Chronic refractory cutaneous sarcoidosis successfully treated with oral tofacitinib

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There are limited effective treatment options for chronic, extensive cutaneous sarcoidosis. Janus kinase/STAT (Janus kinase–signal transducer and activator of transcription) inhibitors are the new potential therapeutic agents for refractory cases to avoid long-term systemic toxicity of glucocorticoids. We describe two cases of refractory, severe cutaneous sarcoidosis successfully treated with oral tofacitinib.

The first case was a 65-year-old man with a 5-year history of disseminated cutaneous sarcoidosis, presenting with worsening of skin lesions. He had other comorbidities including type 2 diabetes mellitus (24 years), chronic kidney disease (10 years) and hypothyroidism (15 years). Cutaneous examination revealed generalised involvement with erythematous to pink, mildly scaly, firm papules and plaques [Figure 1a]. Mucous membrane and nail examination were normal. There was no cervical, occipital, axillary or inguinal lymphadenopathy. Systemic examination was normal. Histopathology of a plaque from the trunk showed multiple non-necrotising epithelioid cell granulomas with multinucleated giant cells suggestive of a sarcoidal tissue reaction [Figure 1b]. High-resolution computed tomography (HRCT) of the chest did not show pulmonary involvement. Electrocardiography (ECG) and ophthalmological evaluation were normal. Serum angiotensin converting enzyme (ACE) level was within normal limits and the Mantoux test was nonreactive. He had been on hydroxychloroquine for 5 years, oral corticosteroids with varying doses for 1 year and tablet methotrexate 15 mg/week for 3 months with mild to moderate improvement, and continued to develop new lesions. Hence, hydroxychloroquine and methotrexate were discontinued and the patient was treated with oral tofacitinib 5 mg twice daily. Oral corticosteroid was tapered and stopped 3 months after starting tofacitinib. After 8 months, he experienced near-complete resolution of the lesions with no side effects to tofacitinib [Figure 1c].

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Figure 1a: Patient 1 with multiple erythematous papules and plaques on the back and upper limbs.

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Figure 1b: Well-circumscribed to coalescent granulomas with moderately dense lymphocytic infiltrate and multinucleated giant cells (black arrows) present in upper and mid dermis (Haematoxylin and eosin, 100x).

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Figure 1c: Patient 1 showing near complete resolution of papules and plaques after 8 months of oral tofacitinib.

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The second patient was a 45-year-old woman with a 2-year history of generalised erythematous papules and plaques [Figures 2a and b], confirmed histologically as sarcoidosis. There were no systemic complaints except for mild dyspnea. Contrast-enhanced CT (CECT) of the chest showed bilateral hilar and mediastinal lymphadenopathy with few micronodules along the bronchovascular structures in bilateral upper lobes of the lungs which was suggestive of pulmonary sarcoidosis. Other investigations towards systemic sarcoidosis (serum ACE level, ECG, ophthalmological evaluation) were normal. The lesions resolved upon initiation of oral prednisolone and hydroxychloroquine for 3 months, but with a relapse within 20 days of stopping the steroid. Oral tofacitinib, 5 mg twice a day, as monotherapy was initiated with complete resolution of lesions in 4 months and with no recurrence on tapering it to once-a-day therapy for 4 months [Figures 2c and d]. Her dyspnea subsided and a repeat CECT chest showed resolution of disease.

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Figure 2: (a, b) Patient 2 with discrete, erythematous plaques on upper back, arm and forearm. (c, d) Complete resolution of lesions after 4 months of tofacitinib therapy.

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Sarcoidosis is a chronic multisystem granulomatous disease, most commonly involving the lungs. Cutaneous sarcoidosis accounts for approximately 25–33% of cases with various treatment options available for disseminated lesions including antimalarial agents, methotrexate, corticosteroids, tetracyclines, thalidomide, TNFα inhibitors and other immunomodulatory drugs.¹ For most agents, there are only small case series published for generalised cutaneous sarcoidosis.¹ In the past few years, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality for both cutaneous and internal organ sarcoidosis.¹ They have shown more consistent clinical outcomes with complete remission, reduction in steroid need and no reported adverse effects on long-term use.

Granuloma formation in sarcoidosis involves a complex immune response, though the exact underlying mechanisms remain unclear. Upregulation of JAK-STAT signalling particularly interferon-gamma activity has been implicated in the pathogenesis of sarcoidosis.² Previous studies have shown activation of STAT1 and STAT3 proteins in granulomas of both cutaneous and pulmonary sarcoidosis.^2-4 Other JAK-STAT–related cytokines, such as type I interferons, interleukin-2, 12 and 15, have also been implicated.⁵ These insights support the potential role of JAK inhibitors as a targeted molecular therapy for sarcoidosis. Till date, few case reports and small case series on their efficacy in chronic cutaneous sarcoidosis are published in literature.^1,6,7 [Table 1]. In a series of 10 patients of sarcoidosis with cutaneous involvement, a mean 82.7% improvement in cutaneous sarcoidosis activity and morphology instrument (CSAMI) score was seen after tofacitinib therapy administered for 6 months, with 6 patients demonstrating complete response.⁵ Thus, JAK inhibitors are the potential treatment option for chronic recalcitrant extensive sarcoidosis, particularly with multiple comorbidities.