JAK inhibitors are the first effective long-term, oral biologic alternative for RA patients.
The Boxed Warning for these drugs explain the risk of serious heart-related events, blood clots, cancer, and death.
Although showing promise in animal models, BTK inhibitors have yet to show clinical efficacy in humans, with more research needed.
Kinase inhibitors have proven transformative in the treatment of rheumatoid arthritis (RA). These drugs can help fill the gap in the current arsenal of available disease-modifying antirheumatic drugs (DMARDs).
Filling the gap in RA care
There have been a spate of biologic DMARDs (bDMARDs) making their way to the market during the past 20 years, as noted by a review in the Journal of Inflammation Research. These drugs were seen as more specifically targeted at immunosuppression vs methotrexate, with the latter originally being developed for chemotherapy in the 1950s.
Janus kinase (JAK) inhibitors are small-molecule oral treatments that can pass through the lipid bilayer of the cellular membrane.
JAK and the signal transducer and activator of transcription (STAT) play a role in cytokine signaling and RA pathogenesis. As such, they could fill an unmet need in RA care.
“Despite the arrival of tumour necrosis factor (TNF) inhibitors, B cell depletion of CD20 cells and interleukin 6 (IL-6) inhibition, there remains a sizeable cohort of RA patients with suboptimal control, loss of response or intolerability to the existing bDMARDs,” wrote the Journal of Inflammation Research review authors.
The three FDA-approved JAK inhibitors for RA are tofacitinib (Xeljanz, Xeljanz XR); baricitinib (Olumiant); and upadacitinib (Rinvoq).
In terms of clinical outcomes, JAK inhibitors exhibit similar efficacy to TNF inhibitors, and early pain relief indicates these drugs mitigate central-pain processing. JAK inhibitors also attenuate radiographic progression of the disease, and there are objective improvements demonstrated in as little as 2 weeks, with maximum benefit extending past 3 months.
JAK-inhibitor safety signals
JAK inhibitors are now approved to treat RA, psoriasis/psoriatic arthritis, IBD, spondyloarthritis, and skin conditions such as atopic dermatitis, as well as ulcerative colitis.
Although effective, JAK inhibitors can be dangerous, and the FDA necessitated revisions to the Boxed Warning for these drugs in 2021 to confer the risks of serious heart-related events, blood clots, cancer, and death, according to an FDA statement.
These adverse events were based on clinical trials of tofacitinib, but because this agent shares mechanisms of action with the other two JAK inhibitors used to treat RA, all three JAK inhibitors may increase risk, per the FDA.Related: That's debatable! Doctors dissect 5 hot topics in rheumatology
The FDA offers specific guidance to HCPs regarding the prescription of JAK inhibitors to RA patients. “Health Professionals should consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Xeljanz/Xeljanz XR, Olumiant, or Rinvoq. This is particularly the case in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer,” they advise.
“Reserve these medicines for patients who have had an inadequate response or intolerance to one or more TNF blockers. Counsel patients about the benefits and risks of these medicines and advise them to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot,” the FDA cautions.
Bruton's tyrosine kinase (BTK) makes for an enviable target for RA treatment, and BTK expressed by many immune cell types. BTK is a chief constituent of the immune response and mediates the B-cell receptor and Fc-receptor signaling pathways crucial to the pathology of RA and other autoantibody-mediated conditions.
Although demonstrating efficacy in mouse models of systemic autoimmune conditions, the role of BTK inhibition has yet to be demonstrated in RA clinical trials.
There are no biomarkers that are linked to treatment response, which could aid with the formulation of BTK inhibitors for RA and a personalized-medicine strategy.
BMS-986142 is an oral, reversible BTK inhibitor that decreases inflammation and joint destruction when compared with standard-of-care treatment. In a recent phase 2 clinical trial published in The Lancet Rheumatology, the drug failed to impress.
“Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis,” according to the study authors.
What this means for you
The three FDA-approved JAK inhibitors for RA are tofacitinib, baricitinib, and upadacitinib. These drugs improve clinical outcomes in RA and slow disease progression. The downside is that they carry a Boxed Warning and can increase serious health risks. These risks should be carefully weighed in patients with cardiovascular disease, those who smoke, and those with a history of cancer. Although promising, BTK inhibitors have failed to prove effective in treating RA in clinical trials, with further research needed.
Read Next: What can precision medicine do for rheumatology?