Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib

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-gamma production by CD41 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-gamma 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-gamma and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

Automated summary

Single-cell RNA sequencing revealed upregulation of IFN-gamma production by CD41 T cells in GA lesions, which is associated with inflammatory polarization of macrophages and fibroblasts. Treatment with tofacitinib inhibited IFN-gamma, oncostatin M, IL-15, and IL-21 activity, leading to clinical and histologic disease remission in some patients and marked improvement in others. The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, and Janus kinase inhibitors appear to be an effective treatment option.