Alice Wang1, Nur-Taz Rahman2, Meaghan K McGeary3, Michael Murphy1, Austin McHenry3, Danielle Peterson1, Marcus Bosenberg4, Richard A Flavell5, Brett King6, William Damsky7. 1. Department of Dermatology, Yale University School of Medicine, New Haven, Conn. 2. Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, Conn. 3. Department of Pathology, Yale University School of Medicine, New Haven, Conn. 4. Department of Dermatology, Yale University School of Medicine, New Haven, Conn; Department of Pathology, Yale University School of Medicine, New Haven, Conn; Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. 5. Department of Immunobiology, Yale University School of Medicine, New Haven, Conn; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Conn. 6. Department of Dermatology, Yale University School of Medicine, New Haven, Conn. Electronic address: brett.king@yale.edu. 7. Department of Dermatology, Yale University School of Medicine, New Haven, Conn. Electronic address: william.damsky@yale.edu.
Abstract
BACKGROUND: Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. OBJECTIVE: We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. METHODS: We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. RESULTS: Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. CONCLUSIONS: The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.
BACKGROUND:Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. OBJECTIVE: We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. METHODS: We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. RESULTS: Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. CONCLUSIONS: The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.