Morphea is a rare chronic inflammatory disease that involves skin and subcutaneous tissues, causing skin sclerosis. Generalized morphea is characterized by extensive cutaneous involvement and poor response to therapy. Although the pathophysiology for morphea is not completely understood, abnormal signaling through the platelet-derived growth factor and transforming growth factor beta axes seems to play a major role in the inflammatory response and sclerotic process. Imatinib, a tyrosine kinase inhibitor, interferes with both transforming growth factor beta and platelet-derived growth factor signaling pathways. Recent studies proved imatinib's efficacy in the prevention and regression of fibrosis associated with systemic sclerosis, nephrogenic sclerosis, and bleomycin-related fibrosis.
We present the case of a 50-year-old Caucasian man with a generalized morphea diagnosed 10 years ago, with multiple ulcers, who was treated with imatinib over the course of 12 months. At the end of the treatment, most of the skin ulcerations had healed, and cutaneous thickness was reduced as demonstrated by skin biopsy and ultrasound evaluation. The patient also experienced an improvement in articular mobility, sustained by a 20° increase in left knee extension.
Although controlled studies are necessary to access the antifibrotic effect of imatinib in morphea, the present report shows its potential role in the treatment of this condition.
Morphea (localized scleroderma) is a rare chronic inflammatory disease, which involves skin and subcutaneous tissues and is characterized by skin induration and sclerosis. It is differentiated from systemic sclerosis (scleroderma) by the absence of sclerodactyly, Raynaud phenomenon, nail fold capillary changes, and organ involvement. Despite being limited to the skin, without systemic involvement, it can cause significant disability in 11% of patients. The generalized form of the disease is characterized by the involvement of two or more anatomic sites and can develop with an extensive and rapidly progressive cutaneous involvement. It usually shows a persistent behavior and poor response to therapy.
Although its pathophysiology is not completely understood, abnormal signaling through the platelet-derived growth factor (PDGF) and transforming growth factor beta axes seems to play a major role in the inflammatory response and sclerotic process, similarly to systemic sclerosis.
Imatinib, a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, interferes with both transforming growth factor beta and PDGF signaling pathways by blocking the activity of c-Abl, c-Kit, and PDGF receptors, respectively. Recent studies suggest imatinib's efficacy in the prevention and regression of fibrosis associated with systemic sclerosis,[3-6] nephrogenic sclerosis, and bleomycin-related fibrosis.
A 50-year-old Caucasian male was referred to a dermatology appointment after a 10-year history of generalized morphea. On physical examination, multiple, large, indurated plaques were seen symmetrically distributed on the trunk and extremities. Several plaques on the forearms and legs had ulceration that was refractory to previous wound care and dressings (Fig. 1a,b). Multiple episodes of wound infection demanding antibiotic therapy were recorded. Doppler ultrasound of the limbs showed no vascular disease. Testing for antinuclear antibodies was negative. The patient was being treated with pentoxifylline 400 mg t.i.d. without response. Taking into account multiple previous wound infection episodes, no immunosuppressive therapy was attempted, and the patient could not come to the hospital three times a week for phototherapy treatments.
After approval by the hospital committee, the patient was started on imatinib 200 mg/d (off-label treatment). Pentoxifylline therapy was discontinued. Baseline cutaneous ultrasound of the plaque of the right abdominal flank (chosen location to access treatment outcome; Fig. 1c) showed a dermal thickness of 4.5 mm. Skin biopsy of the same lesion showed a dermal thickness of 5 mm. Left knee maximum extension was 110°.
Besides self-limited periorbital edema registered during the second month of therapy, no other adverse reactions were recorded. Laboratory profile showed no alterations. After completing three months of treatment, skin ulcerations started to heal, decreasing their sizes (Fig. 2). At this time, the skin biopsy revealed a decrease in the inflammatory infiltrate, and cutaneous ultrasound showed a decrease of dermal thickness to 4.2 mm.
Owing to good clinical response and tolerability, imatinib was increased to 300 mg/d on the fourth month of treatment. The patient maintained a satisfactory clinical response, and almost complete healing of the ulcers was achieved, except for the ulcer on the dorsal right foot; it was the deepest one, with multiple Pseudomonas aeruginosa infection episodes (Fig. 3). After 12 months of treatment with imatinib (3 months on 200 mg/d and 9 months on 300 mg/d), skin biopsy showed a dermal thickness of 4 mm, similar to cutaneous ultrasound evaluation: 3.7 mm (Fig. 4). The patient also experienced a 20° increase in left knee joint extension (Fig. 5).
Published studies accessing the antifibrotic effect of imatinib (primarily on patients with systemic sclerosis) were discrepant concerning the doses and treatment duration: dose range varied from 100 to 600 mg/d, and treatment period varied from 6 to 12 months.[5, 6, 8-10] Despite the fact that imatinib's antifibrotic mechanism is not completely known, Akhmetshina et al. concluded that imatinib might induce regression of fibrosis via its inhibitory effects on collagen synthesis, leading to a relative increase in matrix degradation, rather than by exerting direct effects on matrix degradation.
Mild to moderate severity of superficial edema, most commonly on the eyelids, is reported in 48–65% of patients treated with imatinib.[11, 12] As reported in the present case, it is generally self-limited, not implying withdrawal of the drug. Other common side effects, mainly dose-dependent, include nausea, vomiting, nonspecific skin rash, and pigmentary changes.
Tyrosine kinase inhibitors have been suggested to be promising therapeutic agents for sclerosing conditions such as systemic sclerosis and others. The present report indicates that this pharmacologic group should also be considered for fibrotic stage morphea. In the present study, after 12 months of treatment, thinning of fibrotic plaques and reduction of the inflammatory component were proven by skin biopsy and ultrasound. Furthermore, the healing of the majority of skin ulcerations and the improvement of joint mobility led to a significant improvement in the patient's quality of life.
Further studies should be encouraged as important questions such as treatment duration and appropriate dose are yet unanswered. The hypothetic benefit of associating imatinib with other antifibrotic agents or phototherapy must be clarified.
Controlled studies are necessary to corroborate the antifibrotic effect of imatinib and new tyrosine kinase inhibitors, nilotinib and dasatinib, in the treatment of morphea.