Towards effective targeted therapies in morphea

Morphea is a rare, clinically diverse inflammatory fibrosing skin condition presenting in children and adults. More severe subtypes of morphea can result in significant cosmetic and functional morbidity and warrant early systemic therapeutic intervention to minimize the risk of permanent tissue damage. Significant challenges exist in consensus classification and the development of robust validated measures of disease activity and damage. As a consequence, there are presently no approved therapies, and widely utilized consensus treatment guidelines are also lacking. At the core of the treatment challenge of morphea, is a limited understanding of disease immunopathogenic mechanisms. Pleasingly, some progress has been made in recent years, with advances in transcriptomic and immunologic profiling now defining morphea as a skin-directed, pro-inflammatory disorder which is likely a type 1 interferonopathy. Lesional skin demonstrates enrichment of type I interferon pathways, Th1 and Th17 cytokines, and B-cell activation, with growing evidence implicating keratinocyte-derived signaling in disease propagation. Accordingly, agents including Janus kinase (JAK) inhibitors, abatacept, and tocilizumab have shown some encouraging outcomes in small case series and observational studies, particularly in generalized, deep and/or treatment-resistant disease. Potential novel approaches targeting epidermal-dermal crosstalk, plasmacytoid dendritic cells, or fibroblast positional identity may offer future precision in treatment, but require expansion of our knowledge of molecular etiopathogenesis to be progressed. This narrative review aims to integrate current knowledge of clinical heterogeneity, molecular etiopathogenesis, and therapeutic clinical data to propose a forward-looking, mechanism-based framework for the clinical management of morphea.