Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial

Robert F Spiera, Jessica K Gordon, Jamie N Mersten, Cynthia M Magro, Mansi Mehta, Horatio F Wildman, Stacey Kloiber, Kyriakos A Kirou, Stephen Lyman, Mary K Crow, Robert F Spiera, Jessica K Gordon, Jamie N Mersten, Cynthia M Magro, Mansi Mehta, Horatio F Wildman, Stacey Kloiber, Kyriakos A Kirou, Stephen Lyman, Mary K Crow

Abstract

Objective: To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis (dcSSc).

Methods: In this phase IIa, open-label, single-arm clinical trial, 30 patients with dcSSc were treated with imatinib 400 mg daily. Patients were monitored monthly for safety assessments. Modified Rodnan skin scores (MRSS) were assessed every 3 months. Pulmonary function testing, chest radiography, echocardiography and skin biopsies were performed at baseline and after 12 months of treatment.

Results: Twenty-four patients completed 12 months of therapy. 171 adverse events (AE) with possible relation to imatinib were identified; 97.6% were grade 1 or 2. Twenty-four serious AE were identified, two of which were attributed to study medication. MRSS decreased by 6.6 points or 22.4% at 12 months (p=0.001). This change was evident starting at the 6-month time point (Δ=-4.5; p<0.001) and was seen in patients with both early and late-stage disease. Forced vital capacity (FVC) improved by 6.4% predicted (p=0.008), and the diffusion capacity remained stable. The improvement in FVC was significantly greater in patients without interstitial lung disease. Health-related quality of life measures improved or remained stable. Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology.

Conclusions: Treatment with imatinib was tolerated by most patients in this cohort. Although AE were common, most were mild to moderate. In this open-label experience, improvements in skin thickening and FVC were observed. Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind randomised placebo controlled trial is warranted. ClinicalTrials.gov, NCT00555581.

Conflict of interest statement

Competing interests None.

Figures

Figure 1
Figure 1
Modified Rodnan skin score (MRSS) over the duration of the trial in all patients on treatment. At baseline the MRSS was 30.3±8.7 (n=30). After 3 months of imatinib therapy the MRSS was 29.9±9.4 compared with a baseline mean of 30.4±9.1 in this group (n=27); p=0.428. After 6 months the MRSS was 26.1±9.1; p

Figure 2

(A–D) Depicted are skin biopsy…

Figure 2

(A–D) Depicted are skin biopsy specimens before and after 12 months of imatinib…

Figure 2
(A–D) Depicted are skin biopsy specimens before and after 12 months of imatinib therapy in a single patient at 4× magnification. (A and B). H&E: After treatment there was a decrease in skin thickness. In the post-treatment specimen the collagen bundles are less thick and there is an increase in the interstitial spaces between the bundles. There are also increased numbers of adnexal structures in the post-treatment specimen. This individual patient is anti-Scl70 positive, with a disease duration of 4 months at baseline who had an improvement in MRSS of 9 points over the course of 12 months. In C and D are depicted anti-α-smooth muscle actin staining before treatment in panel C and post-treatment in D, showing a decline in the intensity of staining.
Figure 2
Figure 2
(A–D) Depicted are skin biopsy specimens before and after 12 months of imatinib therapy in a single patient at 4× magnification. (A and B). H&E: After treatment there was a decrease in skin thickness. In the post-treatment specimen the collagen bundles are less thick and there is an increase in the interstitial spaces between the bundles. There are also increased numbers of adnexal structures in the post-treatment specimen. This individual patient is anti-Scl70 positive, with a disease duration of 4 months at baseline who had an improvement in MRSS of 9 points over the course of 12 months. In C and D are depicted anti-α-smooth muscle actin staining before treatment in panel C and post-treatment in D, showing a decline in the intensity of staining.

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