Pharmacology and rationale for imatinib in the treatment of scleroderma

Abstract

Systemic sclerosis (scleroderma) is a chronic, multisystem, fibrotic disease. Although the pathogenesis is not completely understood, early vascular damage leads to an inflammatory reaction and a severe fibrotic response. Therapy of systemic sclerosis is still not convincing and is mainly restricted to the management of organ complications. A wide choice of immunosuppressive and antifibrotic drugs has been used to try to modify the course of the disease, but significant breakthroughs are still lacking. Imatinib is a tyrosine kinase inhibitor known to regulate growth, proliferation, and differentiation as well as apoptosis of cells and is already widely used for several malignancies, eg, chronic myeloid leukemia and gastrointestinal stromal tumors. It has been used in preclinical as well as clinical studies to modulate the fibrotic process in patients with systemic sclerosis. This is based on its activity to interfere selectively with both the transforming growth factor-β and platelet-derived growth factor signaling pathway. Preclinical studies in mouse models of scleroderma showed significant anti-inflammatory and antifibrotic effects; however, several clinical, proof-of-concept trials have not yet confirmed these initially promising results.

Oral submucous fibrosis: a review of the current management and possible directions for novel therapies

“…Aberrent expression of this growth factor has also been reported in keloids, atherosclerosis, pulmonary and liver fibrosis and scleroderma 76 . Imatinib is thought to affect fibrotic pathways by selectively interferring with TGFβ signaling pathways 77 . Imatinib has been used as an antifibrotic drug for experimental treatment of scleroderma 78 protein).…”

Imatinib mesylate induced lichenoid drug eruption masquerading as small plaque parapsoriasis

“…Since the c-kit receptor is implicated as the causative factor in the pathogenesis of dermatofibrosacrcoma protuberans, gastrointestinal stromal tumor, systemic sclerosis and systemic mastocytosis hence IM is indicated at doses of 400 to 600 mg/day is in CML, GIST, dermatofibrosacrcoma protuberans, systemic mastocytosis and a low dose of 200 mg/day in systemic sclerosis. 1,4 Imatinib induced cutaneous adverse effects include macular-papular eruption, superficial edema, pigmentary disorders, hypopigmentation or depigmentation, hyperpigmentation, psoriasis and psoriasiform eruption, pityriasis rosea-like eruption, acute generalized exanthematous pustulosis, stevens-johnson syndrome, urticaria, neutrophilic dermatosis, photosensitivity, porphyria and pseudoporphyria but rarely lichenoid reactions. 1 Patient developed cutaneous eruptions two months after starting of IM of 400 mg/day for GIST which can occur in patients on IM.…”

PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix

“…Aberrant expression of this growth factor has also been reported in keloids, atherosclerosis, pulmonary and liver fibrosis and scleroderma [ 23 ]. Imatinib is thought to affect fibrotic pathways by selectively interferring with TGFβ signaling pathways [ 24 ]. Imatinib has been used as an antifibrotic drug for experimental treatment of scleroderma [ 25 ] and may have a role in placebo-controlled studies in OSF.…”