Morphea: The 2023 update

Abstract

Morphea, also known as localized scleroderma, is a chronic inflammatory connective tissue disorder with variable clinical presentations, that affects both adults and children. It is characterized by inflammation and fibrosis of the skin and underlying soft tissue, in certain cases even of the surrounding structures such as fascia, muscle, bone and central nervous system. While the etiology is still unknown, many factors may contribute to disease development, including genetic predisposition, vascular dysregulation, T_H1/T_H2 imbalance with chemokines and cytokines associated with interferon-γ and profibrotic pathways as well as certain environmental factors. Since the disease may progress to permanent cosmetic and functional sequelae, it is crucial to properly assess the disease activity and to initiate promptly the adequate treatment, thus preventing subsequent damage. The mainstay of treatment is based on corticosteroids and methotrexate. These, however, are limited by their toxicity, especially if applied long-term. Furthermore, corticosteroids and methotrexate often do not sufficiently control the disease and/or the frequent relapses of morphea. This review presents the current understanding of morphea by discussing its epidemiology, diagnosis, management and prognosis. In addition, it will describe recent pathogenetic findings, thus proposing potential novel targets for therapeutic development in morphea.

Keywords: diagnosis; localized scleroderma; morphea; pathogenesis; treatment.

Figure 1

Schematic overview of morphea pathogenesis. Based on current evidence, the pathogenesis of morphea can be divided into three distinct phases: early inflammatory, sclerotic/fibrotic and late atrophic. Environmental factors like radiation, skin trauma and infections may trigger in genetically predisposed patients (1) a T cell-driven skin inflammation, but also plasma cells and eosinophils around the vessels, adnexal structures and in the dermis. The resulted intense endothelial damage will lead to the upregulation of adhesion molecules, such as E-cadherin and VCAM-1 during the inflammatory stage (2), which in turn will recruit pro-inflammatory TH1 and TH17 cells and associated cytokines (CXCL-9/10, TGF-ß, IL-23 and IL-17A, respectively) that will activate fibroblasts. (3) Next, a switch towards a predominant TH2-driven response will facilitate the recruitment of T lymphocytes that are capable of producing profibrotic cytokines like IL-4, IL-6 and TGF-ß. (4) Therefore, sclerosis increases with hyalinized, compact collagen bundles in the dermis, with few sweat glands and blood vessels, the latter with thickened walls and narrow lumens. (5) In the last phase, atrophy slowly increases as sclerosis subsides. The epidermis will decrease in thickness (6), while basal keratinocytes display pigment, with the presence of underlying melanophages. (7) There is loss of skin appendages, blood vessels (8) and inflammatory cells (9).

Figure 2

Clinical and histological hallmarks of morphea. (A) Well-defined oval patch with a central ivory white area surrounded by an erythematous violaceous rim (“lilac ring”) in a patient with plaque-type morphea. (B) The histology from a cutaneous biopsy from a sclerotic morphea lesion typically showing a thin epidermis, basal keratinocytes displaying pigment, scarce lymphocytic inflammatory infiltrates in the papillary dermis and around the vessels, with significant sclerosis in the reticular dermis and atrophy of the adnexal structures (H&E staining, 40×). Magnification displaying minimal periadnexal lymphocytic inflammatory infiltrates in the papillary dermis and thick, hyalinized, eosinophilic collagen bundles in the reticular dermis with entrapped atrophic adnexal structures (H&E staining, 200×). (C,D) Extensive, well-demarcated, coalescing erythematous violaceous patches on the trunk indicative of an early, inflammatory stage of generalized morphea. (E) Band-like, atrophic, hyperpigmented plaque in a blaschko-linear distribution in a child with linear morphea of the limb. (F,G) Ill-defined, coalescing, pink erythematous patches with important central sclerosis in a patient with generalized morphea, sclerotic disease stage. (H) Atrophy of the underlying tissue with asymmetry of the limbs in a patient with deep morphea. (I,J) Median and paramedian linear depressed, sclerotic plaques of morphea en coup de sabre with the presence of cicatricial alopecia.