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Treatment of granuloma annulare with tofacitinib 2% ointment

2019; Elsevier BV; Volume: 6; Issue: 1 Linguagem: Inglês

10.1016/j.jdcr.2019.10.016

2352-5126

William Damsky, Brett King,

Inflammatory Myopathies and Dermatomyositis

Granuloma annulare (GA) is an autoimmune cutaneous disorder characterized by clusters of macrophages and T cells giving rise to pink papules and annular plaques. GA can be challenging to treat, and even localized disease is often unresponsive to topical corticosteroids and calcineurin inhibitors; intralesional triamcinolone can be effective in some cases. Better therapies are needed for GA and other cutaneous granulomatous disorders. In GA, CD4+ helper T cells with a Th1 phenotype tend to predominate among the lymphocytic portion of the infiltrate.1Stefanaki K. Tsivitanidou-Kakourou T. Stefanaki C. et al.Histological and immunohistochemical study of granuloma annulare and subcutaneous granuloma annulare in children.J Cutan Pathol. 2007; 34: 392-396Crossref PubMed Scopus (34) Google Scholar These T cells produce interferon (IFN)-γ, a cytokine that has a well-characterized role in macrophage activation and granuloma formation.2Smith D. Hansch H. Bancroft G. Ehlers S. T-cell-independent granuloma formation in response to Mycobacterium avium: role of tumour necrosis factor-alpha and interferon-gamma.Immunology. 1997; 92: 413-421Crossref PubMed Scopus (107) Google Scholar In GA, IFN-γ is likely a key driver of macrophage recruitment, activation, and retention in lesional skin. IFN-γ (and other cytokines) signals through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway inside target cells. Thus, drugs that inhibit the activity of IFN-γ (and other cytokines) via blocking JAK-STAT signaling, may offer a pathogenesis-directed treatment approach for GA and other granulomatous disorders. Along these lines, we recently showed that JAK-STAT signaling is constitutively activated in GA (and sarcoidosis) in a pattern consistent with IFN-γ–dependent activation of macrophages.3Damsky W. Thakral D. Emeagwali N. Galan A. King B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis.N Engl J Med. 2018; 379: 2540-2546Crossref PubMed Scopus (102) Google Scholar,4Damsky W. Thakral D. McGeary M.K. Leventhal J. Galan A. King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare.J Am Acad Dermatol. 2019; Google Scholar We showed that treatment of patients with recalcitrant sarcoidosis and GA with an oral JAK inhibitor, tofacitinib, induced dramatic disease remission in these patients.3Damsky W. Thakral D. Emeagwali N. Galan A. King B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis.N Engl J Med. 2018; 379: 2540-2546Crossref PubMed Scopus (102) Google Scholar,4Damsky W. Thakral D. McGeary M.K. Leventhal J. Galan A. King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare.J Am Acad Dermatol. 2019; Google Scholar In most patients with localized GA, treatment with an oral JAK inhibitor would be inappropriate. Despite the apparent efficacy of oral tofacitinib in cutaneous granulomatous disorders, it remains unknown whether a topical JAK inhibitor might show similar efficacy. Here we evaluate the efficacy of tofacitinib 2% ointment in a patient with localized GA. A 69-year-old man with a 1-year history of GA presented for evaluation and treatment. The lesions were asymptomatic. He also had type 2 diabetes and hypertension. Cutaneous examination revealed pink papules and annular plaques without scale on the neck, forehead, arms and hands (Fig 1). A skin biopsy from the forearm showed a perivascular lymphocytic infiltrate associated with a perivascular and interstitial histocytic infiltrate in the dermis, with focal areas of degenerated collagen palisaded by histiocytes, consistent with GA (Fig 2). Solar elastosis was minimal, and elastophagocytosis was not observed.Fig 2Skin biopsy shows GA. Histocytes and lymphocytes in the dermis, with focal areas of degenerated collagen palisaded by histiocytes, consistent with GA. (Original magnification: ×200.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient was previously treated with triamcinolone 0.1% ointment without effect. Treatment of a single plaque on the dorsal hand with intralesional triamcinolone led to flattening of that lesion. The patient was offered repeat intralesional triamcinolone and/or oral hydroxychloroquine but declined. Instead, compounded tofacitinib 2% ointment was initiated twice daily. He was instructed to apply the tofacitinib to all but 1 lesion (on the forearm); this lesion was left untreated to control for the observation that localized GA can occasionally undergo spontaneous remission. After 15 weeks, there was marked improvement and near resolution of all treated lesions (Fig 1). The untreated lesion on the forearm persisted. No adverse effects occurred. JAK inhibition is an emerging, molecularly targeted approach for cutaneous granulomatous disorders. We previously showed that patients with recalcitrant GA and sarcoidosis experienced disease remission on oral tofacitinib.3Damsky W. Thakral D. Emeagwali N. Galan A. King B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis.N Engl J Med. 2018; 379: 2540-2546Crossref PubMed Scopus (102) Google Scholar,4Damsky W. Thakral D. McGeary M.K. Leventhal J. Galan A. King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare.J Am Acad Dermatol. 2019; Google Scholar Others have reported a similar effect in patients with sarcoidosis treated with oral ruxolitinib (another JAK inhibitor), administered for concomitant myeloproliferative neoplasms.5Wei J.J. Kallenbach L.R. Kreider M. Leung T.H. Rosenbach M. Resolution of cutaneous sarcoidosis after Janus kinase inhibitor therapy for concomitant polycythemia vera.JAAD Case Rep. 2019; 5: 360-361Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,6Rotenberg C. Besnard V. Brillet P.Y. Giraudier S. Nunes H. Valeyre D. Dramatic response of refractory sarcoidosis under ruxolitinib in a patient with associated JAK2-mutated polycythemia.Eur Respir J. 2018; 52Crossref Scopus (42) Google Scholar Clinical trials are underway to better characterize the role of oral JAK inhibitors in the treatment of severe cutaneous sarcoidosis and GA (NCT03910543, NCT03793439). We show that tofacitinib 2% ointment was effective in a patient with localized GA. Tofacitinib 2% ointment was chosen because this concentration of tofacitinib has been used in clinical trials. A specific effect of tofacitinib is supported by the observation that a single untreated lesion did not also improve during tofacitinib treatment of the other lesions. Biopsy after clinical improvement of the GA was not pursued; however, in patients treated with oral tofacitinib, histologic clearance of granulomas has been observed.3Damsky W. Thakral D. Emeagwali N. Galan A. King B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis.N Engl J Med. 2018; 379: 2540-2546Crossref PubMed Scopus (102) Google Scholar,4Damsky W. Thakral D. McGeary M.K. Leventhal J. Galan A. King B. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare.J Am Acad Dermatol. 2019; Google Scholar These data suggest that topical JAK inhibitors may be beneficial in patients with cutaneous granulomatous disorders with limited involvement. Larger studies are warranted to better characterize the role of topical JAK inhibitors in treating GA and related disorders.