Morphea: progress to date and the road ahead

Abstract

Morphea is a rare autoimmune condition causing inflammation and sclerosis of the skin and underlying soft tissue. It is characterized by periods of activity (inflammation admixed with fibrosis), ultimately resulting in permanent damage (pigment change and tissue loss). Damage resulting from unchecked activity can lead to devastating, permanent cosmetic and functional sequelae including hair loss; cutaneous, soft tissue and bony atrophy; joint contractures; and growth restriction of the affected body site in children. This makes the early identification of activity and initiation of appropriate treatment crucial to limiting damage in morphea. To this end, recent investigative work has focused on validation of clinical, biomarker, imaging, and histologic outcomes aimed at accurately quantifying activity and damage. Despite promising results, further work is needed to better validate these measures before they can be used in the clinic and research settings. Although there has been recent approval of less toxic, targeted therapies for many inflammatory skin conditions, none have been systematically investigated in morphea. The mainstays of treatment for active morphea are corticosteroids and methotrexate. These are often limited by substantial toxicity. The paucity of new treatments for morphea is the result of a lack of studies examining its pathogenesis, with many reviews extrapolating from research in systemic sclerosis. Recent studies have demonstrated the role of dysregulated immune and fibrotic pathways in the pathogenesis of morphea, particularly interferon (IFN) gamma related pathways. Active morphea lesions have been found to display an inflammatory morphea signature with CXCR3 receptor ligands, as well as a distinct fibrotic signature reflecting fibroblast activation and collagen production. CXCL9 and 10 have been associated with increased measures of disease activity. While immune dysfunction is thought to play the primary role in morphea pathogenesis, there are other factors that may also contribute, including genetic predisposition, environmental factors, and vascular dysregulation. There remains an essential need for further research to elucidate the pathogenesis of morphea and the mode of action of dysregulated upstream and downstream immune and fibrotic pathways. These studies will allow for the discovery of novel biomarkers and targets for therapeutic development.

Keywords: Localized scleroderma; evaluation; morphea; pathogenesis; treatment.

Figure 1

Morphea is characterized by periods of activity (A,C) and damage (B,D). (A) Right arm affected with significant inflammation, evidenced in swelling of digits and forearm. (B) Damage from morphea including joint contractures and hyperpigmented sclerotic plaques. (C) Active, inflammatory plaque on abdomen with striae. (D) Morphea damage with hyperpigmented, sclerotic plaques, atrophy.

Figure 2

CXCL9 is increased in inflammatory morphea skin, supporting its role as a potential biomarker. (A) CXCL9 mRNA expression is increased in lesional, inflammatory skin when compared to site-matched unaffected skin. (B,C) CXCL9 is present in dermal interstitial infiltrates and stains dendritic appearing cells. Arrows indicate typical perinuclear cap staining pattern of CXCL9. Scale bar in B =100 mm; scale bar in C =25 mm. Reprinted from (80).

Figure 3

MRI findings in morphea. Red boxes indicate area imaged. (A) Subtle morphea involving the left thigh. (B) Axial fat-saturated T2-weighted image of bilateral thighs, with hyperintense areas corresponding to morphea involvement. (C) Morphea of the lower right extremity. (D) Axial 3-dimentional subtracted postcontrast image of bilateral thighs showing fascial involvement as demonstrated by hyperintense signal on affected right thigh (red arrows), with unaffected left thigh (yellow arrows) presented for comparison. Reprinted from (80).

Figure 4

CXCL9 and CXCL10 are elevated in morphea serum, emphasizing the role that the dysregulated IFN gamma pathway plays a role in the pathogenesis of morphea. (A) CXCL9 and CXCL10 are present at increased concentrations compared with control samples. (B,C) CXCL9 is increased in active morphea, decreases in inactive disease, and correlates with disease activity, but CXCL10 does not. (D) Both correlate with measures of disease damage. (E) CXCL9 concentrations correlate with CXCL10 concentrations. LoSDI, Localized Scleroderma Skin Damage Index; mLoSSI, modified Localized Scleroderma Skin Severity Index. Reprinted from (80).