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JAK Inhibitors in RA
JAK Inhibitors in Rheumatoid Arthritis: Weighing the Anticipated Options

Released: September 09, 2016

Expiration: September 08, 2017

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When comparing the JAK inhibitors tofacitinib and baricitinib, one might expect to see differences in efficacy and/or safety because they target different JAK pairs. Tofacitinib is a pan-JAK inhibitor, with selectivity for JAK 3/JAK 1/JAK 2, whereas baricitinib is more specific for JAK 1/JAK 2. Yet overall, the clinical trial data to date have shown them to be largely similar in efficacy and safety. Both work rapidly and produce clinical responses (ACR20, ACR50, ACR70), reduce disease activity scores, achieve low disease activity and remission in a proportion of patients, improve patient-reported outcomes such as the Health Assessment Questionnaire and Short Form 36 and both agents are able to inhibit radiographic progression. Thus, choosing between them will likely prove challenging in clinical practice.

Efficacy
Although we have no data from a head-to-head comparison between baricitinib and tofacitinib, there may be some minor differences between the two. One difference is that tofacitinib monotherapy was statistically significantly different vs methotrexate at inhibiting radiographic progression whereas baricitinib monotherapy was not. In the ORAL START study, tofacitinib monotherapy was statistically superior to methotrexate monotherapy by clinical, functional, and radiographic assessments in methotrexate-naive patients with early RA. Conversely, in the RA-BEGIN trial of baricitinib either in combination with methotrexate or as monotherapy vs methotrexate monotherapy in early RA, both baricitinib arms were superior to methotrexate alone in clinical responses and patient-reported outcomes; baricitinib plus methotrexate was superior to methotrexate in slowing radiographic progression but baricitinib monotherapy was not. However, this may not be clinically significant, as both methotrexate and baricitinib monotherapy were effective in limiting radiographic progression. Thus, for patients who cannot tolerate methotrexate or who wish to taper off of methotrexate, I would consider either tofacitinib monotherapy or baricitinib monotherapy. One possible difference is that baricitinib appears to improve patient pain very early after initiation of therapy and was superior to adalimumab in this outcome (RA-BEAM); tofacitinib, on the other hand, was similar to adalimumab (ORAL-Standard).

When compared with adalimumab plus methotrexate in biologic-naive patients, baricitinib plus methotrexate had superior clinical and functional responses, with similar radiographic responses. On the other hand, although it was not a head-to-head comparison of tofacitinib vs adalimumab, results from the ORAL Standard study showed a numerically comparable efficacy of tofacitinib plus methotrexate and adalimumab plus methotrexate (both treatments were statistically significant vs placebo). There appears to be a trend of higher efficacy with tofacitinib, but we cannot conclude that it is superior because the trial was not designed to directly compare them; the ongoing ORAL STRATEGY trial will answer this question. We may learn that both agents are superior to adalimumab plus methotrexate in biologic-naive patients, but we must await further data to conclude this for tofacitinib.

In patients who have had an incomplete response to methotrexate or TNF inhibitors, baricitinib and tofacitinib appear to be equally efficacious. Meanwhile, it remains to be seen if patients who do not respond with one of the JAK inhibitors will respond with the other. We may have to wait for postapproval, real-world data to answer this question. However, it seems like a rational approach given what we know about how patients respond to different TNF inhibitors.

Safety
Regarding safety, both drugs appear to have similar adverse event profiles. Serious infections, herpes zoster, tuberculosis, neutropenia, lymphopenia, and increases in lipids and liver function tests have been reported with both. Minor elevations in creatinine and creatinine phosphokinase have been observed with both drugs for reasons that are unclear. Notably, early trials of both baricitinib and tofacitinib showed lower rates of serious infections vs methotrexate. However, we should still consider the risk for serious infections before administering any RA treatment. Although it is difficult to compare across clinical trials due to inherent differences in the patient populations, there may be slightly lower rates of herpes zoster with baricitinib vs tofacitinib. Nonetheless, it remains a risk with both drugs, and clinicians should closely monitor patients.

Dosing
Both tofacitinib and baricitinib offer once-daily dosing. Tofacitinib offers dose flexibility (11 mg once daily or 5 mg twice daily), and baricitinib may also have dose flexibility based on the finalized FDA recommended dosing. Personally, I am hopeful that both the 2-mg and 4-mg doses will be approved, as it would allow for dose reduction as a useful strategy to minimize the adverse event profile. Moreover, a recent study from EULAR showed that approximately 80% of patients in stable remission with 4-mg/day baricitinib maintained disease control following dose reduction to 2 mg/day (but this was following only 12 weeks of observation). In my practice, I have employed tofacitinib dose reduction in a small number of patients with good success.

Summary
In summary, although tofacitinib and baricitinib target different JAK dimers, their clinical efficacy and safety appear to be largely similar. In my practice, I routinely use tofacitinib for patients with an inadequate response to methotrexate or a biologic. When baricitinib is approved, as I expect it will be, choosing between them will be quite difficult and may ultimately be decided by the preference of the patient or a third party payer.

Your Thoughts?
How do you anticipate choosing between tofacitinib and baricitinib in your practice? Answer the polling question and post your thoughts in the comments section below. And for more discussion of indications, mechanisms of action, and recent pivotal trial data on JAK inhibitors in RA, watch this CME-certified interactive video featuring Gregg J. Silverman, MD, and William F. C. Rigby, MD.

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Following the approval of baricitinib, which factor do you anticipate will be most helpful when choosing between it and tofacitinib for patients with an inadequate response to methotrexate?
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