Background Pulmonary involvement represents a major cause of death of scleroderma patients. Cyclophosphamide showed a small beneficial effect in RCTs. There is a rational for the use of tyrosine kinase inhibitors as potential therapy for systemic sclerosis (SSc) and other fibrosing disorders. Preliminary published clinical trials are inconclusive about imatinib efficacy and showed relevant side effects.
Objectives To verify efficacy and tolerability of low dose of imatinib on lung and skin fibrosis in a cohort of scleroderma patients refractory to conventional therapy.
Methods A phase II multicentric open trial, which included 30 consecutive patients affected by SSc, with active pulmonary involvement, refractory to cyclophosphamide. The study followed a ‘Simon’s two-stage design’. Patients were treated with oral Imatinib 200 mg/day for 6 months. A “good response” was defined as the improvement both of pulmonary function tests and HRCT-scan pattern. Secondary outcomes were cutaneous involvement (mRSS) and quality of life.
Results Seventy-two patients were screened, 42 were excluded. The mean age was 50.83 ± SD 13.8 years and mean disease duration was 5.5 ± SD 4.1 years, 9 (30%) were males and 21 (70%) were females, all Caucasian. According to cutaneous involvement 14 (46%) had limited and 16 (53.3%) had diffuse cutaneous SSc; 93.3% were anti-SCL-70 positives. At the end of the study (month 12) we had 27 completers, 3 patients were lost prematurely because of death. Data refer to 26 patients. Seven of 26 (27%) met the criteria for response. As for mean changes in pulmonary function tests and PaO2 in the whole group, after therapy we observed a worsening of FVC (mean delta -2,74 ± SD 8,13%) and PaO2 (a mean delta of -2.27 ± SD 1.3), with a further worsening after stopping therapy. TLC and DLCO remained substantially stable. The analysis of thoracic HRCT showed a significant reduction in the number of pulmonary segments interested by a ground glass pattern, which persisted after completion of therapy. No changes were detected in the areas interested by a honeycombing pattern. We didn’t observe any significant improvement either in the skin fibrosis or in quality of life. Among serious adverse events we registered 4 cases not related with the experimental drug. Three patients died prematurely and one developed a severe pneumonia in the follow up phase. Concerning minor adverse events they were present in less than 20% of patients, mainly transient and well tolerated.
Conclusions According to Simon’s protocol 27% of patients responded, instead of 30% of expected rate, nevertheless, this trial demonstrated that low dose of imatinib stabilized lung involvement in scleroderma patients after failure of conventional therapy with cyclophosphamide, with radiographic improvement of the alveolitis. There was no significant improvement of skin involvement. Except for the 4 SAE the low dose was well tolerated. Together with other published trials these data will provide useful suggestions to design future RCTs.
Acknowledgements This study was partially funded by AIFA (Agenzia Italiana del Farmaco).
Disclosure of Interest None Declared