Introduction
The use of Janus kinase (JAK) inhibitors in dermatology is rapidly increasing to treat
various diseases such as psoriasis, alopecia areata, vitiligo, and a variety of other
inflammatory skin disorders.1, 2 Ruxolitinib is a JAK inhibitor that is approved by
the US Food and Drug Administration for the treatment of myelofibrosis and polycythemia
vera (PCV).
3
In dermatology, ruxolitinib has been tried as a topical cream for treating psoriasis
and vitiligo, and has been used both topically and orally for the treatment of alopecia
areata.2, 4 Here we report a photo-distributed papulopustular skin rash in a patient
on ruxolitinib for PCV.
Case report
A white man in his 80s with PCV was referred to the integrated care clinic for evaluation
of a pruritic eruption on the upper chest, neck, and face. He was being treated with
concurrent ruxolitinib and hydroxyurea for his PCV, and the rash developed 1 month
after ruxolitinib was introduced. On cutaneous examination, there was an unusual photo-distributed
eruption composed of papules and pustules on the face, V area of the neck, and chest
(Fig 1). The patient had received topical steroids from his oncologist without improvement.
Serologic workup was within normal limits including low creatine kinase levels (40
U/L), a normal antinuclear antibody titer (1:80) and negative anti SS-A/B antibodies.
Two skin biopsies were performed, and empiric therapy with doxycycline, 100 mg twice
daily, was started. This treatment was quickly discontinued because of severe headache
and stomach upset. The skin biopsies found a folliculocentric neutrophilic infiltrate
with small foci of suprabasal acantholysis (Fig 2, A). The patient did not respond
to oral antibiotics or multiple topical treatments including various steroids, pimecrolimus
cream, chlorhexidine washes, ivermectin cream, and clindamycin gel and a brief course
of oral prednisone. Additional biopsies were performed because of the recalcitrant
nature of his eruption. Results showed interface dermatitis with lymphocytes at the
dermoepidermal junction (Fig 2, B). During this 2- to 3-month period, 5 new squamous
cell carcinomas developed. Because of PCV stability and his recalcitrant rash, the
patient had his ruxolitinib discontinued, and in about 3 weeks, significant clinical
improvement was noted. The rash has not returned in 6 months since cessation of ruxolitinib,
although he continues to have additional new keratinocytic carcinomas.
Fig 1
Cutaneous eruption. Papules and pustules with background erythema are seen over the
centro-facial area, neck, and upper chest, with distinct sparing of the upper arms
and the lower chest.
Fig 2
Histopathologic findings. Hematoxylin-eosin stains of the initial biopsy showed prominent
folliculocentric inflammation (A1) composed of lymphocytes, histiocytes, and numerous
neutrophils (A2). The epidermis was eroded and surmounted by neutrophilic serum crust.
Focal suprabasal acantholysis was present (A3). Additional biopsies found parakeratosis
overlying an atrophic epidermis (B1) and lymphohistiocytic inflammation at the dermoepidermal
junction with associated dyskeratosis (B2).
Discussion
Several inflammatory dermatoses are driven by molecular pathways that converge on
the common JAK signal transducer and activator of transcription (STAT) signaling pathway.
Thus, inhibition of this proinflammatory pathway using the JAK inhibitors is a promising
new addition to the existing treatment options for several dermatologic conditions
including psoriasis, atopic dermatitis, vitiligo, alopecia areata, dermatomyositis,
and graft-versus-host disease.1, 2 Broadly, there are 2 generations of JAK inhibitors.
The first generation of JAK inhibitors includes tofacitinib, ruxolitinib, baricitinib,
and oclacitinib. The second generation of JAK inhibitors includes peficitinib, filgotinib,
fedratinib, momelotinib, lestaurtinib, and decernotinib and is mostly still under
development.
5
JAK inhibitors can result in various cutaneous and noncutaneous side effects. The
former includes herpes zoster, reactivation of herpes simplex, disseminated molluscum
contagiosum, eruptive squamous cell carcinoma, and drug eruptions including drug rash
with eosinophilia and systemic symptoms (DRESS) syndrome.2, 6 The US Food and Drug
Administration–approved dose of ruxolitinib for myelofibrosis and polycythemia vera
ranges from 5 mg to 25 mg twice daily.
3
Our patient had received 10 mg/d.
There could be a few explanations for the photodistributed nature of the rash. The
patient was also receiving hydroxyurea apart from the ruxolitinib, and there is a
possibility that the hydroxyurea-induced photosensitivity may have contributed to
the distribution of the rash. Alternatively, it could be caused by a ultraviolet recall–type
reaction or because the affected areas are sites of previously damaged skin (ie, locus
minoris resistentiae). However, the clinical course of the eruption suggests that
it was primarily caused by the JAK inhibitor. Our patient experienced his eruption
shortly after the addition of ruxolitinib to his regimen. The eruption remained treatment
resistant throughout his ruxolitinib course and resolved on discontinuation of the
ruxolitinib without any recurrence at follow-up. The development of numerous squamous
cell carcinomas while on treatment in this patient is consistent with prior reports
of eruptive squamous cell carcinomas in the setting of JAK inhibitor therapy, which
is thought to promote tumorigenesis by inhibiting the antineoplastic effects of interferons
as well as natural killer and T cells.
7
The use of JAK inhibitors is growing, and dermatologists will need to be aware of
the cutaneous side effects of this class of medications. To the best of our knowledge,
a case of ruxolitinib-associated photo-distributed rash, with overlapping interface
dermatitis and neutrophilic inflammation, has not been previously reported.