Treatment of granuloma annulare with tofacitinib

Abstract

Granuloma annulare (GA) is a granulomatous, idiopathic, inflammatory skin disorder characterized by the formation of papules and plaques with annular and acral distribution.1 GA is often limited and self-resolving, but in some cases, it can be generalized and refractory to treatments.1 New advances in the pathophysiology of GA have favoured Janus kinase (JAK) inhibitors as a promising therapeutic option.1, 2 Here, we report three cases of resistant generalized GA successfully treated with tofacitinib. The first was a 69-year-old woman with a 6-year history of generalized GA who had been treated with oral corticosteroids, retinoic and tranexamic acid, indomethacin, hydroxychloroquine and methotrexate without improvement or intolerance, and the second a 73-year-old woman with a history of dyslipidemia receiving simvastatin treatment who was diagnosed with generalized GA in 2016. She had received oral corticosteroids, hydroxychloroquine, pentoxifylline and dapsone, without improvement (Figure 1a). The third patient was a 64-year-old man with a 3-year evolution of a generalized GA who had received oral corticosteroids, phototherapy, methotrexate, hydroxychloroquine and adalimumab with partial response. Furthermore, he had begun experiencing flares of bilateral uveitis in the context of skin outbreaks (Figure 1c). In all three cases, the diagnosis was confirmed histologically and due to difficulties in management, treatment with off-label oral tofacitinib was requested and approved by the therapeutic committee. After the three patients gave written informed consent, tofacitinib was initiated at a dose of 5 mg twice daily. The three patients showed complete response after 4, 8 and 6 months, respectively (Figure 1b and d), without relapses after dose tapering or suspension of the treatment. The characteristics of all the reported GA patients treated with tofacitinib are summarized in Table 1. JAK inhibitors represent a promising approach for cutaneous granulomatous disorders.2 Damsky et al demonstrated that JAK–STAT signalling was constitutively activated in GA lesional macrophages, and that tofacitinib treatment induced histologic clearance of granulomas and downregulation of the JAK–STAT pathway.2 Further, Wang et al recently found that IFN-γ, oncostatin M, IL-21 and IL-15, four important cytokines that signal via the JAK–STAT pathway, are upregulated in GA skin lesions.1 Further, Min et al identified a significant upregulation of inflammatory T-helper cell types 1 and 2, and Janus kinase immune pathways in GA patients.3 Tofacitinib is a potent inhibitor of JAK 1 and 3 in human cells. Currently, it is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and ulcerative colitis with a recommended dose of 5 mg twice daily. Recent data from post-marketing surveillance have shown an increased risk of death, major adverse cardiovascular events, malignancies and thrombosis related to tofacitinib prompting the FDA to issue a safety communication. We found eight previous reports in the literature of patients treated with oral tofacitinib for GA1, 2, 4 and two reports of treatment with topical tofacitinib.5, 6 All patients improved ranging from a partial response of 60% to complete remission. Topical treatment showed improvement between weeks 12 and 15, while oral treatment took about 6 months. None of the cases described have reported any adverse effects. In addition, other JAK inhibitors such as baricitinib and upadacitinib have recently been used in two generalized GA patients with good results.7, 8 In conclusion, advances in GA pathophysiology have allowed the introduction of JAK inhibitors as a new treatment option. To our knowledge, there are only about a dozen reports of GA patients treated with tofacitinib. So far, it has shown an excellent response rate, with both oral and topical administration. Further studies are necessary to assess the safety and the long-term remission of GA patients treated with tofacitinib, and to study the efficacy of other JAK inhibitors in these patients. None. The authors declare that there is no conflict of interest.

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