CHICAGO — Daniel Furst, MD, a Carl Pearson Professor of Medicine and director of the Rheumatology Clinical Research Center at the University of California Los Angeles School of Medicine, said rheumatologists need to “get creative” in the treatment of rheumatoid arthritis and use the best-known data to combine therapies for patients with symptoms that are difficult to resolve.
Some combinations of disease-modifying anti-rheumatic drugs (DMARDs) and biologic therapies make more sense than others, depending on their effects and side effects, according to Furst.
“You want to look at mechanisms that do not overlap, and you want to look at toxicities that do not overlap,” Furst said during the American College of Rheumatology State-of-the-Art Clinical Symposium.
Furst cited methotrexate and sulfasalazine, which have a great deal of overlap in their method of action in the treatment of patients with rheumatoid arthritis (RA), as an example. Contrastingly, there is not much overlap between abatacept and cyclosporine, nor between tofacitinib and tumor necrosis factor-alpha (TNF-a) inhibitors, he said.
“When you do not have overlap of mechanisms, you have higher probability that they will work together and be additive to each other, not work against each other,” Furst said. “This isn’t infallible, but it is a reasonable way to approach it.”
Furst said he uses the same method with toxicity. Although cyclosporine and methotrexate have some tendency to overlap in mechanisms, they do not in terms of toxicity, and data from clinical trials show that the two can work well together. In the case of adding tocilizumab to methotrexate, no overlap in toxicity is present; however, because both affect interleukin-6 activity, little improvement is seen in the data, with the exception of patients with very low disease activity, according to Furst.
“In this case, the idea of non-overlap means we might not get the kick that we might get with TNF inhibitors plus methotrexate.”
In some cases, medications can work against each other. Furst explained the mechanism by which sulfasalazine inhibits the reception of methotrexate into cells; however, he also noted that “triple therapy,” or the combined use of methotrexate, sulfasalazine and hydroxychloroquine, has been studied and has demonstrated improvements in patients with RA. According to Furst, hydroxychloroquine stimulates the cell influx pump, which allows methotrexate to enter the cell, thereby counteracting the blocking effect of sulfasalazine.
In patients who have not responded well to numerous prior treatments, or in those who responded initially but then failed to respond, Furst said he may combine abatacept and cyclosporine and later add tofacitinib if the patient needs an additional reduction of symptoms.
“We are adding some pretty strong drugs, but there should not be overlap of mechanisms and, even though the data are not there, it is something to do in this patient in whom nothing seems to work,” Furst said. - by Shirley Pulawski
Furst, D. Session III, presentation #1. Presented at: American College of Rheumatology State-of-the-Art Clinical Symposium. May 2-3, 2015; Chicago.
Disclosure: Furst reports relationships with AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Cytori, Gilead, GSK, Janssen, NIH, Novartis, Pfizer, Roche/Genentech and UCB.