Tofacitinib for adolescent alopecia areata: Balancing the risk-benefit ratio
Jan. 17, 2017
There has been acute interest in utilizing Janus kinase (JAK) inhibitors for alopecia areata (AA). Does the media’s fervor touting tofactinib’s success translate into a rational decision to prescribe it for young patients?
According to Crispin et al, “The effect of tofacitinib on the JAK/STAT pathway in AA is evidenced by the downregulation of pSTAT3 in hair follicles during treatment. A recent study of normal murine cycling hair demonstrated that JAK signaling induces a telogen block, preventing the hair from entering anagen phase and that JAK inhibitors induce anagen hair growth similar to a hedgehog pathway agonist. Another study demonstrated upregulation of pSTAT1 and pSTAT3 signaling in hair follicles in AA but not normal hair follicles due to IFN-γ signaling, supporting the idea that immune dysregulation enforces a similar hair cycle arrest.” (1)
There have now been several reports of the benefit of tofacitinib in AA; Craiglow et al evaluated the benefit and adverse effects of tofacitinib, in a series of 13 adolescent patients, aged 12 to 17 years, with AA. The severity of disease was assessed using the Severity of Alopecia Tool (SALT). Adverse events were evaluated by laboratory monitoring, physical examinations, and review of systems. Nine patients experienced clinically significant hair regrowth. Median percent change in SALT score was 93% (mean 61%; 1%-100%) at an average of 6.5 months of treatment. Adverse events were mild (headaches in 3 patients, upper respiratory infections in 4 patients, and mild elevations of transaminases which reverted to normal despite continuation of therapy). Of the 13 patients, there were 4 non-responders, all of whom had alopecia universalis. The authors concluded that tofacitinib is a promising therapy for AA in adolescents and that its use (and other Janus kinase inhibitors) for the treatment of AA in this age group should be further evaluated in prospective clinical trials (2)
A vital question is the durability of response. If you are administering immunosuppressive agents, it is essential to know if this is a short or long-term proposition.
In Crispen et al’s study of 66 patients with AA treated with tofacitinib, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than alopecia totalis and alopecia universalis subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks (1).
Assuming long-term therapy, the potential risk of increased infections and malignancy must be addressed. It is most appropriate to survey the rheumatoid arthritis literature in this regard. The risks appear to be similar to those of other disease-modifying antirheumatic drugs for infections (3) and malignancies (4).
Aside from the issue of whether you can get the drug approved for AA, it is difficult to make general recommendations. Last week I had a student from Yale who was 100% gung ho about joining a trial of tofacitinib at his school (site of reference 2) with a full understanding of potential risks. Unquestionably, AA in its most severe forms, can be emotionally traumatic for anyone, but especially so for children and adolescents. Each patient (and their parents) must be handled individually, balancing the risks and benefits. My approach is like that of recommending biologics for psoriatics; the drugs are marvelous, reasonably safe, require long-term monitoring, and a good choice for the appropriate patient.
1. Crispin MK, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight 2016; 1(15): e89776.
2. Craiglow BG, et al. Tofacitinib for the treatment of alopecia areata and variants in adolescents. J Am Acad Dermatol 2017; 76: 29-32.
3. Strand V, et al. Systematic review and meta-analysis of serious infection with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther 2015; 17: 362.
4. Curtis JR, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis 20167; 75: 831-41.
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