Arthritis Today

When an Anti-TNF Fails for Rheumatoid Arthritis, What’s Next?

A study weighs various biologics as second-line treatment for RA patients.


Even though biologic disease-modifying antirheumatic drugs, or biologic DMARDs, have been around for more than a decade, rheumatologists are still trying to understand how to target the right treatment to the right patient at the right time. And while biologics have been game changers for many patients with rheumatoid arthritis, or RA, the success has not been uniform – some patients don’t respond completely or at all, some stop responding after a while, and some can’t tolerate them. What to do with those patients?

That issue has become a priority for rheumatologists as the gap in outcomes between responders and non-responders grows. A new study has provided some preliminary answers to a key question with which rheumatologists have been grappling: Should a patient who doesn’t improve or respond well to a type of biologic called an anti-tumor necrosis factor drug, or anti-TNF, try a second anti-TNF or another type of biologic altogether? 

The study, published in Arthritis Care & Research, suggests that RA patients who don’t respond to an anti-TNF may get better results if they try a biologic called rituximab, or Rituxan, instead of a second anti-TNF.

The treatment options for new RA patients are relatively well understood up to a point. Typically, a patient newly diagnosed with RA is put on one or a combination of traditional DMARDs, such as methotrexate; hydroxychloroquine, brand name Plaquenil; or leflunomide, brand name Arava. If the patient can’t tolerate or doesn’t respond to traditional DMARDs, he or she is stepped up to a biologic, a complex medication made from living proteins. The American College of Rheumatology, or ACR, guidelines for DMARD therapies, revised in 2012, lists anti-TNFs as the first-line choice among biologics.

Anti-TNFs – also called TNF inhibitors or TNF blockers – work by blocking tumor necrosis factor, a cytokine, or protein, that promotes an inflammatory response. The five anti-TNFs on the market are adalimumab, or Humira; certolizumab pegol, or Cimzia; etanercept, or Enbrel; golimumab, or Simponi; and infliximab, or Remicade.

When an anti-TNF works, it works well, but when it doesn’t, the alternatives are other anti-TNFs or other biologic DMARDs that work via different mechanisms. Rituximab is a selective B-cell inhibitor; anakinra, or Kineret, is an interleukin-1 inhibitor; tocilizumab, or Actemra, is an interleukin-6 inhibitor; and abatacept, or Orencia, is a selective costimulation modulator.

“Our study showed that, overall, the response was slightly better in patients who were switched to rituximab,” says study author Kimme Hyrich, MD, PhD, from the Arthritis Research Epidemiology Unit at the University of Manchester in the United Kingdom.

But she acknowledges that the study findings don’t tell the entire story. “We do not yet have the ability to predict what will be the best treatment for any individual patient, and there may still be circumstances where a second anti-TNF or even a different biologic altogether may be a better choice,” she says.

In the study, researchers analyzed information from a database called the British Society for Rheumatology Biologics Register. They looked at two different subgroups of patients who had “failed” a first anti-TNF treatment (for any reason – either inadequate or no response, loss of response or inability to tolerate) and then switched to either rituximab or another anti-TNF. Because this was a retrospective analysis of existing data, the patients were not randomly assigned to receive a particular second biologic.  

Both groups were evaluated when they started the second therapy and again six months later. Improvements in one subgroup were measured using the Disease Activity Score, or DAS28, an assessment based on 28 tender and swollen joints. Improvements in the second subgroup were measured using the Health Assessment Questionnaire, or HAQ, a patient-reported measure of physical function and disability levels.

In the group with DAS28 scores, 54.8 percent of those who took rituximab reported a “good” or “moderate” response (according to the European League Against Rheumatism criteria) six months after they had switched, compared to 47.3 percent of those who took a second anti-TNF. In the group with HAQ scores, 38.4 percent on rituximab reported they experienced a clinically important improvement compared to 29.6 percent in the anti-TNF group. In both subgroups, the differences in improvement between the rituximab and the anti-TNF groups were considered statistically significant.

“We are continuing to learn about the nature of inflammation in rheumatoid arthritis, and for some patients it may be better to try to block their inflammation using rituximab, which inhibits B-cells, as opposed to anti-TNF therapies, which block the cytokine tumor necrosis factor, which is an important protein involved in inflammation,” says Dr. Hyrich. This research builds on a previous, smaller study that found similar results when rituximab was used as a second-line therapy, he added.

But there is still much to learn. She says researchers are still trying to understand why some patients respond better to one drug than another. “I don't think we fully understand the way in which rituximab is controlling symptoms in rheumatoid arthritis. There is some evidence that patients who are positive for rheumatoid factor or anti-CCP antibodies will respond better to rituximab compared to those who are negative for these antibodies,” she says. “In other patients, TNF may be less important in their inflammation and other proteins or cells more important.”

Dr. Hyrich says the most important thing patients should do is discuss their individual treatment options with their rheumatologist.

Daniel E. Furst, MD, the Carl M. Pearson Professor of Rheumatology at UCLA Medical Center, believes some imbalances may exist in the patient groups in this study because patients were not randomly assigned a second biologic. That could have biased the results to favor rituximab, he says. For example, among the DAS28 group, nearly 60 percent of patients who switched to a second anti-TNF stopped the first one because of inefficacy. “If that group stopped because of primary inefficacy – rather than for loss of response or adverse event – one wouldn’t expect the second [anti-TNF] to work, but they switched to the [anti-TNF] anyway,” Dr. Furst explains. “There’s a chance these [results] were biased because of the reasons patients switched.”

Dr. Furst, who was one of the lead authors of the ACR’s revised guidelines for DMARD therapy, believes one must understand why a patient failed the first anti-TNF to get a sense of how well he or she will do with the medication they try next. That’s what he and his colleagues tried to keep in mind when they were revising the guidelines, thus allowing for greater flexibility and choice, he says.

The updated guidelines recommend that patients who have no response or an inadequate response to an anti-TNF after three months try either a second anti-TNF or a different type of biologic. If a patient experienced a serious adverse event, the guidelines recommend switching to a biologic that isn’t an anti-TNF.

“If the patient ‘failed’ because they had absolutely no response, it makes good sense to try a drug like Rituxan or another non-TNF biologic,” Dr. Furst says. “This approach is supported by the medical literature.”

Robert Katz, MD, professor of medicine at Rush University Medical Center in Chicago, says patients should also keep in mind practical considerations when making a switch to a second biologic. “There could be problems regarding insurance, method of administration [infusion vs. injection], and doctor preference and the location of infusion facilities that could also influence this decision,” he says.

Dr. Hyrich says the British Society for Rheumatology receives funding from a number of pharmaceutical companies including Abbott, Amgen, Roche, Schering-Plough, and Wyeth. But she says all decisions regarding analysis and publication were independent from pharmaceutical funding.