Efficacy of imatinib mesylate in a case of Churg-Strauss syndrome: evidence for the pathogenic role of a tyrosine kinase?

SIR, Churg Strauss syndrome (CSS) is a systemic vasculitis with eosinophilia, associated with anti-neutrophil cytoplasmic antibodies (ANCAs) in 40% of patients. Its pathophysiology remains unknown, but activated eosinophils could be the effector cells in this vasculitis. We report the case of a patient with CSS who responded well to a prolonged course of imatinib mesylate, suggesting the pathogenic role of a tyrosine kinase (TK) in CSS. The patient, a 26-year-old woman, was treated between 2001 and 2002 with prednisone and mesalazine for recurrent bloody diarrhoea associated with elevated transaminases attributed to Crohn’s disease with auto-immune hepatitis. In 2003 she was hospitalized for bloody diarrhoea, facial oedema, cutaneous vasculitis and newonset asthma. Blood tests showed an elevated peripheral eosinophil count of 13 500 10/l. Colonoscopy revealed pancolitis, with marked eosinophilic infiltration on histology. Although an extensive blood workup failed to establish the diagnosis of myeloproliferative or lymphoid variant of hypereosinophilic syndrome (HES), she was treated with IFN-a then hydroxycarbamide, with poor results. She reported worsening asthma and frequent sinusitis. Imatinib mesylate 400 mg/day was introduced in 2004, with rapid efficacy on clinical symptoms and eosinophil count, allowing prednisone withdrawal (Fig. 1). She stopped imatinib mesylate in July 2008 and was admitted 15 days later in our internal medicine department because of fatigue, high-grade fever, generalized oedema and dyspnoea. On examination she showed upper and lower limb purpuric patches, wheezing, abdominal pain and arthritis of the right ankle. The peripheral eosinophil count was 27 000 10/l. A CT scan revealed a dysmorphic liver with thrombosis of two hepatic veins and ascites. A skin biopsy showed leucocytoclastic vasculitis. The search for a JAK2 V617F mutation and FIP1L1-PDGFRA fusion gene were negative. The bone marrow karyotype (45XX-21/46XX) did not show any translocation involving chromosome 5. Complete sequencing of exons of the KIT and PDGFRA genes revealed no significant mutation. A repeated search for ANCA was negative. She was diagnosed with CSS and Budd Chiari syndrome and therapy with prednisone, AZA and anticoagulants led to rapid clinical and biological remission, which has persisted ever since. This case, which meets the 1990 ACR criteria for CSS, is the first report of imatinib mesylate efficacy in this disease [1]. This drug acts as a specific inhibitor of TK enzymes by blocking the acquired kinase activation induced by bcr-abl, c-kit and PDGF-R mutations. Its efficacy in our case and the relapse after withdrawal both suggest possible, yet unproven, involvement of TK in CSS pathogenesis that might be responsible for an uncontrolled expansion of eosinophils, as seen in the myeloproliferative form of HES [2]. The concomitant Budd Chiari syndrome, which has been reported in association with idiopathic HESs, but also described in CSS [3, 4], could be secondary to a pro-thrombotic state linked to the eosinophil granule proteins or to a latent myeloproliferative disorder associated with a TK mutation as seen in patients with JAK2 mutations. The reported case also meets the criteria for HES published by Chusid [5], although new-onset asthma and sinusitis strongly suggest a diagnosis of CSS. Moreover, after 11 years of follow-up, our patient does not exhibit clinical or biological signs of a myeloproliferative or lymphoid disorder. Based on this case report, we hypothesize that an imatinib mesylate sensitive TK could be involved in the pathogenic mechanism underlying CSS.