title: A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease.
abstract: OBJECTIVE
  Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFβ and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy.
  
  
  METHODS
  We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy.
  
  
  RESULTS
  The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001).
  
  
  CONCLUSIONS
  Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, USA. khannad@med.umich.edu
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.forename: Rajeev
authors.initials: R
authors.lastname: Saggar
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Fereidoun
authors.initials: F
authors.lastname: Abtin
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Clements
authors.forename: Paul
authors.initials: P
authors.lastname: Maranian
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.forename: Ram R
authors.initials: RR
authors.lastname: Singh
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
mesh_terms: D000328:Adult; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D017563:Lung Diseases, Interstitial / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000150:complications*; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate