Tofacitinib: A JAK inhibitor of all trades
By Warren R. Heymann, MD
April 3, 2019
Vol. 1, No. 4
The Janus kinase inhibitors are taking the dermatologic therapeutic world by storm — at least in the literature. By now, most dermatologists are familiar with studies that have demonstrated efficacy in alopecia areata, vitiligo, psoriasis, psoriatic arthritis, and atopic dermatitis. (1)
This commentary will focus on tofacitinib and potential new indications for the drug. Tofacitinib is currently approved for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. It is available in 5 mg pills or as 11 mg extended release tablets. My experience using the drug is limited to only one patient — a woman in her 60s with devastating atopic dermatitis and rheumatoid arthritis, recalcitrant to multiple immunosuppressive therapies (she could not afford dupilumab). She demonstrated a remarkable response to tofacitinib within weeks — her radiant smile obviated the need for a SCORAD assessment.
According to Ciechanowicz et al, tofacitinib is a reversible, competitive inhibitor of JAK that binds to adenosine triphosphate in the kinase domain, specific to JAK1 and JAK3 with a lesser degree of interaction with JAK2. Lower doses of tofacitinib, such as 5 mg BID, inhibit JAK1 and JAK3 signaling. Higher doses may inhibit hematopoietic cytokines and hormones [erythropoietin, thrombopoietin, prolactin, growth hormone, leptin, IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF)] via JAK2 blockade. Tofacitinib inhibits the phosphorylation of STAT5 (in response to IL-15) and STAT1, STAT3 (in response to IL-6). Tofacitinib inhibits IFN-γ and the STAT1-dependent acute lipopolysaccharide-induced inflammatory response. Additionally, IFN-γ signaling inhibition by the blockade of JAK1 decreases the production of tumor necrosis factor and IL-6. Tofacitinib also may inhibit the differentiation of T-helper lymphocytes (type 1 and type 2) and inhibit type 17 T-helper cells. (2).
Will tofacitinib be approved for psoriasis?
Strober et al pooled data from one phase II trial, four phase III trials and one long-term extension study comprising 5,204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician’s Global Assessments of ‘clear’ or ‘almost clear’, ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (PASI) and improvements in Dermatology Life Quality Index (DLQI) score, and other measures at weeks 16 and 52. Safety data were summarized for 3 years. Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID. The lower dose was comparable to the efficacy of either methotrexate or etanercept 25 mg twice weekly; the higher dose efficacy was similar to that of etanercept 50 mg twice weekly. The authors concluded that tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments. For patients where oral therapy is desired (or injectable biologics contraindicated), tofacitinib may be a good option. (3)
Fleming, in an editorial accompanying Strober et al, notes that the crude incidence rate of herpes zoster in tofacitinib-treated psoriatic patients is 2.55, which is comparable to the rheumatoid arthritis population. I concur with the comment; “It may be prudent to advise all patients treated with tofacitinib about this risk [for herpes zoster] and ensure that they are immunized.” (4)
Examples of the expanding therapeutic horizon of tofacitinib include:
- Sarcoidosis. A 48-year-old woman with extensive cutaneous and pulmonary sarcoidosis, recalcitrant to topical steroids, (her hypertension and diabetes prevented the use of oral steroids), minocycline, hydroxychloroquine, methotrexate, adalimumab, and systemic tacroliumus, responded impressively (skin, not pulmonary) to tofacitinib (5 mg bid) while on the drug. (5)
- Pyoderma gangrenosum (PG). Three patients with Crohn disease associated with an inflammatory arthritis and refractory PG, who had failed several therapies with biologics, responded favorably to tofacitinib within several weeks of administration. (6)
- Lichen planopilaris (LPP). A retrospective review of 10 patients with recalcitrant LPP treated with oral tofacitinib was performed. Patients received oral tofacitinib 5 mg twice or three times daily for 2-19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). The LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). No adverse effects were reported. The authors concluded that oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP. (7) A limitation of this study is that only 5 of the cases were biopsy-proven LPP.
Unquestionably, wherever there are immunologic aberrations, reports of tofacitinib (and other Janus kinase inhibitors) will follow. It is clear that tofacitiinib is a JAK inhibitor of all trades — what needs to be determined is which disease(s) it will master.
Addendum: On Feb. 19, Pfizer announced it has taken steps to transition rheumatoid arthritis (RA) study patients who were on tofactinib 10 mg twice daily to tofacitinib 5 mg twice daily in the Food and Drug Administration (FDA) post-marketing requirement study A3921133. This action was taken as the result of notification from the tofacitinib Rheumatology Data Safety Monitoring Board (RDMB) of an increase in the frequency of pulmonary embolism and overall mortality in patients in the trial who were taking the 10 mg twice daily dose of tofacitinib.Point to remember: Tofacitinib may be of value for multiple disorders where the JAK/STAT pathway may be pathogenic.
Our expert’s viewpoint
Professor and Chair, Department of Dermatology
Lewis Katz School of Medicine
Oral tofacitinib is an important drug for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Though Pfizer (the tofacitinib sponsor) withdrew its psoriasis application because of FDA concerns about the drug’s safety in psoriasis patients, Janus kinase inhibitors have shown promise in many other dermatologic disorders, such as alopecia areata, atopic dermatitis, vitiligo, dermatomyositis, lupus erythematosus, graft-versus-host disease, allergic contact dermatitis, erythema multiforme, lichen planus, and mycosis fungoides. Numerous clinical trials are underway to evaluate the use of Janus kinase inhibitors in these dermatologic diseases. This class of drugs has the potential to significantly advance the treatment of numerous autoimmune and inflammatory dermatoses, where we still have unmet needs.
1. Cinats A, Heck E, Robertson L. Janus kinase inhibitors: A review of their emerging applications in dermatology. Skin Therapy Lett 2018; 23: 5-9.
2. Ciechanowicz P, Rakowska A, Sikora M, Rudnicka L. JAK-inhibitors in dermatology: Current evidence and future applications. J Dermatolog Treat 2018; Nov 15: 1-22
3. Strober BE, Gottlieb AB, van de Kerkhof PCM, Puig L, et al. Benefit-risk profile of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: Pooled analysis across six clinical trials. Br J Dermatol 2019; 180: 67-75.
4. Fleming P. Tofacitinib: A new oral Janus kinase inhibitor for psoriasis. Br J Dermatol 2019; 180: 13-14.
5. Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis. N Engl J Med 2018; 379: 2540-6.
6. Kochar B, Herfarth N, Mamie C, Navarini AA, et al. Tofacitinib for the treatment of pyoderma gangrenosum. Clin Gastroenterol Hepatol. 2018 Nov 4 [Epub ahead of print].
7. Yang CC, Khanna T, Sallee B, Christiano AM, Bordone LA. Tofacitinib for the treatment of lichen planopilaris. Dermatol Ther 2018; 31: e12656.
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