Refractory granuloma faciale successfully treated with adjunct topical JAK inhibitor

Introduction

Granuloma faciale (GF) is a rare chronic inflammatory dermatosis with histopathological findings including inflammatory perivascular infiltrates in the dermis and the presence of a Grenz zone (a narrow area of uninvolved dermis). Clinical findings are non-specific, but can include reddish-brown or violaceous papules, nodules, or plaques on the face. Lesions are often asymptomatic but can be pruritic and persistent.¹

GF is notoriously difficult to treat with limited data available due to the low incidence of disease.² When symptomatic, topical, and intralesional corticosteroids are commonly used first-line therapies with mixed reported efficacy. Topical calcineurin inhibitors and cryotherapy have shown benefit in several published cases but lack evidence available from larger analytical studies. Dapsone has been reported as a potential systemic therapy for patients who fail topicals. Other therapies used with limited available evidence of efficacy include dapsone gel, lasers, systemic steroids, antimalarials, clofazimine, adalimumab, and intralesional rituximab.^2,3

Herein, we report the first case of severely symptomatic extra-facial GF refractory to multiple therapies that responded extremely well to treatment with adjunct topical tofacitinib.

Case report

A 54-year-old female with asplenia and 40 pack-year smoking history presented with a 9-month history of persistent, severely pruritic plaques behind her left ear. Outside biopsy revealed lichenoid eosinophilic inflammation consistent with angiolymphoid hyperplasia with eosinophilia. She had previously tried antihistamines (fexofenadine, loratadine, hydroxyzine), clobetasol, intralesional methotrexate, intralesional 5-fluorouracil, as well as oral methotrexate 15 mg weekly with minimal relief. Oral cyclosporine had been discontinued after 5 days due to gastrointestinal side effects.

Initial exam revealed a reddish-brown lichenified plaque with excoriation and telangiectasias on the left postauricular scalp (Fig 1). Two additional biopsies of this area over the next several years revealed mixed acute and chronic inflammatory infiltrates with prominent eosinophils, leukocytoclastic vasculitis, and a Grenz zone (Fig 2, A and B)—histopathologic changes consistent with granuloma faciale. She also had a distinctly different rash over her body consistent with dermal hypersensitivity reaction which responded to oral methotrexate. However, the GF symptoms persisted despite numerous additional therapies including oral dapsone, hydroxychloroquine, gabapentin, minocycline, mupirocin, tacrolimus, doxepin, cryotherapy, and repeated intralesional steroid injections while continuing oral methotrexate, loratadine, and clobetasol (Table I). The patient continued to experience recalcitrant pruritus interfering with daily activities and sleep. She also continued to smoke tobacco despite counseling and experienced a significant pruritic flare following a temporary reduction in dapsone dosage due to methemoglobinemia.

Fig 1.

Clinical image of a reddish-brown lichenified plaque with excoriation and telangiectasias on the left postauricular scalp.

Fig 2.

Hematoxylin and eosin stain of left postauricular skin biopsy demonstrating mixed acute and chronic granulomatous inflammatory infiltrates with prominent eosinophils and a Grenz zone at (A) 10× and (B) 20× magnification.

Table I.

Treatments received at our institution prior to topical tofacitinib

Treatment	Dose	Dates of treatment	Duration
Oral dapsone (daily)	25 mg	October 10, 2018-December 05, 2018	1 mo
	100 mg	December 05, 2018-November 22, 2019	1 y
	150 mg	November 22, 2019-September 18, 2020	10 mo
	100 mg∗	September 18, 2020-November 20, 2020	2 mo
	50 mg∗	November 20, 2020-July 16, 2021	8 mo
	100 mg	July 16, 2021-March 31, 2022	8 mo
	150 mg†	March 31, 2021-June 02, 2022	2 mo
Oral methotrexate (weekly)	15 mg	December 13, 2017-April 26, 2018	4 mo
	25 mg	May 18, 2018-April 15, 2019	11 mo
	15 mg	April 15, 2019-May 23, 2019	1 mo
	25 mg†	May 23, 2019-Current	>3 y
Hydroxychloroquine (daily)	400 mg†,‡	November 02, 2020-June 02, 2022	1.5 y
	200 mg	June 02, 2022-October 21, 2022	5 mo
Gabapentin (daily)	300 mg†	March 31, 2022-October 21, 2022	7 mo
Minocycline (twice daily)	100 mg	September 05, 2018-October 17, 2018	1 mo
Hydroxyzine (daily, as needed)	25-50 mg§	May 18, 2018-August 22, 2018	3 mo
	10 mg	June 12, 2020-September 29, 2020	3 mo
Loratadine (daily, as needed)	10 mg†	May 18, 2018-Current	>4 y
Mupirocin ointment (twice daily)	2%	November 22, 2019-February 17, 2020	3 mo
	2%	June 12, 2020-January 21, 2021	7 mo
Tacrolimus ointment (twice daily)	0.1%	January 08, 2021-August 20, 2021	7 mo
	0.1%	March 21, 2022-May 04, 2022	2 mo
Doxepin (daily)	10 mg/mL	April 14, 2021-August 13, 2021	4 mo
Clobetasol foam (2-3 times weekly)	0.05%†	December 05, 2018-Current	>3 y
Clobetasol ointment (daily, as needed)	0.05%	May 18, 2018-December 05, 2018	7 mo
Intralesional Kenalog injections (every 6-12 wk)	40 mg/mL	December 05, 2018-April 14, 2021	2.5 y
Cryotherapy	-	April 04, 2022, May 04, 2022	-

^∗Dose reduced due to methemoglobinemia.

^†Treatments continued at topical tofacitinib 2% initiation on May 4, 2022 include dapsone 150 mg daily, oral methotrexate 25 mg weekly, hydroxychloroquine 200 mg twice daily, gabapentin 300 mg daily, and as needed clobetasol foam 0.05% 2-3 times weekly and loratadine 10 mg daily. She was also on tacrolimus at the time which was stopped at the initiation of topical tofacitinib. One month after starting topical tofacitinib, dapsone was stopped and hydroxychloroquine was reduced to 200 mg once daily. Four mo later, hydroxychloroquine and gabapentin were both stopped.

^‡Hydroxychloroquine taken at 200 mg twice daily.

^§Hydroxyzine 25 mg 1-2 pills daily as needed.

Following the advent and success of topical JAK inhibitors in treating various inflammatory dermatologic conditions and a compounding pharmacy that made it more affordable, a trial of topical tofacitinib 2% was initiated. The patient reported significant symptomatic improvement within weeks of starting twice daily compounded tofacitinib cream while continuing dapsone, oral methotrexate, hydroxychloroquine, gabapentin, and as needed loratadine and clobetasol foam (Table I). On most recent exam, she endorsed minimal itching and exam revealed mild erythema of the left post auricular scalp without active induration (Fig 3, A and B).

Fig 3.

A and B, Clinical images of the left postauricular region after starting topical JAK inhibitor therapy showing minimal residual erythema without induration.

Discussion

Although usually asymptomatic, GF can cause severe pruritus with impact on quality of life as observed in this case.³ Management remains challenging given its persistent nature and lack of consensus on treatment. Another layer of complexity is added in patients with comorbidities such as in this case. Systemic immunosuppressants should be used with caution given increased infection susceptibility post-splenectomy and potentially elevated risk of methemoglobinemia on dapsone while smoking due to altered methemoglobin levels.^4,5 Dapsone is also associated with serious side effects like hemolysis and hypersensitivity syndrome and has multiple drug interactions.^2,4 GF generally presents with a solitary lesion, making topical therapy the preferred treatment modality when feasible.

JAKs are a family of kinases that bind to the intracellular domains of type I/II cytokine receptors.⁶ The JAK-dependent cytokines, including but not limited to interleukin 4, interleukin 5 (IL-5), interleukin 6, and interleukin 12, are major drivers of inflammation in many immune-mediated diseases. The overexpression of IL-5 is implicated in multiple diseases associated with eosinophilia, including 2 cases of GF.^6,7 Although the pathophysiology of GF remains unclear, the common histopathologic finding of mixed inflammatory infiltrates with eosinophils and association with serum eosinophilia provides biological basis for targeting IL-5.¹ IL-5 blocking has also shown great efficacy in treating other eosinophilic diseases including hypereosinophilic syndrome and allergic asthma. The concurrent targeting of multiple JAK-dependent cytokines with JAK inhibitors introduces the possibility of greater therapeutic efficacy.⁶ Furthermore, given this patient initially had overlapping dermatopathology with angiolymphoid hyperplasia with eosinophilia, it would seem logical to trial topical JAK inhibitors in recalcitrant cases of this rare dermatosis as well.

JAK inhibitors are small molecule inhibitors proven to be safe and efficacious for the treatment of several inflammatory dermatoses.⁸ Tofacitinib is a nonspecific JAK inhibitor with both oral and topical forms available. Topical JAK inhibitors have received great attention in recent years, demonstrating therapeutic benefit and safety in atopic dermatitis as well as difficult to treat conditions like alopecia areata and vitiligo.⁸ In a phase II trial, topical JAK inhibitor ruxolitinib demonstrated equal therapeutic response as triamcinolone (the standard care) among patients with atopic dermatitis .⁹ The most common reported side effects for topical ruxolitinib are mild and include application site acne, pruritus, nasopharyngitis, and headache.¹⁰ Compared to systemic therapies, topical JAK inhibitors have fewer safety concerns and are therefore likely a better option for patients with immunosuppression and/or multiple comorbidities.^8,9

While additional studies are needed to elucidate the efficacy of topical JAK inhibitors in GF, our case provides initial evidence supporting their use in the hope of adding to the limited repertoire of treatments available for patients with this rare skin condition.

Conflicts of interest

None disclosed.