Behçet's Disease, Myelodysplastic Syndrome, Trisomy 8

Case report Behçet’s disease, myelodysplastic syndrome, trisomy 8, gastroenterological involvement – An association

L. Eder1, M. Rozenbaum2,3, N. Boulman2, E. Aayubkhanov2, E. Wolfovitz4, D. Zisman1, I. Rosner2

1Internal Medicine A, Carmel Medical ABSTRACT immunosuppressive treatment, review Center, Haifa; 2Department of Rheumatol- Only a limited number of cases of Beh - the literature and discuss the relevant ogy, Bnai Zion Medical Center, Haifa; çet’s disease and hematological malig - issues. 3 Zvulon Clinic, Clalit Health Fund, Kiryat nancies have been reported in the liter - Motzkin; 4Internal Medicine C, Bnai-Zion Medical Center, Haifa, Israel. ature. We report the case of a 45 year Case report old female patient with Behçet’s disease A 45 year old female patient, first pre- Lihi Eder, MD; Michael Rozenbaum, MD; Nina Boulman, MD; Elena Aayubkhanov, who developed myelodysplastic syn - sented to the rheumatology clinic in MD; Efrat Wolfovitz, MD; Devi Zisman, drome, refractory anemia with excess 1995 with persistent arthritis of both MD; Itzhak Rosner, MD. blasts in transformation subtype, with ankles and knees as well as erythema Please address correspondence to: complex chromosomal abnormalities, nodosum. She reported rheumatic sym- Lihi Eder, MD, Kibbutz Usha 30031, including excess of chromosome 8, fol - ptoms on and off for 15 years, but no Israel. E-mail: [email protected] lowing several years of treatment with details or medical records were avail- Clin Exp Rheumatol 2005; 23 (Suppl. 38): chlorambucil for Behçet’s disease. As able. An evaluation of her arthritis, in- S91-S94. has been described in most such cases, cluding evaluation of inflammatory bo- Received on ; accepted in revised form on gastrointestinal involvement was most wel disease was unrevealing. She was Clin Exp Rheumatol 2005; 23 (Suppl. 38): prominent. This case is described and treated with low dose steroids, hydro- S91-S95. the occurrence of myelodysplastic syn - xychloroquine and colchicine. T h e Copyright CLINICAL AND EXPERIMENTAL drome in Behçet’s disease reviewed. symptoms were controlled with this RHEUMATOLOGY 2005. regimen. Introduction In January 1997, while under therapy, Key words: Behçet’s disease, myelo- Behçet’s disease is an inflammatory di- the patient presented with a flare of her dysplastic syndrome, trisomy 8, gas- sorder of unknown etiology, character- disease: oral and genital ulceration, trointestinal Behçet’s. ized by recurrent oral and genital ulcer- erythema nodosum and disabling arth- ation, arthritis, ophthalmic and skin le- ritis of multiple upper and lower extre- sions. Involvement of the intestines, mity joints. The cardiovascular, resp- central nervous system, other visceral iratory, abdominal and ophthalmologic o rgans and vascular system can also examinations were unremarkable. Ini- occur (1). In addition to colchicine and tial laboratory work revealed antinu- low dose steroids, Behçet’s disease pa- clear antibodies, rheumatoid factor ne- tients are often treated with immuno- gative; C3 and C4 normal. A pathergy suppressive therapy, such as azathio- test was not performed. prine, and occasionally drugs like chlo- The diagnosis of Behçet’s disease was rambucil and cyclosporine A. Current made (9) and the patient treated with therapy options also include alpha-in- increased steroids. Attempts at treat- terferon and anti-TNF agents (2-3). ment with methotrexate, sulfasalazine, Only a limited number of cases of Beh- cyclosporine A and azathioprine failed çet’s disease and hematological malig- due to adverse reactions. As the patient nancies, all lymphomas, have been re- continued to suffer from non-scarring, ported in the literature (4-8), except for intractable oral and genital ulcers and an unlikely cluster of patients with an arthritis and required high dose steroids association of myelodysplastic syn- for control, treatment with chloram- drome (MDS) and Behçet’s disease. bucil 4 mg per day was initiated. We present the case of a patient with From 1998 to the end of 2003 her dis- Behçet’s disease who developed mye- ease was managed in the community lodysplastic syndrome which evolved and controlled under a regimen of chlo- to secondary acute leukemia following rambucil 4 mg/d, colchicine 1 mg/d

S-91 CASE REPORT BD and hematological malignancies / L. Eder et al. and prednisone 15 mg/d. Repeated lated to progressing MDS. She was +22,+X,+dm. Due to her poor general blood counts were normal. treated with intravenous pulse methyl- condition and uncontrolled Behçet’s In September 2003, treatment with col- prednisolone 1 gr/d with only transient disease she was not felt to be a candi- chicine and chlorambucil was with- improvement in her condition. A short date for chemotherapy treatment for drawn due to pancytopenia. The patient term trial of treatment with infliximab her progressing MDS. was asymptomatic at that time. T h e also failed. Despite intensive treatment the pa- course of her disease, laboratory tests A second bone marrow biopsy was in- tient’s condition deteriorated and she and treatments from this point are sum- terpreted as Refractory Anemia (RA) died with multi-organ system failure. marized in Table I. The patient returned with excess of blasts, in transformation to the hospital 2 weeks later with an up- to acute leukemia. Bone marrow chro- Discussion per respiratory tract infection. Her tem- mosome analysis showed complex The association of Behçet’s disease perature was normal. The blood count chromosomal abnormalities: 55,XX,- with malignancies has rarely been re- showed persistent pancytopenia. Chest 5 q - , + i ( 8 q ) , + i ( 8 q ) , + 11 , + 1 3 , + 1 4 , + 1 9 ,- ported, and even less so with hematolo- and sinus X rays were interpreted as normal. Antibiotic treatment with cef- Table I. Summary of the patient's terminal illness. uroxime was started. Two weeks later the patient was admit- Clinical picture Treatment ted to the hospital suffering from severe watery diarrhea, abdominal pain and 30/9/2003 Asymptomatic pancytopenia (Hb 9, WBC 2.5, PLT76)* Colchicine and chlorambucil stopped fever, 38°C, still under prednisone 20 mg/d. Abdominal and chest X ray were ¯ interpreted as normal. Stool culture grew Campylobacter jejuni. The pa- 13/10/2003 tient was treated with azythromycin Upper respiratory tract infection Cefuroxime Tx with relief of her symptoms and fever. Pancytopenia (Hb 8.8, WBC 2.1, PLT90) Observation Sinus and chest x-ray normal A week later, while still under treatment, her condition deteriorated with ¯ profuse watery diarrhea and abdominal pain, this time accompanied by poly- 3/11/2003 arthritis and oral and genital ulceration GI symptoms, fever Azythromycin Tx with a fever of 39°C. Laboratory work Pancytopenia (Hb 7.6, WBC 3, PLT30) Prednisone dose increased Stool culture – C. jejuni revealed worsening of pancytopenia, hypokalemia, hypoalbuminemia, CRP- ¯ 494 mg/l (normal less than 6 mg/ml) and positive occult blood in the stool. 10/11/2003 Small bowel series showed multiple GI symptoms, fever, arthritis, oral and genital ulcers Pipracillin-tazobactam filling defects in the ileum, suggestive Pancytopenia + electrolyte abnormalities + gentamycin + metronidazol of ulceration. Due to her poor general Small bowel passage – filling defects ¯ condition an endoscopic evaluation Bone marrow biopsy – RAEB Vancomycin + meropenem + Ampho B was not performed. A bone marrow as- IVpulse steroids piration and biopsy established the diagnosis of myelodysplastic syndrome, ¯ FAB subtype-refractory anemia with excess of blasts. 20/11/2003 No response IVsteroids, IVinfliximab Treatment with broad spectrum anti- Blood, urine, stool cultures – negative biotics, pipracillin-tazobactam, gentamycin, metronidazole later replaced by ¯ meropenem, vancomycin, and ampho- tericin B was ineffective. She was re- 5/12/2003 suscitated with IV fluids, electrolyte re- Clinical and laboratory deterioration Blood products and supportive care Bone marrow biopsy – RAEB-t placement and blood transfusions. All blood, urine and stool cultures were ¯ negative for bacteria, viruses and para- sites. As the patient’s condition contin- 20/12/2003 ued to deteriorate under the treatment, Patient died with multi-organ system failure. her symptoms could be attributed to a *WBC x 109/L; Hb in mg/dL; PLTx 10 9/L. flare of Behçet’s disease, possibly re-

S-92 BD and hematological malignancies / L. Eder et al. CASE REPORT gical malignancies. We present a case toms, fever and skin lesions. Eye le- Behçet’s disease and MDS (26). of Behçet’s disease in association with sions and arthritis were infrequently re- A relationship between malignancies MDS in transformation to acute leu- ported. MDS was diagnosed before or and immunosuppressive treatment in kemia, which raises a number of issues: concomitantly with Behçet’s in most of rheumatic diseases has been demon- the relationship of MDS to Behçet’s di- the patients. Only one patient whose strated in studies (42). Specifically an sease and the role of gastrointestinal in- MDS was diagnosed after Behçet’s dis- increased risk of malignancies of the volvement and chromosome abnorma- ease received immunosuppressive (chlo- immune system, lymphoma and multi- lities there in. rambucil and cyclosporine) treatment ple myeloma, has been observed in The association of MDS and immuno- before the diagnosis. rheumatic disease patients treated with logical abnormality disorder has been Whereas trisomy 8 has been the most azathioprine as compared to untreated well described in the literature. Clinical common chromosomal abnormality re- patients (43). Other studies, have ob- manifestations of such phenomena may ported in MDS associated with Beh- served an increased risk of leukemia in include systemic vasculitic syndrome, çet’s disease, 18 out of 23 patients in- rheumatoid arthritis patients treated skin vasculitis, fever, arthritis, inflam- vestigated, its reported incidence is on- with chlorambucil (44). A causal rela- matory bowel disease and even classi- ly 10-20% among untreated general tionship between alkylating agents, cal connective tissue disorders (10). MDS patients with chromosomal ab- such as chlorambucil and secondary The prevalence of these manifestations normalities (39). Thus the percentage malignancies, in general, is well estab- among MDS patients has been estimat- of trisomy 8 in MDS patients with Beh- lished (45). These agents form DNA ed at between 10-18.5% (11-12). MDS çet’s disease is markedly higher than in cross links that interfere with replica- associated with vasculitis has been re- patients with MDS alone. In addition tion, repair and translation of DNAand ported to affect mostly cutaneous ves- considering the high frequency of tri- may thus be mutagenic. sels or joints. The literature also in- somy 8 in this setting with associated There is evidence in the literature that cludes case reports on Takayasu’s arte- GI manifestations, Shinya et al. sug- the use of immunosuppressive drugs is ritis (13), Henoch-Schonlein purpura gested that trisomy 8 might predispose associated both with chromosomal ab- (14) and other vasculitic syndromes. patients with MDS and Behçet’s di- normalities as well as with myelodys- The association between malignant dis- sease to intestinal ulceration (33). plastic syndrome (47-48). Le Beau et eases and Behçet’s disease has not been GI involvement of Behçet’s disease ty- al. reported a series of patients with widely investigated. The present litera- pically affects the ileocecal region and therapy-related MDS, 97% of them de- ture suggests an increased risk of mali- colon. The frequency of GI involve- monstrating chromosomal abnormali- gnancies in connective tissue diseases, ment varies in different countries, with ties, 87% with abnormalities of chro- with a more marked increment in der- a lower frequency in Israel (14-25%) mosome 5 and/or 7 (48). Our patient al- matomyositis and mixed connective (40) as compared to Japan (50-60%) so had deletion of the long arm of chro- tissue disease and a slight increase in (41). Our patient’s severe GI involve- mosome 5 (del 5q). It has been sugges- systemic lupus erythematosus, rheuma- ment, unusual for her locale, dovetails ted that the cytogenetic abnormalities toid arthritis and polymyositis reported well with the patients reviewed in the induced by the drugs are more impor- (15-17). The autoimmune nature of the literature who had prominent GI symp- tant than the mere prolonged use of im- diseases and the immunosuppressive toms when MDS was present with munosuppressive therapy in the patho- drugs used in their management are re- Behçet’s disease. genesis of MDS. Due to the complex garded as underlying this association. Although the relationship between tri- chromosomal abnormalities in our pa- In reference to Behçet’s disease and somy 8 and GI manifestations of Beh- tient it is not possible to infer clear cau- malignancy the literature is sparse. çet’s disease is reported frequently in sality between the immunosuppressive Cengiz et al. reported on 13 patients the literature, as stated above, the me- therapy and development of MDS in with only 3 of the patients having he- chanism of this relationship remains the present case. matological malignancies (18). unclear. Shinya suggested that the pres- In summary, we present a case of a wo- Notably, most of the cases of Behçet’s ence of trisomy 8 facilitates cytokine man with Behçet’s disease who devel- disease and hematological malignancy production in both lymphocytes and oped pancytopenia, diagnosed as MDS, reported in the literature are of MDS. supporting tissues and that their elevat- after immunosuppressive treatment of Until now, 26 patients with this associ- ed level may result in the findings (33). her underlying condition. Cytopenias ation have been reported in the litera- Another proposed mechanism related are common in patients with rheumatic ture (19-38). Their main clinical and la- to an increase in reactive oxygen spe- diseases and may be the consequence boratory findings are summarized in cies (ROS) production. In Behçet’s di- of varying etiologies. Prior immuno- Table II together with those of the cur- sease there is increased production of suppressive treatment should raise the rent study patient. Most of the patients ROS by activated neutrophils and these possibility of evolving secondary hem- reported are from Japan. Their median functions may be increased in the sub- atological malignancy. In Behçet’s dis- age is 45 years, range 10-74. The ma- group of MDS patients with trisomy 8 ease, the peculiar association with jority of the patients had oral and geni- and thus may play an important role in MDS, trisomy 8 and gastrointestinal tal ulcers, gastrointestinal (GI) symp- the complications associated with involvement is highlighted.

S-93 CASE REPORT BD and hematological malignancies / L. Eder et al.

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