Dr. Levesque: To answer this question, I would point to three large trials that have been published recently; each of them addressed the issue of efficacy as it relates to the agent tofacitinib, [a JAK inhibitor,] in the treatment of rheumatoid arthritis.1-3 Overall, there were excellent responses noted for tofacitinib when compared to placebo in all of the studies.1-3 The greatest responses were in those patients who were methotrexate-inadequate responders; those who were TNF-inadequate responders had lesser ACR20 responses. One of the studies also addressed the issue of using tofacitinib as a monotherapy,3 and in this particular study, excellent results were also obtained, and so it appears likely that tofacitinib will be very efficacious, even without the use of methotrexate or other DMARDs in combination.
One of the other points, though, that was made in the Fleischmann monotherapy study: There wasn't a big difference between the tofacitinib and the placebo group as it relates to achieving remission.3 The other thing to note is that at the currently approved dose of 5 mg of tofacitinib twice a day, that dose did not achieve radiographic endpoints as related to the prevention of joint damage.4 The endpoint was reached at a higher dose of [tofacitinib] 10 mg twice a day,4 but 10 mg twice a day is not the currently approved dose for the treatment of rheumatoid arthritis. So there do still remain some questions about tofacitinib, at least in terms of its ability to induce remission and inhibition of radiographic progression.
The other big issue that comes up in this context is how well tofacitinib compares to the TNF therapies. There has been a comparison—the van Vollenhoven study that was published in New England Journal [of Medicine]—and adalimumab given every other week at its standard dose of 40 mg did achieve a similar level of efficacy to tofacitinib.2
Overall, there were somewhat more adverse events in the patients that received tofacitinib compared to those that received adalimumab, and there did appear to be somewhat greater numbers of infectious problems.2 Other studies have suggested that there may be a higher rate of herpes zoster or shingles in the context of receiving tofacitinib5—higher than what we're used to seeing with anti-TNFs. Patients receiving tofacitinib have also had somewhat greater amounts of diarrhea and nausea.6
When one compares the effects of tofacitinib and adalimumab on white blood cell counts, on lipid levels, [and] on liver abnormalities, there was about an equal incidence of neutropenia that occurred in both groups, and it was relatively minor. In contrast, lipid levels and liver tests were significantly higher for patients receiving tofacitinib compared to those receiving adalimumab.2 However, generally these were not great enough that it necessitated discontinuation of tofacitinib in this particular study. So overall, the safety profile of tofacitinib is relatively acceptable for most of our patients with rheumatoid arthritis.
I should also note that there are other small molecules that are currently in development for rheumatoid arthritis. Prominent among these is baricitinib, which is also a JAK kinase inhibitor. It's somewhat different than tofacitinib in that it inhibits primarily JAK1 and JAK2, whereas tofacitinib primarily inhibits JAK1 and JAK3, and also to some extent JAK2. Baricitinib is currently in phase 3 studies; it showed promising results in [a] phase 2 study.7 And so I think one should understand that there is some caution to these agents, but overall they were relatively well tolerated and efficacious.