piperidines and Granuloma-Annulare

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized controlled studies that will in turn help lead to the recommendation of evidence-based treatments for GA.

Topics: Anti-Infective Agents; Antimalarials; Biological Therapy; Comorbidity; Dermatologic Agents; Diabetes Complications; Diagnosis, Differential; Glucocorticoids; Granuloma Annulare; Humans; Iatrogenic Disease; Infections; Methotrexate; Neoplasms; Pentoxifylline; Phosphodiesterase 4 Inhibitors; Phototherapy; Piperidines; Pyrimidines; Thalidomide

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.. We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease.. 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.. Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4. 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.

Topics: Aged; CD4-Positive T-Lymphocytes; Cytokines; Fibroblasts; Granuloma Annulare; Humans; Janus Kinase Inhibitors; Macrophages; Middle Aged; Piperidines; Pyrimidines; Sequence Analysis, RNA; Skin

Topics: Granuloma Annulare; Humans; Piperidines; Pyrimidines

Sarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.. To evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.. A prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.. Tofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA.. The study is limited by the small number of participants.. Tofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.

Topics: Adult; Aged; Biopsy; Female; Granuloma Annulare; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Remission Induction; Sarcoidosis; Severity of Illness Index; Skin; Treatment Outcome