To the Editor:
Imatinib mesylate is a potent and selective inhibitor of tyrosine kinases such as Bcr-Abl, platelet-derived growth factor (PDGF) receptor, and c-Kit, and it is widely used to treat chronic myeloid leukemia (CML) and c-Kit-positive gastrointestinal stromal tumors. Imatinib also exerts potent immunomodulatory effects in vitro and in vivo1. Recent reports described the efficacy of imatinib in treating patients with various autoimmune and inflammatory diseases such as rheumatoid arthritis (RA), systemic scleroderma, pulmonary arterial hypertension, and lupus nephritis2–5.
We describe a patient with steroid-resistant adult onset of Stills disease (AOSD), who incidentally developed CML. Treatment with imatinib induced hematological remission of CML as well as improvement of symptoms of AOSD. Immunosuppressants were tapered and discontinued 2 years after the initial imatinib treatment. The patient has maintained remission of AOSD for 5 years under imatinib treatment.
In August 2000, a 25-year-old Japanese man was admitted to the Department of GeneralMedicine, Kyushu University Hospital, due to fever of unknown origin. He exhibited symptoms of pharyngitis, arthralgia, typical rash, leukocytosis, high level of C-reactive protein (CRP; 33.0 mg/dl), and hyperferritinemia (19,777 ng/ml). A diagnosis of AOSD was made based on his symptoms and these results. He was treated with prednisolone (PSL; 1 mg/kg daily). However, the disease proved to be steroid-resistant. Treatment with methylprednisolne pulse therapy (1000 mg for 3 days) in combination with cyclosporine (CSP) and cyclophosphamide resulted in gradual clinical improvement (Figure 1). Cyclophosphamide was discontinued, and PSL (0.25 mg/kg/day) and CSP (5 mg/kg/day) were taken daily as outpatient medication. However, he was frequently readmitted because of high fever, rash, and arthralgia. He experienced frequent AOSD flares, for which he eventually received treatment with pulse methylprednisolne along with increased doses of PSL and CSP (Figure 1).
Clinical course of AOSD before and after treatment with imatinib mesylate. mPSL: methylprednisolne; CY: cyclophosphamide; CSP: cyclosporine; CRP: C-reactive protein; WBC: white blood cell count.
In July 2002, he was referred to the Department of Hematology, Kyushu University Hospital, for evaluation of leukocytosis. A peripheral blood test revealed a white blood cell count of 69.9 × 109/l (0.4% blasts, 0.4% promyelocytes, 14.4% myelocytes, 5.4% metamyelocytes, 70.3% neutrophils, 7% eosinophils, 1.7% basophils, and 3.8% lymphocytes). A bone marrow aspirate showed hypercellular marrow with marked myeloid predominance. Chromosomal and molecular analyses revealed 46,XY, t(9;22)(q34;q11) in all metaphases and the presence of major-BCR/ABL fusion transcript. He was diagnosed with chronic-phase CML. Treatment with imatinib 400 mg daily was initiated, resulting in a prompt decrease in the number of white blood cells; he exhibited a hematological and molecular response to CML. Following treatment with imatinib, he experienced no more high fevers, rashes, and arthralgia as in previous episodes. In July 2003, he was finally cured of these symptoms and had a marked decrease in serum levels of ferritin and CRP (Figure 1). Immunosuppressants were tapered, and PSL and CSP were discontinued in January and July 2004, respectively (Figure 1). Thereafter, he has maintained a molecular remission of CML. Since imatinib treatment he has completed 4 years with no symptoms of AOSD.
To our knowledge, this is the first report of the efficacy of imatinib in a patient with AOSD. Despite the standard immunosuppressive treatment for AOSD, our patient exhibited frequent flares that required increased dosage of corticosteroids and calcineurin inhibitors, in addition to methylprednisolne pulse therapy and cyclophosphamide therapy. Alternative therapy of biological agents such as interleukin 1 (IL-1) receptor antagonist, IL-6 receptor antibody, and tumor necrosis factor (TNF) inhibitors might have been considered for this patient. However, 2 years after the diagnosis of AOSD, he incidentally developed CML. Treatment with imatinib 400 mg daily resulted in a hematological and molecular remission of CML as well as a gradual clinical improvement of AOSD, allowing tapering of CSP and PSL. One year after imatinib treatment, AOSD symptoms had completely disappeared, and after 2 years of treatment, immunosuppressants were finally discontinued with no signs of AOSD flares.
Our case suggests that, in contrast to PSL and CSP, imatinib might be useful for treatment of AOSD. Selective inhibition of tyrosine kinases could provide a potent therapeutic option for a variety of autoimmune and inflammatory disorders1. Imatinib mesylate is a signal transduction inhibitor that targets Bcr-Abl, c-Kit, PDGF receptor, c-fms, and LCK. Recent reports have shown that imatinib proved beneficial in patients with various autoimmune disorders, including RA, systemic scleroderma, pulmonary arterial hypertension, lupus nephritis, ankylosing spondylitis, psoriasis, and Crohn’s disease1–5. Consistent with the clinical findings, in vitro studies demonstrated that imatinib can inhibit multiple signaling pathways implicated in the pathogenesis of various autoimmune disorders, including T-cell proliferation, macrophage c-fms activation and cytokine production, c-Kit-mediated mast-cell release of TNF-α and IL-6, and synovial fibroblast PDGF receptor signaling and proliferation3,7–10. AOSD is a systemic inflammatory disease that includes the participation of various cytokines such as IL-1, IL-6, IL-18, TNF-α, macrophage colony-stimulating factor, PDGF, and interferon-γ. Biological agents such as anti-TNF-α and anti-IL-1 have been successfully used in cases of refractory AOSD6. Therefore, as in our case, imatinib could prove beneficial in patients with AOSD, an inflammatory disorder involved with various cytokines and multiple signaling pathways; the precise etiology of AOSD remains unclear1,9.
Imatinib shows promise for treatment of AOSD and other autoimmune and inflammatory diseases. However, to clarify the efficacy of imatinib as well as other tyrosine kinase inhibitors, it is necessary to define which kinases and cellular responses mediate the disease pathogenesis. Moreover, since the effect of imatinib on autoimmune disorders has been observed in patients with CML treated with 400 mg imatinib per day, it is critical to define the therapeutic dosages suitable for treatment of these disorders2,3,5.
CML arises from primary mutations in Bcr-Abl, and relatively high doses of imatinib are required to inhibit proliferation of the leukemic cells1. In contrast, autoimmune diseases are not associated with mutations in kinases, and wild-type kinases participate in the dysregulated cellular responses that mediate tissue injury. Therefore, lower doses of imatinib may prove beneficial in autoimmune diseases1. Further studies are needed to define the course of therapy required for imatinib treatment, and the influence of treatment, in autoimmune and inflammatory diseases.
