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Localized scleroderma, or morphea, is a chronic inflammatory disease that involves skin and subcutaneous tissues, causing skin sclerosis. Several classifications have been published including those of Laxer and Zulian1: circumscribed, linear, generalized, pansclerotic, or mixed. In contrast to systemic sclerosis, morphea does not involve internal organs. Generalized morphea (GM) is a form of severe morphea with substantial effect on quality of life and survival. First-line systemic treatments for severe morphea include phototherapy, systemic steroids, and methotrexate. Data regarding therapeutic management of GM are scarce, limited to case reports and small case series. We describe a case of GM that was successfully treated with everolimus, an mTOR (mechanistic target of rapamycin) inhibitor.
A 57-year-old woman was referred for skin sclerosis. At disease onset, she presented with 2 cutaneous lesions, on the right breast and the right arm. A few months later, the whole trunk was involved due to rapidly progressive disease, from the neck to the thighs, with active inflammatory borders. A skin biopsy revealed homogeneous fibrosis of the reticular derma with an important inflammatory response, while adnexal structures were rare, and the epidermis was normal. She lacked features of systemic sclerosis, including Raynaud phenomenon. These findings were suggestive of morphea. Treatment with oral daily prednisone (1 mg/kg) and weekly methotrexate (30 mg) was started but stopped after 16 months because of severe adverse events (hypertension, weight gain) and lack of efficacy. The patient was then treated with extracorporeal photochemotherapy, followed by psoralen plus UV-A therapy.
After 1 year, the skin sclerosis had extended to the whole body (with the exception of the face), as shown in the Figure, A. Her Rodnan score was 43 of 51 indicating substantial negative effect on quality of life. The patient could not bend her fingers or her toes; walking was difficult. Fourth-line treatment with oral daily prednisone (0.5 mg/kg) and mycophenolate mofetil (1250 mg twice daily) was given for 6 months without clinical improvement.
Finally, the mTOR inhibitor everolimus (0.5 mg twice daily) was introduced as salvage therapy. After 6 months, clinical examination revealed a clinically significant improvement Figure, B. Her Rodnan score had improved to 22 of 51 (vs 43 of 51). Everolimus treatment (combined with physiotherapy) was continued and well tolerated (no infection, cytopenia, renal insufficiency, or hypertension) with regular monitoring of residual blood levels (remained within normal range, 3-8 ng/mL). At 18 months after the start of everolimus treatment, the patient did not experience any inflammatory flare, and her functional impairment was reduced.
The synthesis of type I collagen in human fibroblasts is regulated by mTOR, and mTOR inhibition has been shown on human dermal fibroblasts to decrease extracellular matrix deposition.2 Mechanistic target of rapamycin is a downstream target of transforming growth factor β signaling, which is a key factor implicated in fibrogenesis.2 Treatment of severe morphea includes oral steroids, methotrexate, cyclosporine, cyclophosphamide, imatinib, mycophenolate mofetil, extracorporeal photochemotherapy, and infliximab. Sirolimus has been shown to be effective in eosinophilic fasciitis, a disease belonging to the spectrum of localized scleroderma.3 It has also exhibited some success in the treatment of systemic sclerosis, nephrogenic systemic fibrosis,4 and sclerodermatous chronic graft vs host disease as a third-line treatment.5
The condition of the present patient improved as evaluated by clinical pictures and the modified Rodnan Skin Score (which is not a validated score in localized scleroderma). The localized Scleroderma Cutaneous Assessment Tool (LoSCAT)6 could not be retrospectively evaluated in this patient. We cannot exclude that skin sclerosis improvement was not due to everolimus treatment but to the natural history of morphea. However, mTOR inhibition could be a promising treatment of severe morphea. Further clinical studies are warranted to confirm these preliminary findings.
Corresponding Author: Jean-David Bouaziz, MD, PhD, Dermatology Department, Hôpital Saint Louis, 1 av Claude Vellefaux, Paris, France 75010 (firstname.lastname@example.org).
Published Online: July 20, 2016. doi:10.1001/jamadermatol.2016.2338
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for granting permission to publish this information.
Frumholtz L, Roux J, Bagot M, Rybojad M, Bouaziz J. Treatment of Generalized Deep Morphea With Everolimus. JAMA Dermatol. 2016;152(10):1170–1172. doi:10.1001/jamadermatol.2016.2338