ReviewJAK inhibitors in dermatology: The promise of a new drug class
Section snippets
Atopic dermatitis
The pathogenesis of AD is complex but in part involves increased helper T cell type 2 (TH2) immunity driven by JAK-STAT signaling downstream of cytokines, such as IL-4, IL-5, and IL-13.57 In experimental models, tofacitinib and oclacitinib inhibit IL-4 and IL-13–dependent TH2 differentiation.14, 55, 58 In a mouse model of AD, a topical JAK inhibitor, JTE-053, resulted in decreased IL-4 and IL-13 signaling and improved skin barrier function.59
The efficacy of oral tofacitinib was recently
Alopecia areata
The pathogenesis of AA involves hair follicle attack by autoreactive CD8+ T cells.60 In AA, JAK-STAT dependent cytokines, including IFN-γ and IL-15, drive proliferation and activation of autoreactive T cells,60 suggesting that JAK inhibition might be an effective treatment. In a mouse model of AA, both systemic and topical JAK inhibitors (tofacitinib and ruxolitinib) promoted hair regrowth.26
In 2014, a patient with both alopecia universalis (AU) and psoriasis was treated with tofacitinib, and
Psoriasis
JAK-STAT–dependent cytokines IL-12 and IL-23 are fundamental mediators of psoriasis.61, 62 IL-23 stimulates TH17 cells to produce IL-17, another important pathogenic molecule in psoriasis. Although IL-17 does not rely on JAK-STAT signaling, blockade of upstream IL-23 using JAK inhibitors such as tofacitinib indirectly results in a decrease in IL-17.55, 61 To date, in dermatology, psoriasis has been the most heavily studied indication for JAK inhibitors. JAK inhibitor use in psoriasis has
Vitiligo
Vitiligo is mediated by targeted destruction of melanocytes by CD8+ T cells, with IFN-γ playing a central role in disease pathogenesis.63, 64 Because IFN-γ signaling utilizes the JAK-STAT pathway, vitiligo might be susceptible to treatment with JAK inhibitors. For example, treatment of a patient with generalized vitiligo with tofacitinib resulted in near complete repigmentation of affected areas of the face, forearms, and hands over 5 months53; however, depigmentation recurred after
Topical JAK inhibitors
While not commercially available, the use of topical JAK inhibitors has been explored in AD, psoriasis, AA, and vitiligo. Multiple studies are ongoing in this area. The data for topical therapy in each disease are discussed above and summarized in Table II.
Safety data
Safety data for tofacitinib is derived from large clinical trials in rheumatoid arthritis and psoriasis,65, 66, 67, 68 and data for ruxolitinib are from clinical trials in myelofibrosis and polycythemia vera.69, 70, 71
The risk of infection and overall mortality in patients treated with tofacitinib is not significantly different from that observed with other targeted immunosuppressive therapies.65, 66, 67 With ruxolitinib, the most common infection was urinary tract infection.69, 71 With both
Use of JAK inhibitors
The FDA-approved dosage for tofacitinib in rheumatoid arthritis is 5 mg twice daily. A new extended-release formulation (11 mg once daily) is also available. In clinical trials on psoriasis, tofacitinib 10 mg twice daily was more efficacious than 5 mg twice daily and adverse events did not seem to increase with the higher dosage.48, 49 On the basis of the current literature describing treatments for inflammatory skin disorders, 5 mg twice daily is often sufficient but 10 mg twice daily is
Conclusions and future directions
In addition to the conditions already discussed, JAK inhibitors have shown promise in multiple other dermatologic diseases, including dermatomyositis, chronic actinic dermatitis, erythema multiforme, hypereosinophilic syndrome, cutaneous graft-versus-host disease, and lupus, among others (Table II). Preclinical data suggests that JAK inhibition might be a viable strategy to treat multiple other dermatoses, including allergic contact dermatitis86, 87 and interface dermatoses, such as lichen
References (100)
Janus kinase inhibitors for rheumatoid arthritis
Curr Opin Chem Biol
(2016)- et al.
Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients
J Am Acad Dermatol
(2017) - et al.
Tofacitinib for the treatment of alopecia areata in adolescents
J Am Acad Dermatol
(2017) - et al.
Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis
J Invest Dermatol
(2014) - et al.
Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA)
J Am Acad Dermatol
(2016) - et al.
Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib
EBioMedicine
(2015) - et al.
Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate
J Am Acad Dermatol
(2015) - et al.
Idiopathic erythema multiforme: evidence of underlying JAK-STAT activation and successful treatment with tofacitinib
JAAD Case Rep
(2016) - et al.
JAK1/2 inhibitor ruxolitinib controls a case of chilblain lupus erythematosus
J Invest Dermatol
(2016) - et al.
Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children
J Allergy Clin Immunol
(2016)
Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial
Lancet
IL-5 and eosinophilia
Curr Opin Immunol
Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches
J Allergy Clin Immunol
Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies
Autoimmun Rev
A mouse model of vitiligo with focused epidermal depigmentation requires IFN-gamma for autoreactive CD8(+) T-cell accumulation in the skin
J Invest Dermatol
Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis
BMC Musculoskelet Disord
Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study
J Am Acad Dermatol
Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis
J Am Acad Dermatol
Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor
Semin Arthritis Rheum
Evaluation of the effect of tofacitinib exposure on outcomes in kidney transplant patients
Am J Transplant
Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients
Am J Transplant
Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year
Am J Transplant
Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation
The Journal of investigative dermatology
Clinical perspectives and murine models of lichenoid tissue reaction/interface dermatitis
Journal of dermatological science
Targeting the IFN-gamma/CXCL10 pathway in lichen planus
Med Hypotheses
The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia
Eur J Pharmacol
Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome
Blood
Type I/II cytokines, Jaks, and new strategies for treating autoimmune diseases
Nat Rev Rheumatol
The jaK-STAT pathway: impact on human disease and therapeutic intervention
Annu Rev Med
Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID)
Nature
Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development
Science
Genetics of Cutaneous T cell lymphoma: from bench to bedside
Curr Treat Options Oncol
Genomic landscape of cutaneous T cell lymphoma
Nat Genet
STAT3 mutations in the hyper-IgE syndrome
N Engl J Med
Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases
J Med Chem
Baricitinib in patients with refractory rheumatoid arthritis
N Engl J Med
A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis
Br J Dermatol
Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor
Science
A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel(R)) in client-owned dogs with atopic dermatitis
Vet Dermatol
Oclacitinib (APOQUEL((R))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy
J Vet Pharmacol Ther
Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata
JCI Insight
Topical ruxolitinib for the treatment of alopecia universalis
JAMA Dermatol
Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata
JCI Insight
Tofacitinib Citrate for the treatment of nail dystrophy associated with alopecia universalis
JAMA Dermatol
Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers
Exp Dermatol
Transient efficacy of tofacitinib in alopecia areata universalis
Case Rep Dermatol
Efficacy of tofacitinib in treatment of alopecia universalis in two patients
J Eur Acad Dermatol Venereol
Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition
Nat Med
Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia
Am J Hematol
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Funding sources: Dr King received funding support from The Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.
Conflicts of interest: Dr King has served on advisory boards or is a consultant for Aclaris Therapeutics Inc, Pfizer Inc, Eli Lilly and Company, and Concert Pharmaceuticals Inc. Dr Damsky has no conflicts of interest to declare.
Reprints not available from the authors.