JAK Inhibitors: Are All Promises Fulfilled?

However, Dr. Schulze-Koops noted that “only about 15% of patients reached the treatment goal that we have given ourselves for RA [low disease activity or remission] in these trials.”^3,5

“I would say that in RA, JAK inhibitors are at least as effective as other bDMARDs in terms of clinical response in methotrexate and TNFα inhibitor non-responder populations,” he concluded. “The promise that they’re as good as bDMARDs is fulfilled, but a promise beyond that—100% remission—is not fulfilled.”

Promise 2: Drug Survival

Dr. Schulze-Koops next addressed JAK inhibitor drug survival (i.e., the length of time until discontinuation of drug). Drug survival considers discontinuation for all reasons e.g., tolerability, side effects, safety, effectiveness). “The half-life of TNFα inhibitor therapy is about two years because these drugs lose their effect and patients become secondary non-responders,” he said. “On the other hand, the half-life of JAK inhibitors is close to five years. So I would say that promise no. 2 is fulfilled.”^6,7

Promise 3: Safety

Since JAK inhibitor development, numerous attempts have been made to document the safety of JAK inhibitors for patients, and an enormous amount of data exist from which to deduce safety statements. Studies have pooled data from phase 1, 2, 3 and 3B/4 randomized controlled trials (RCTs) and open-label, long-term extension studies.

Initial long-term safety data indicated that safety profiles were generally comparable between JAK inhibitors and bDMARDs. “Tofacitinib and baricitinib fell almost in the middle when it came to problems we detect with bDMARDs, with the exception of [an increased rate] of the incidence of herpes zoster,” Dr. Schulze-Koops remarked.^8,9

Regarding major adverse cardiovascular events (MACE), a 2019 systematic review and meta-analysis of 26 RCTs didn’t demonstrate an increased risk of MACE with JAK inhibitors over placebo.¹⁰ Recent observational data from RABBIT, the German register for the long-term observation of therapy with biologics in adult patients with RA, also didn’t demonstrate an increased incidence rate of MACE compared with TNFα inhibitors or conventional synthetic DMARDs.¹¹ This held true for a higher risk group of patients aged 50 and above with one or more cardiovascular risk factors.

The most important clinical reason for a physician to prescribe a JAK inhibitor was the hope for strong overall efficacy.

Finally, a 2020 systematic review and meta-analysis of 82 studies comprising 66,159 patients with immune-mediated diseases (inflammatory bowel disease, RA, psoriatic arthritis and ankylosing spondylitis) didn’t demonstrate an increased risk of malignancy or MACE, either.¹²