Feedback AAD 2017

Treating Alopecia Areata, Vitiligo and Atopic Dermatitis: JAK Inhibitors, Something New for Dermatology

Janus kinase (JAK) inhibitors are small molecule drugs that can inhibit cytokine-mediated cell signaling in target cells by inhibiting JAK-1, JAK-2, and/or JAK-3 subtypes.

There is growing interest in the potential use of these medications for alopecia areata (AA), vitiligo, and atopic dermatitis (AD). The cytokines involved in each of these diseases differ, however, in all three; the effects of cytokine binding are mediated via the JAK pathway, providing a rationale for JAK inhibition. In his presentation, Brett Andrew King, assistant professor of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA described his experiences using JAK inhibitors in these diseases, as well as some supporting research.

Though there are many JAK inhibitors in the pipeline, just two are presently approved and available: tofacitinib, which targets JAK-1 and JAK-3, which is approved for moderate to severe rheumatoid arthritis (RA), and ruxolitinib, a structurally similar drug which targets JAK-1 and JAK-2 and is approved for myelofibrosis and polycythemia.

Let’s look first at alopecia areata (AA), a condition that affects 1% to 2% of the population and has a significant effect on health-related quality-of-life (HRQoL), with high rates of concomitant generalized anxiety disorder and major depressive order.

Current models of AA suggest a prominent role for the cytokine IL-15, which may be secreted by hair follicles. IL-15 activates T cells via JAK-1 and JAK-3, promoting secretion of interferon-gamma (IFN-g). This IFN-g then binds the hair follicle via JAK-1 and JAK-2, promoting further IL-15 secretion. With JAK-1 and JAK-3 playing a role at the T cell and JAK-1 and JAK-2 active at the hair follicle, there are two potential mechanisms for interrupting the pathogenesis of AA via JAK inhibition.

With these mechanisms in mind, King treated a patient in his 20s with alopecia universalis (AU) and plaque psoriasis with tofacitinib 5 mg twice daily (BID). At 8 months, the patient, who had been totally bald for 7 years, had regrown a full head of hair and experienced regrowth of eyebrows and eyelashes. Investigators at Columbia reported similar results using ruxolitinib in a mouse model of alopecia and in a single human subject.

These findings prompted King at Yale and his colleagues at Stanford to evaluate the efficacy and safety of tofacitinib in patients with severe AA, alopecia totalis (AT), and AU in an open label study. All patients had >50% scalp hair loss for ≥6 months without evidence of regrowth, and thus were unlikely to experience a placebo effect. Patients received tofacitinib 5 mg BID for 3 months. Treatment response was measured by assessing the percent change in scalp hair loss using the Severity of Alopecia Tool (SALT). At baseline, the vast majority of patients (71%) had AU. At 3 months, about a third of patients had >50% scalp hair regrowth, another third had between 5% to 50% regrowth, and about one-third were nonresponders. Reported side effects were relatively mild, and included acne and weight gain.

Limitations of this study include the lack of placebo control, the high proportion of patients with long-standing severe disease, and relatively short duration of therapy.

Results with ruxolitinib published around the same time noted similar findings, with a 75% patient response at 4 to 6 months.

Based on his initial findings, King starts patients on tofacitinib monotherapy at 5 mg BID for 10 to 12 weeks. If hair growth is occurring at that time, treatment is continued at the same dose, and response is assessed again after another 10 to 12 weeks. If hair growth has not occurred at the 10 to 12 week mark, the dose may be increased, or pulsed prednisone may be added.

An analysis of his patients treated with tofacitinib suggests that patients who have been completely bald for 11 years are unlikely to respond.

Promising results have also been reported with adolescents 12 to 17 years of age with AA, and in patients with severe AA-associated nail dystrophy receiving oral tofacitinib. Topical use of JAK inhibitors in AA is also being investigated.

Vitiligo affects about 1% of the population, and like AA, has a significant negative effect on patients’ QoL. Current treatment options are only moderately effective. Why consider JAK inhibitors for vitiligo? JAK-1 and JAK-2 in skin cells are thought to play an important role in mediating the stimulatory effects of IFN-g on keratinocytes, ultimately leading to CXCL10 expression and secretion and recruitment of T cells to the skin. This provides a theoretical rationale for JAK inhibition in vitiligo.

A trial of tofacitinib 5 mg once daily for 5 months in a patient with generalized vitiligo achieved complete or nearly complete repigmentation of the face and hands. Similar results have been reported in a patient with AA and concomitant vitiligo who received ruxolitinib. There are still many unknowns with regard to JAK inhibition in vitiligo, such as the relationship between duration of disease and response and whether to target JAK-1/JAK-2 or JAK-1/JAK-3.

Lastly, JAK inhibition may have a future role in the management of AD. Recent models support the importance of cytokines such as the interleukins IL-4 and IL-13 in the pathogenesis of AD, with intracellular signaling occurring via the JAK pathway. Based on this model, King and colleagues investigated the use of tofacitinib 5 mg BID in 6 patients with moderate to severe AD who had not significantly responded to multiple medical interventions. Tofacitinib was associated with significant reductions in pruritus, sleep loss, and composite scores as assessed by the SCORing Atopic Dermatitis (SCORAD).