Imatinib in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs and widespread vasculopathy. Patients with SSc are classified according to the extent of cutaneous sclerosis: patients with limited SSc have skin thickening of the face, neck, and distal extremities, while those with diffuse SSc have involvement of the trunk, abdomen, and proximal extremities as well. The disease course varies depending on the subtype of SSc. However, common features that result in significant morbidity and mortality, in addition to cutaneous fibrosis, include Raynaud's phenomenon and digital ulcerations, interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH). Current therapeutic options for patients with SSc and these clinical manifestations have shown limited efficacy. Imatinib antagonizes specific tyrosine kinases that mediate fibrotic pathways involved in the pathogenesis of SSc, including c-Abl, a downstream mediator of transforming growth factor (TGF)-beta, and platelet derived growth factor (PDGF) receptors. The efficacy of imatinib has also been reported in the treatment of patients with refractory idiopathic PAH through its effects on vascular remodeling. Based on the mechanism of action and preliminary patient data, we hypothesize that imatinib may be effective in the treatment of the fibrotic and vasculopathic features of patients with SSc. This is an open label pilot study to evaluate the safety and efficacy of imatinib in patients with progressive SSc refractory to other treatment(s). Validated measures of skin thickness and disease activity will be determined over 6-months of therapy and compared with baseline measures.

100 mg orally daily increased by 100 mg/day every 2 weeks to maximum of 400 mg daily as tolerated. Treatment for 6 months total.

Modified Rodnan skin score (mRSS) on scale of 0 (no skin disease) to 51 severe skin disease. %change in mRSS=(score at 6 months - baseline score)/baseline score. Negative values indicate improvement in skin disease. Clinical important improvement defined as > 25% improvement.

Change in % predicted Forced Vital Capacity (FVC) at 6 months compared to baseline. FVC is the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition.

Change in Health Assessment Questionnaire disability index at 6 months compared to baseline. The Questionnaire is comprised of a 20 question instrument pertaining to specific activities with possible integer responses of 0 (without any difficulty) to 3 (unable to do), and five additional scleroderma-specific visual analog scale (VAS) domains with possible values ranging from 0.0 to 15.0. The 20 questions are divided into eight domains. A mean score is calculated for each domain ranging from 0 to 3. A composite score is calculated by dividing the summed domain scores by the number of domains answered. The composite score is reported, falling between 0 and 3 on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal impairment of function).

Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline

To determine which cell types may be contributing to the gene expression changes associated with imatinib therapy, imatinib-responsive genes were isolated from from patient biopsies. From the total number of imatinib-responsive genes that were isolated, the percentage that came from endothelial cells, fibroblasts, B-cells, and multiple cell types was calculated. Reported values do not total to 100% because of rounding.

Inclusion Criteria: Adults with refractory diffuse or limited SSc and any or all of the following: Progressive cutaneous fibrosis, Interstitial lung disease, Pulmonary arterial hypertension, Digital ulcerations. Exclusion Criteria: Uncontrolled congestive heart failure, hypertension, or coronary artery disease. HIV, hepatitis B, and/or hepatitis C infection. Serious infection within the past month. Significant hematologic, renal, or hepatic abnormalities. Concurrent use of intravenous immunoglobulin or cyclophosphamide within 4 weeks of the first treatment dose. Concurrent use of a biologic agent (ie. etanercept, infliximab, adalimumab, abatacept) within 8 weeks of the first treatment dose (6 months for rituximab). Women who are pregnant or breastfeeding.

Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MK. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12319-24. doi: 10.1073/pnas.1635114100. Epub 2003 Oct 6.

Chung L, Fiorentino DF, Benbarak MJ, Adler AS, Mariano MM, Paniagua RT, Milano A, Connolly MK, Ratiner BD, Wiskocil RL, Whitfield ML, Chang HY, Robinson WH. Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum. 2009 Feb;60(2):584-91. doi: 10.1002/art.24221.