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FAQS: JAKi Safety
Safety of JAK Inhibitors in RA

Released: December 18, 2020

Expiration: December 17, 2021

Sheetal Desai
Sheetal Desai, MD, MSEd
Eric M. Ruderman
Eric M. Ruderman, MD
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In this commentary, rheumatologists Stanley B. Cohen, MD; Sheetal Desai, MD, MSEd; and Eric M. Ruderman, MD, answer safety questions from a CCO Webinar on the management of patients with rheumatoid arthritis (RA) receiving JAK inhibitors. Webinar slides are also available for self-study or to use in your noncommercial presentations.

What is the risk of venous thromboembolism (VTE) with JAK inhibitors?
Stanley Cohen, MD:
The question of VTE first came up in the placebo-controlled portion of the baricitinib RA studies. When they took a look at extended portions of the trials for both 2 mg and 4 mg and then looked at the totality of the patients’ long‑term extension, however, the rates of VTE were similar to what we’ve seen reported for RA in observational and claims based data. In the SELECT series, the event rate with upadacitinib was basically no different from adalimumab or methotrexate or placebo. And in the FINCH series, the event rate was also low with filgotinib, adalimumab, or methotrexate.

But then came some data from an FDA mandated trial, a postmarketing trial looking at tofacitinib 5 mg and 10 mg BID in patients with RA who had higher risk for cardiovascular disease. With the 10-mg BID dose of tofacitinib, there was a statistically different rate of pulmonary emboli compared with 5-mg BID of tofacitinib and compared with etanercept or adalimumab. There was also a statistically different all‑cause mortality with the nonapproved tofacitinib 10-mg BID dose. There was a numerical trend for deep vein thrombosis, but that was not statistically significant between the 2 different doses of tofacitinib or the TNF inhibitors.

Based on the findings, the European Medicines Agency (EMA) recommended that tofacitinib should be used with caution in any patients with known risk factors for VTE.

Are some patients with RA at greater risk for VTE?
Sheetal Desai, MD, MSEd:
The data are evolving and currently there are no recommendations on how to reduce the risk of VTE while receiving JAK inhibitors. The only way to reduce risk would be by avoiding these agents in patients who have additional risk factors that place them at higher risk for VTE.

For example, in someone who has had a previous VTE, someone who is obese, or someone with cardiovascular risk factors, if you have an alternative therapy that you could use, then move on and use a different therapy other than a JAK inhibitor.

Can a JAK inhibitor be given to a patient receiving a therapeutic anticoagulant for previous deep vein thrombosis?
Sheetal Desai, MD, MSEd:
Given the known risk, you should avoid it if you can, but we’re in a data‑free zone when it comes to using JAK inhibitors in patients receiving chronic anticoagulation. Thus, it is an individual decision by patients and their treating rheumatologist, and it will very much depend on what other options are available for that patient.

Can you comment on sperm parameters with filgotinib?
Eric M. Ruderman, MD:
The EMA approved filgotinib for RA in September 2020, but the FDA did not. I believe potential testicular toxicity was part of the FDA’s concern.

Changes in semen parameters came up during preclinical studies in rats and dogs. This was at high doses, and at this point, we don’t know if it is relevant at the doses that are going to be used in humans. It appears that this issue may be specifically related to the filgotinib molecule and not to JAK inhibition in general. It has not been seen with any other JAK inhibitors.

We should learn more from the MANTA and MANTA-Ray studies, which are examining the safety of filgotinib in men with inflammatory bowel disease or rheumatologic diseases, respectively. Data should be available in 2021.

Can you comment on infections in patients with RA?
Eric M. Ruderman, MD:
As with any of the agents we use in RA, infections tend to be our number one concern and, in particular, a serious infection, which means either hospitalization for infection or requirement for IV antibiotics. Of interest and of importance for JAK inhibitors, it turns out that a flare for herpes zoster is a unique infectious adverse event that shows up in clinical trials. This underscores the importance of encouraging the use of the widely available zoster vaccine for patients with RA.

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