New targets in treating granuloma annulare

Granulomatous inflammation is an evolutionarily conserved immunologic reaction with macrophage-predominant patterns, and granuloma a more specific term referring to tightly associated clusters of macrophages epithelioid morphology.1Wang A. Singh K. Ibrahim W. King I. Damsky The promise JAK inhibitors for treatment sarcoidosis other inflammatory disorders macrophage activation: review the literature.Yale J Biol Med. 2020; 93: 187-195PubMed Google Scholar Granuloma annulare (GA) granulomatous, skin disorder unknown etiology.2Min M.S. Wu J. He H. Sanz-Cabanillas J.L. Del Duca E. Zhang N. et al.Granuloma profile shows activation T-helper cell type 1, 2, Janus kinase pathways.J Am Acad Dermatol. 83: 63-70Abstract Full Text PDF PubMed Scopus (10) Scholar, 3Piette E.W. Rosenbach M. annulare: pathogenesis, disease associations triggers, therapeutic options.J 2016; 75: 467-479Abstract (69) 4Damsky Thakral D. McGreary M.K. Leventhal Galan B. inhibition induces remission in cutaneous annulare.J 82: 612-621Abstract (28) 5Rosenbach offer new era targeted granulomatous disorders.J e91-e92Abstract (7) It characterized by formation erythematous papules plaques, which are often annular shape.6Wang Rahman N.T. Murphy McHenry Peterson al.Treatment suppression proinflammatory cytokine activity tofacitinib.J Allergy Clin Immunol. 2021; 147: 1795-1809Abstract (5) Although GA localized extremities self-resolving, it can be generalized refractory current treatments.2Min Scholar,6Wang Effective options limited due lack understanding pathogenic mechanism GA.2Min More than 50 cytokines, including IFN-γ, IL-2, IL-6, IL-12, IL-23, rely on (JAK)-signal transducer activator transcription (STAT) pathway.1Wang Medications inhibiting proteins block these cytokines simultaneously, critical formation.1Wang Scholar,5Rosenbach King’s group recently demonstrated efficacy selective oral JAK1/3 inhibitor, tofactinib, 1 patient sarcoidosis, another inflammation.7Damsky Emeagwali Tofacitinib molecular analysis sarcoidosis.N Engl 2018; 379: 2540-2546Crossref (66) Recently, they also reported prospective evaluation tofacitinib 4 consecutive patients recalcitrant (n = 3) 1).4Damsky Complete or near-complete clinical was observed all patients, histologic resolution seen.4Damsky Immunohistochemical biopsy specimens reduction JAK-STAT signaling via reduced phosphorylated STAT1 STAT3 tissue specimens. RNA sequencing showed expression JAK-STAT–dependent pathways known development maintenance.5Rosenbach In this issue, Wang al6Wang investigated immunopathogenesis using single-cell (scRNAseq) characterize microenvironment lesions, found that oncostatin M (OSM), and, lesser degree, IL-21 IL-15 mediate communication between T cells, macrophages, fibroblasts drive lesion (Fig 1). Because signal pathway, al proposed might respond inhibition, tofacitinib, 5 long-lasting effect targets. Interestingly, comparison profiles complete responders those partial suggested incomplete clearance lesions activity. This indicates turn either higher doses would result responses alternate specificity effective. IFN-γ OSM both JAK1/2 appear most proximal drivers disease, possible directed JAK1 effective providing potent cytokines. Larger, randomized controlled studies needed further delineate GA. published study, Min al2Min upregulation TH1/innate immunity prominent TH2 skewing very high IL-4 upregulation, JAK3 elevation, suggesting potential role treatments Upregulation its receptor noted lesional nonlesional normal skin. compared select genes quantitative RT-PCR bulk biopsies from 8 11 healthy controls. contrast, used scRNAseq 3 results cells clinically total, 19,766 were analyzed, median 5084.5 unique identifiers. These data included 11,544 libraries (mean 3,848 per library) 8,222 control 2,471 library). Clustering performed 197 revealed 34 clusters. They proteomic samples, as well multiplexed analyses interstitial fluid, representing secreted, extracellular mediators present within tissue.6Wang major discrepancy 2 relates (IL-4 IL-31). marked (15,600-fold) modest IL-31, whereas nearly no undetectable RNAseq data. However, levels elevated plasma relative controls, indicating some personal factors (such comorbidities, previous treatments, different stages) affect results. reason relate methodologies because relies single primer set detect transcript interest, thus has amplification off-target transcripts. any case, understand roles IL-31) Several have similar histological features formation, driven autoreactive produced lymphocytes.1Wang include necrobiosis lipoidica affecting skin, Crohn gastrointestinal tract, multiple organ systems (most commonly lungs, lymph nodes, and/or skin), hemophagocytic lymphohistiocytosis systemic activation. overlapping distinct challenging treat. Previous case reports shown treating disorders,1Wang may share common pathways. Therefore, clearer pathogenesis immune mechanisms could value identifying novel therapies disorders. Treatment tofacitinibJournal Clinical ImmunologyVol. 147Issue 5PreviewGranuloma accumulation Its poorly understood, there treatments. health implications severe unknown. Full-Text