α inhibitor agent. However, research has indicated that TNF-α inhibitor drugs may lose their efficacy over time as the body develops antidrug antibodies.5

Non-TNF-targeted therapy also may be a feasible treatment course, considering patients have shown positive results from taking alternative non-TNF treatments, such as rituximab, tocilizumab, and abatacept.6,7,8

The Study

To take this into consideration, the study focused on what type of drug – not the specific label – patients received. The 52-week long trial recruited 300 hundred patients with RA from numerous French clinical centers from December 2009 to August 2012. All patients were diagnosed with RA, showed presence of erosions, had a disease activity score (DAS28-ESR) of 3.2 or more, and a clinically determined insufficient response to a TNF-α inhibitor drug. Other patient requirements for the study included:

  • A stable dose of synthetic disease-modifying antirheumatic drugs and of oral corticosteroids of 15 mg/d or less of equivalent prednisone within 4 weeks of enrollment into the study
  • Informed written consent

*Not every patient received the right medication as randomized and some patients also withdrew consent to be included in the study, hence the final cohort numbers for the non-TNF group (n=146) and anti-TNF group (n=146).

Most patient characteristics were similar between the two patient groups, including:

  • Sex
  • Age
  • Disease duration
  • Rheumatoid factor
  • Anticyclic citrullinated peptide positivity
  • Number of previous synthetic DMARDs taken
  • Baseline DAS28-ESR
  • HAQ score

Stronger Efficacy with Subsequent Non-TNF therapy

After 52 weeks of treatment, more patients taking a non-TNF drug achieved a good response compared to patients taking an anti-TNF drug, at 38% vs 21%, respectively. Moderate responses at week 52 were even between the 2 groups, at 22% vs 22% (OR, 1.99; 95% CI, 1.22-3.25; P = .006; absolute difference, 17.0; 95% CI, 5.1-28.9).

This positive trend for non-TNF intervention persisted when researchers measured patients’ mean DAS28-ESR change from baseline. More patients taking a non-TNF drug also achieved a low disease activity score or even disease remission, compared to patients taking an anti-TNF drug.

The results suggest patients, who may not respond well to taking a TNF-α inhibitor, could achieve a far better physiological response after being switched onto a non-TNF biologic. Patients on non-TNF biologics showed significantly better improvements in inflammation markers compared to patients on an anti-TNF medication.

*(OR, 2.12; 95% CI, 1.31-3.46; P = .003; absolute difference, 17.6%; 95%CI, 6.4-28.8, without imputation of missing data; OR, 2.06; 95% CI, 1.27-3.37; P = .004; absolute difference, 17.2%; 95% CI, 6.2%-28.2%, with imputation of missing data (4 in each group).

Problems to Consider with Non-TNF Medicines

“It is not surprising that biologics with a mechanism of action that differs from the TNF inhibitors may work better than switching to a different TNF inhibitor,” and as more non-TNF inhibitors are found effective for RA, there may be more enthusiasm to utilize them for this condition, Dr. Goldenberg noted.

“However, most rheumatologists have far more experience and are more comfortable with the TNF inhibitors than with other biologic drugs…There are still many rheumatologists who believe that so called ‘triple therapy,’ using methotrexate, hydroxychloroquine and sulfasalazine is as effective and much less costly than any biologic drug,” Dr. Goldenberg said.

Evaluating the safety and cost-effectiveness of non-TNF versus anti-TNF medications also should be a major goal, especially considering adverse effects and insurance coverage are major factors in how clinicians choose the appropriate pharmacological treatment.

For instance, recurrent infections are often a primary reason for clinicians to switch a patient onto a non-TNF medication after a bad trial with an anti-TNF drug, according to Jessica Farrell, PharmD, a co-director at the Steffens Scleroderma Center, Albany College of Pharmacy and Health Sciences, in Albany, New York.

Unfortunately, the study was not powered to compare the safety of both medication types, although researchers did find a higher percentage of non-TNF patients (11%; n=16) experienced serious adverse events compared to anti-TNF patients (5%; n=8) (P=.10). Seven patients from each group had serious infections.

Perhaps one of the biggest limitations of the JAMA study was about 40% of patients from each treatment group were not taking concomitant methotrexate with their non-TNF or anti-TNF medication. This is a serious factor to consider, since methotrexate is known to improve the efficacy of most biologics.

This study was sponsored by the French Ministry of Health and promoted by The Direction de la Recherche Clinique et de l’Innovation, Strasbourg University Hospital. All authors of the study submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. All relevant information on disclosed conflicts of interest can be accessed from the full study here.

Last updated on: January 10, 2017
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Alternative Treatments for Rheumatoid Arthritis

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