Long-standing remission of Crohn's disease under imatinib therapy in a patient with Crohn's disease.

Crohn’s disease (CD) is a chronic and relapsing gastrointestinal disease. New therapies to maintain patients in remission are needed. An 18-year-old white women developed abdominal pain, vomiting, and diarrhea in June 2000. Her hemoglobin was 11 g/dL, white blood cell count 9.3 10/L, platelet count 505 (normal 150Y450) 10/L, and the sedimentation rate (SR) 73 (normal 1Y18) mm/ 1st hour. Radiologic examination showed ulcers in the terminal ileum and narrowing of the lumen. At colonoscopy, ulceration of the ileocecal valve and ileum was seen. A biopsy specimen of the mucosa of terminal ileum and ileocecal valve showed mucosal ulceration with extensive inflammatory infiltrate. On the basis of clinical, radiologic, and histologic findings, a diagnosis of CD was made. Since 2001 she had been treated with prednisolone 40 mg/day and mesalamine 3 g/day. However, she was frequently symptomatic with abdominal pain and diarrhea, and the levels of SR were frequently high (Fig. 1A). For the treatment of chronic active disease, azathioprine was proposed; however, she refused. In September 2002, she developed fever and abdominal pain. The hemoglobin was 9.6 g/dL, white blood cell count 21.57 (normal, 4.0Y10.0) 10/L, platelets 906 10/L, C-reactive protein 138.9 (normal G 5.0) mg/L, and SR was 47 mm/1st hour. After a single infusion of infliximab (5 mg/kg intravenous), she became asymptomatic, without abdominal pain or diarrhea. At that moment, she was taking prednisolone 40 mg/day and mesalamine 3 g/day orally. After improvement with infliximab, prednisolone tapering was started. However, although there was clinical induction of remission, platelet counts were persistently high (Fig. 1B), and a hematologic evaluation was performed. Laboratory findings were as follows: white blood cell count 19 10/L (neutrophils 79 %, eosinophils 2%, basophils 1%, lymphocytes 10%, monocytes 1%, myelocytes 3%, metamyelocytes 3%, myeloblasts 1%), leukocyte alkaline phosphatase 120 (normal G 90) U/L, iron 10 (normal, 49Y151) mg/dL. Genetic analysis disclosed 46,XX, BCR-ABL positive tested by reverse-transcriptase polymerase chain reaction (RT-PCR). Since the diagnosis of chronic myeloid leukemia BCRABL (+) with thrombocythemia was made, she started hydroxyurea at a dose of 1,000 mg/day over 2 to 3 weeks without any improvement (white blood cells count 25.3 10/L, platelet count 1300 10/L). Thus, treatment with imatinib 600 mg/day was started (February 2003). A remarkable clinical, hematologic, and cytogenetic response was observed. Hematologic remission was kept under maintenance therapy with imatinib 400 mg/day until present. Bone marrow (aspirate and trephine) was normocellular. Genetic analysis showed complete molecular remission in qualitative (tested RT-PCR) and quantitative (real time-quantitative PCR) analysis. Because of the unexpected hematologic problem, the normal sequence of infliximab therapy was not performed. The therapy with imatinib was started in February 2003, when she was taking 15 mg/day of prednisolone. It is interesting to note that after imatinib, the patient experienced a sensation of general well being and stopped prednisolone and mesalamine at her own initiative. Surprisingly, the patient persisted asymptomatically despite the very long period without any medication known to be active against CD. Clinically, she never again complained of abdominal pain, vomiting, diarrhea, or other symptoms. The inflammatory parameters changed to normal levels (Fig. 1A), and the radiologic findings showed narrowing of the ileum, without evident ulcerations however. Thus, imatinib was the only drug taken by the patient for 3 years. Our patient had a chronic active disease for 2 years, and she denied taking immunosuppressant therapy. In the context of chronic myeloid leukemia, she started therapy with imatinib. The signal transducing inhibitor, STI-571 (imatinib mesylate), is a 2-phenylaminopyrimidine derivative that was designed as a selective competitive inhibitor of the Bcr-Abl tyrosine kinase. It also has strong activity against platelet-derived growthfactor receptor, c-Kit, and the Abl related gene. Bcr-Abl may function either by enhancing the proliferation potential of hematopoietic progenitors or by protecting these progenitors from apoptosis. Imatinib may mediate its proapoptotic effect at two different levels: 1) by a rapid and sustained inhibition of Bcr-Abl kinase activity, leading to inactivation of survival pathways and 2) by inducing long-term activation of caspases 9 e 3 responsible for the degradation and inactivation of Bcr-Abl tyrosine kinase. Imatinib has been also associated with a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2. Dietz et al also found that imatinib inhibits T-cell proliferation and reduced the levels of activated nuclear factor (NF)-kB. Although the precise etiology of CD remains unknown, there is increasing evidence for dysfunction of the immune regulation mechanisms in patients with CD. CD represents a T-helper (Th)1mediated condition because mucosal immune cells from affected individuals secrete interferon-g and tumor necrosis factor (TNF) as well as interleukin (IL)12 and IL-18, but not Th2-type cytokines. Moreover NF-kB appears to have an important role in CD, and several studies have shown that lamina propria T lymphocytes (LPL) from CD patients, compared with LPL from noninflammatory intestinal mucosa, LETTERS TO THE EDITOR