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Review
. 2023 Aug 10;3(5):100220.
doi: 10.1016/j.xjidi.2023.100220. eCollection 2023 Sep.

Molecularly Targeted Therapies for Inflammatory Cutaneous Granulomatous Disorders: A Review of the Evidence and Implications for Understanding Disease Pathogenesis

Erica Hwang  1 , Mariam Abdelghaffar  2 , Bridget E Shields  3 , William Damsky  1   4
Affiliations
Review

Molecularly Targeted Therapies for Inflammatory Cutaneous Granulomatous Disorders: A Review of the Evidence and Implications for Understanding Disease Pathogenesis

Erica Hwang et al. JID Innov. .

Abstract

Inflammatory cutaneous granulomatous diseases, including granuloma annulare, cutaneous sarcoidosis, and necrobiosis lipoidica, are distinct diseases unified by the hallmark of macrophage accumulation and activation in the skin. There are currently no Food and Drug Administration-approved therapies for these conditions except prednisone and repository corticotropin injection for pulmonary sarcoidosis. Treatment of these diseases has generally been guided by low-quality evidence and may involve broadly immunomodulatory medications. Development of new treatments has in part been limited by an incomplete understanding of disease pathogenesis. Recently, there has been substantial progress in better understanding the molecular pathogenesis of these disorders, opening the door for therapeutic innovation. Likewise, reported outcomes of treatment with immunologically targeted therapies may offer insights into disease pathogenesis. In this systematic review, we summarize progress in deciphering the pathomechanisms of these disorders and discuss this in the context of emerging evidence on the use of molecularly targeted therapies in treatment of these diseases.

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Figures

Figure 1
Figure 1
Overview of proposed GA molecular pathogenesis and mechanisms of immunologically targeted therapy. The question mark ? denotes hypothetical and needs further evaluation. GA, granuloma annulare; Jaki, Jak inhibitor; M, macrophage; OSM, oncostatin M; PDE4, phosphodiesterase-4; STAT, signal transducer and activator of transcription; TNFi, TNF inhibitor.
Figure 2
Figure 2
Overview of Jak–STAT-dependent and -independent cytokines of therapeutic relevance. Lines indicate that signal transduction of a cytokine occurs through a given Jak protein. Checked boxes indicate which Jak proteins each Jak inhibitor targets. EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; OSM, oncostatin M; STAT, signal transducer and activator of transcription; TPO thrombopoietin; TYK2, tyrosine kinase 2.
Figure 3
Figure 3
Overview of proposed cutaneous sarcoidosis molecular pathogenesis and mechanisms of immunologically targeted therapy. The question mark ? denotes hypothetical and needs evaluation. cDC, conventional dendritic cell; Jaki, Jak inhibitor; M, macrophage; STAT, signal transducer and activator of transcription; Th1, T helper cell 1; TNFi, TNF inhibitor; TYK2i, tyrosine kinase 2 inhibitor.
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