Presentation: Imatinib Mesylate Treatment Improves Skin Changes of Nephrogenic Systemic Fibrosis (2007)

32 Imatinib Mesylate Treatment Improves Skin Changes of Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is an extremely debilitating and painful condition that affects individuals with chronic kidney disease (CKD), usually following gadolinium exposure during magnetic resonance (MR) imaging studies. It is characterized by rapidly progressive skin hardening, tethering, and hyperpigmentation, predominantly on the extremities. Flexion contractures develop in advanced NSF that may severely impair physical function. NSF has not been observed to improve spontaneously without return of normal renal function and even may develop after successful renal transplantation. Most treatment modalities attempted, such as topical and oral steroids, immunosuppressive drugs, and plasmapheresis, have failed to improve the skin changes of NSF.
Increased TGFβ has been identified in skin, fascia, and striated muscle involved by NSF (SA Jiménez et al. Arthritis Rheum 2004; 50:2660-2666). TGFβ stimulates extracellular matrix (ECM) protein synthesis through a signaling pathway that involves the tyrosine kinase, c-Abl. By inhibiting the c-Abl kinase, imatinib mesylate (Gleevec) decreases ECM protein synthesis by dermal fibroblasts and reduces ECM synthesis and accumulation in bleomycin-induced experimental dermal fibrosis (JHW Distler et al. Arthritis Rheum 2007; 56:311-322).
PURPOSE: To assess the efficacy of imatinib mesylate treatment of patients with NSF.
METHODS: Two patients with stage 5 CKD, on dialysis treatment, and NSF were treated with imatinib mesylate 400 mg p.o. daily. Skin tethering was assessed using the modified Rodnan Skin Score (mRSS, maximum score = 51). Range-of-motion of each elbow and knee was measured with a goniometer. Pain was assessed on a 10-cm visual analogue scale.
RESULTS: After up to 15 weeks of follow-up, each patient exhibited softening of previously hardened skin with >60% reduction in the mRSS, as illustrated for one of the patients:

At baseline, one of the two patients reported pain and had significant fixed contractures of his elbows and knees. His pain decreased from 5/10 to 0/10 and he exhibited a 20° reduction of each knee flexion contracture, after 11 weeks of imatinib mesylate therapy. Other than for fluid retention that was successfully corrected by dialysis treatment, neither patient experienced adverse effects of imatinib mesylate.
CONCLUSIONS: Imatinib mesylate appears to improve skin changes and reduce joint flexion contractures rapidly in patients with NSF. Further study of imatinib mesylate in additional patients is warranted to confirm that this may be an effective treatment for NSF and other systemic fibrosing disorders, such as scleroderma.

  J. Kay, Novartis, 5.

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