Rheumatology Advance Access originally published online on March 7, 2008
Rheumatology 2008 47(5):735-737; doi:10.1093/rheumatology/ken104
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Imatinib for the treatment of refractory, diffuse systemic sclerosis
1First Department of Propedeutic and Internal Medicine, Laikon Hospital, 2Histology-Embryology Department, 3Pulmonary Unit, Department of Clinical Therapeutics, Alexandra Hospital, Athens University Medical School, Athens, Greece and 4Royal Free Hospital, University College London, London, UK.
Correspondence to: P. P. Sfikakis, 18, Ipsilantou Str, 10676, Athens, Greece. E-mail: psfikakis{at}med.uoa.gr
SIR, We report on the beneficial, 6-month compassionate use of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) in a 24-yr-old woman with severe diffuse systemic sclerosis of 7 yrs duration. The patient presented in 1999 with Raynaud's phenomenon, followed shortly after by widespread diffuse scleroderma. A year later she was seen at the Royal Free Hospital, having a modified Rodnan skin score of 39 (maximum 51), muscle weakness, flexed hands and evidence of early interstitial lung fibrosis. She received 6-monthly intravenous (IV) pulses of cyclophosphamide, resulting in a decrease of skin score to 30. Subsequently, she received maintenance therapy with azathioprine (2 mg/kg daily) for 16 months. Despite a further 16 months of treatment with mycophenylate mofetil and bimonthly 5-day IV pulses of iloprost, the disease progressed (skin score of 40 and evidence of worsening interstitial lung disease). She then received oral cyclophosphamide for 3 months followed by 24-monthly cyclophosphamide pulses combined with iloprost, prednisolone and bosentan, resulting in stabilization of the disease and a skin score of around 34. In September 2006, she had a further exacerbation; re-institution of cyclophosphamide pulses for 6 months, in addition to all other medications was ineffective. In March 2007, we decided to discontinue cyclophosphamide and initiate compassionate treatment with imatinib after obtaining written informed consent.
Within 6 weeks of imatinib treatment (400 mg/day orally) skin score decreased from 44 to 33 with a marked improvement of flexion contractures and her general condition. At 3 and 6 months, skin score was 28 and this clinical improvement was also evident on histology (Fig. 1). Her mood, physical function and exercise capacity improved remarkably, she gained 3 kg of weight, and her periods normalized. The following changes in measures of clinical and laboratory parameters from baseline to 3/6 months were noted: visual analogue scale (0–100 mm) for pain from 93 to 33/38; physician global assessment from 94 to 40/42; health assessment questionnaire (0–60) from 46 to 33/33; elbow contractures (range of motion, degrees by goniometer, right–left) from 125–120 to 160–170/160–170; total lung capacity from 61.7% to 61.5%/64.5% predicted; DLCO from 38.7% to 39.5%/41.7% predicted; mid-expiratory flow between 25% and 75% of the forced vital capacity from 68.0% to 78.1%/88.3% predicted; score of lung fibrosis severity/extent in high-resolution computed tomography (maximum 30) from 13 to 13/13; pulmonary artery systolic pressure by echocardiography from 36 to 39/<30 mmHg; oxygen saturation at maximum cardio-pulmonary exercise from 89% to 94%; haemoglobin from 10.2 to 11.8/12.6 g/dl; C-reactive protein, from 4.9 to 2.0/0.8 mg/l. At 6 months, the daily prednisolone dose was decreased from 0.5 to 0.25 mg/kg, while acetaminophen, celecoxib, fluoxetine and bosentan were discontinued. Imatinib was well tolerated and no side-effects were noted. At the time of writing this letter in December 2007, the patient's condition remains stable and she is reluctant to discontinue imatinib.
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This case report is our first experience of imatinib administration for the treatment of a fibrotic human disease. Imatinib interferes with both TGF-β and PDGF signalling by blocking c-Abl and PDGF receptors, respectively [1, 2]. Several lines of evidence suggest that these pathways are involved in the pathogenesis of systemic sclerosis [3]. Imatinib has been approved for the treatment of patients with chronic myelogenic leukaemia and gastrointestinal stromal tumours, and has an excellent safety profile [2].
Experimental evidence indicates that oral imatinib attenuates collagen biosynthesis in mouse models of lung [4], renal [5] and hepatic fibrosis [6] in vivo. Moreover, imatinib efficiently reduced basal, as well as TGF-β- and PDGF-stimulated synthesis of extracellular matrix (ECM) proteins in dermal fibroblasts derived from SSc patients in a dose-dependent manner and blocked the development of dermal fibrosis elicited in mice by repeated injections of bleomycin [7]. Baroni et al. [8] found stimulating autoantibodies to the receptor of PDGF in all 46 tested scleroderma patients, further indicating a role of this pathway in the fibrotic process.
Among the abnormalities in the expression of ECM components in systemic sclerosis, increased accumulation of the interstitial collagen type III in the skin, lungs and gastrointestinal tract [9] is a characteristic pathological feature. Early studies in normal skin revealed that collagen III is only found around small blood vessels, adipocytes and smooth muscle cells, corresponding to the distribution of reticulin [10]. As demonstrated in serial skin biopsies, the increased expression of collagen type III in our patient's skin was abolished and could be detected around blood vessels only, within 6 weeks of imatinib therapy (Fig. 1). This result was sustained at 6 months of treatment indicating an imatinib-induced reduction of ECM production. We acknowledge the limitations of this single case report, but we believe that treatment with tyrosine kinase inhibitors may be a promising new targeted therapy for scleroderma. Reversal of unrestrained ECM deposition, rather than cytotoxic drug therapy is the concept underlying the use of imatinib, or newer similar compounds with better efficacy and tolerability in systemic sclerosis.
Disclosure statement: C.B. receives an honorarium for lecturing, from pharmaceutical companies, on average twice a year. All other authors have declared no conflicts of interest.
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