JAK inhibitors offer safe, effective ‘patient-centric approach’ to broad range of IMIDs
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While FDA- and EU-approved JAK inhibitors have shown comparable efficacy and safety across a spectrum of immune-mediated diseases, more study is required to fully parse the mechanism of action, according to a presenter at the 2020 Interdisciplinary Autoimmune Summit.
“The objective is to evaluate the role of JAK-inhibitors within the RA and other immune-mediate inflammatory diseases (IMID) treatment armamentarium,” Vibeke Strand, MD, MACR, FACP, adjunct clinical professor in the division of immunology/rheumatology at Stanford University, said in her presentation. “Also, to leverage new and emerging JAK-inhibitors for patient-centric approaches to IMIDs.”
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Strand provided an overview of the JAK/STAT signaling pathway for tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Lilly), upadacitinib (Rinvoq, Abbvie) and filgotinib (Galapagos NV), among others. “JAK inhibitors display different in vitro profiles and different cytokine signals,” she said. “Despite these differences, they behave more similarly than they do differently.”
While understanding of the mechanism of action of JAK inhibitors is growing, Strand noted that there is still work to be done in this area. “It is unclear which cell types and what signaling pathways are affected at any given time,” she said.
This has not hindered the FDA and EU in approving these drugs, with at least one JAK inhibitor approved for rheumatoid arthritis and psoriatic arthritis and phase 3 clinical trials underway for use in spondyloarthropathies and juvenile inflammatory arthritis.
Regarding dermatology indications, trials are underway in atopic dermatitis, chronic actinic dermatitis, alopecia areata, erythema multiforme, graft vs. host disease and facial vitiligo. Abrocitinib (Pfizer) has been granted breakthrough status in atopic dermatitis, according to Strand.
In gastroenterology, although tofacitinib has been approved for ulcerative colitis, an indication for Crohn’s disease has yet to emerge. “Crohn’s tofacitinib trials did not show efficacy,” Strand said. “It is unclear if it was the trial design or the outcome measures. That has always been a problem in Crohn’s.”
Further evidence of the potential broad-spectrum utility of JAK inhibitors can be gleaned from research being conducted in their utility in a range of other immune-mediated conditions.
Researchers are investigating baricitinib in autoinflammatory interferonopathies and tofacitinib in so-called SAPHO syndrome, defined as synovitis, acne, pustulosis, hyperostosis and osteitis, according to Strand. Trials also are underway or completed in systemic lupus erythematosus, primary Sjogren’s syndrome, dermatomyositis and giant cell arteritis.
“All [JAK inhibitors] studied to date are effective across a broad range of IMIDs,” Strand said. “They have an early onset of benefit, usually within 1-2 weeks, and reach maximal benefit at 3 months.”
She added that patient-reported outcomes are frequently strong, regardless of the disease or patient population.
If there are safety concerns with drugs in the JAK/STAT pathway, they largely fall into two key categories: thromboembolic events and herpes zoster risk. Strand offered commentary on both.
“We do not know the details about thromboembolic events, specifically in RA populations,” she said. “It is unknown how much of this risk may be due to underlying comorbidity of disease.”
Regarding herpes zoster, the message was clear: “Vaccination is important,” Strand said.
“I hope I have convinced you that this is a very effective therapy across many IMIDs,” Strand concluded. “We look forward to using them for many indications of diseases.”
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Strand VS. The Expanding Role of JAK Inhibitors across IMIDs. Presented at: Interdisciplinary Autoimmune Summit; July 10-12, 2020 (virtual meeting).
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