Modern Management of RA: A Look at Emerging Treatment Approaches

Course Director

Marc C. Levesque, MD, PhD

Marc C. Levesque, MD, PhD
Associate Professor
University of Pittsburgh
Division of Rheumatology and Clinical Immunology
Pittsburgh, Pennsylvania


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Part 1 of a 2-part series

Dr. Levesque provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

Despite the availability of disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA), treatment may remain suboptimal for many patients. Therefore, the new concept of RA treatment stresses early intensive therapy with optimal doses of classic DMARDs, followed by early introduction of biologic agents if improvement is inadequate. Given this paradigm shift, rheumatologists not only need to incorporate the latest treatment options into their management plans for their patients with RA, but they also have to keep abreast of the evolving clinical data on the emerging standard of care. In this activity, Dr. Marc C. Levesque provides expert feedback on two of the most pressing questions submitted by your peers during a recent survey on this topic.


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How do JAK inhibitors and other new agents compare with anti-TNFs for remission and safety outcomes in rheumatoid arthritis [RA]?

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.

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Do we have any sense of the preferred order for using biologic therapies in rheumatoid arthritis?

Dr. Levesque: Currently, the treatment paradigm is to use biologics roughly in the order in which they were introduced to the marketplace, mostly because much is known about the safety profile of these drugs, especially the ones that were introduced earlier on. Generally, most rheumatologists, when they select a biologic, start by using an anti-TNF therapy. And that's actually what's currently recommended by the American College of Rheumatology [ACR].8 I would point out, though, that abatacept and tocilizumab are indicated as first-line therapy for patients who have had an inadequate response to methotrexate and who have moderate or severe rheumatoid arthritis.

One of the reasons for bringing this up is that the [agents’] safety profiles are relatively comparable—or even perhaps in some ways better—than the safety profiles associated with anti-TNF therapy. Anti-TNF therapies are contraindicated for patients who have a recent history of a malignancy, and also in patients who have congestive heart failure. And in that sense, abatacept and tocilizumab may have certain advantages, especially in patients with heart failure. In the case of patients who’ve had a recent malignancy, the current ACR guidelines suggest that those patients be treated with rituximab.8 One of the other questions that came up was whether or not any of these agents can be used in combination. The answer to that is no. When specific combinations of biologics have been tested together, generally it results in an unacceptable toxicity profile, and in particular, it increases the rate of infections.

So I think that the standard paradigm of treating first with an anti-TNF therapy may be brought into question, especially as we continue to gather new data about all of these agents. I think one of the big questions that arises is where do JAK inhibitors fit in this treatment scheme? And I think right now that the answer for that is not known. There are still, as I mentioned, some concerns about the JAK inhibitors as it relates to their infection risk and the prevention of radiographic progression. And so right now, at least in my opinion, the JAK inhibitors would not be at the front of the line for the preferred order for use.

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References

  1. Burmester GR et al. Lancet. 2013;381:451-460.
  2. van Vollenhoven RF et al. N Engl J Med. 2012;367:508-519.
  3. Fleischmann R et al. N Engl J Med. 2012;367:495-507.
  4. van der Heijde D et al. Arthritis Rheum. 2013;65:559-570.
  5. Winthrop KL et al. American College of Rheumatology/Association of Rheumatology Health Professionals 2012 Annual Meeting (ACR/ARHP 2012). Abstract 26957.
  6. Wollenhaupt J et al. ACR/ARHP 2012. Poster 1282.
  7. Genovese MC et al. ACR/ARHP 2012. Oral presentation 2487.
  8. Singh JA et al. Arthritis Care Res (Hoboken). 2012;64:625-639.

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