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JAK Inhibitors: An Innovation in Treatment

At the 2020 Winter Clinical Dermatology Conference, Seemal R. Desai, MD, discussed the latest breakthroughs with janus kinase (JAK) inhibitors to the 1500 attendees. His presentation divided JAK inhibitors into “disease-state buckets” and described the potential therapeutic effects of each product.

The therapeutic pathway of JAK inhibitors seeks to stop inflammation before it starts. “When you have your cytokine mediator, for example IL-6 or IL-31 in atopic dermatitis or it’s IL-1α or IL-3 in vitiligo, whatever your cytokine is ends up binding to that cellular receptor,” explained Dr Desai. “That subsequently is what turns on that phosphorylation in bringing these two JAK molecules together, which releases the safety signals. Ultimately, when the cytokine binds, bringing these JAK molecules together, that subsequently turns on the recruitment of STAT, which goes into the nucleus and turns on the inflammatory cascade.” JAK inhibitors, however, bind to the kinase domain of JAK to prevent additional inflammation.

The current players, and their indications, include tofacitinib (Xeljanz), indicated for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis; ruxolitinib (Jakafi), approved for polycythemia vera and myelofibrosis; and upadacitinib (Rinvoq), which can be used to treat rheumatoid arthritis. There are several other JAK inhibitors under study, including:

  • Oclacitinib (approved for veterinary use for atopic dermatitis in dogs);
  • BMS-986165 (being studied in phase 2 trials for the treatment of psoriasis and psoriatic arthritis);
  • Abrocitinib (phase 3 study on atopic dermatitis just completed);
  • Baricitinib (Olumiant; approved in Europe for rheumatoid arthritis);
  • Fedratinib (Inrebic; approved for myelofibrosis);
  • Momelotinib (FDA fast-track designation for myelofibrosis); and
  • Decernotinib (in phase 2/3 studies for the treatment of rheumatoid arthritis)

Dr Desai noted that knowing which JAKs are being inhibited by a drug is incredibly important to understanding the safety profile of the drug. “For example, we typically end up seeing more systemic lab abnormalities and issues with blood counts with ruxolitinib than with tofacitinib, and that’s because ruxolitinib blocks JAK2 whereas tofacitinib does not,” said Dr Desai. He suggested performing a blood count, lipid panel, and comprehensive metabolic panel to monitor the patient’s response to the JAK inhibitor. “Generally, if you monitor monthly for the first one to three months, and you don’t see any abnormalities and you’ve kept [the patient] on the same dose, the data is pretty good and you’re likely not to see a major drop in white count,”

For atopic dermatitis, tofacitinib and ruxolitinib block IL-6, IL-15, and IL-23, which are all important in signaling in eczema. Abrocitinib has also shown potential and promising results as a treatment for eczema and will be released soon for use.

Alopecia areata also can be treated with JAK inhibitors. Dr Desai suggested using topical tofacitinib 2%. Some recent studies, he continued, have shown patients getting on a JAK inhibitor therapy sooner may help with downregulation of transforming growth factor beta and possibly reduce scarring of the hair follicles.

In vitiligo, tofacitinib on a lower dose can be. Ruxolitinib cream 1.5% is an effective treatment, but it can cause some adverse events.

Psoriasis has also been studied as a possible target for JAK inhibitor therapy. Most notably, BMS-986165 has been shown to reduce the pathologic hallmarks of psoriasis.

Reference

Desai SR. JAK inhibitors: the new breakthroughs in the treatment of dermatologic disease. Presented at: 2020 Winter Clinical Dermatology Conference; Kohala Coast, HI; January 18, 2020.

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