Rheumatol Int (2006) 26: 857–861 DOI 10.1007/s00296-005-0100-5
CASE REPORT
Soner Senel Æ Emin Kaya Æ Ismet Aydogdu M. Ali Erkurt Æ Irfan Kuku
Rheumatic diseases and chronic myelogenous leukemia, presentation of four cases and review of the literature
Received: 4 October 2005 / Accepted: 18 December 2005 / Published online: 11 January 2006 Springer-Verlag 2006
Abstract We report four patients with rheumatic disease (RD) and chronic myelogenous leukemia (CML). In two patients with Behcet’s disease (BD) and rheumatoid arthritis (RA), CML developed after RD, in two patients with diffuse cutaneous systemic sclerosis and spondyloarthropathy, RD was diagnosed after CML. A variety of interactions have been described between hematological malignancies and RD. Nevertheless, few cases of RD have been documented associated with CML. It is unclear whether the development of CML in patients with RD and RD development after CML occurs by chance alone, is due to the underlying disease, or is facilitated by drugs. Whatever the cause is, it should be kept in mind that CML may develop in the course of RD and RD may be seen in CML patients.
functional impairment. The CML cells display translocation t (9; 22), which is named as the Philadelphia chromosome (Ph1 ) [1]. A variety of interactions have been described between hematological malignancies and RD [2]. In patients with RA, over 10 years of follow-up, an increased risk of hematopoietic cancer was shown by Thomas et al. [3]. SSc was reported as more frequently associated with hematopoetic malignancies. Here, we present four patients who were diagnosed with BD and RA before developing CML and others with diffuse cutaneous systemic sclerosis (dcSSc) and SPA developed after CML. Tendency between diseases, the association with drugs, and possible pathomechanisms are discussed and the literature is reviewed.
Keywords Chronic myelogenous leukemia Æ Behcet’s disease Æ Diffuse cutaneous systemic sclerosis Æ Rheumatoid arthritis Æ Rheumatic disease
Case 1
Introduction Rheumatoid arthritis (RA), systemic sclerosis (SSc), Behcet’s disease (BD), and spondyloarthropathies (SpA) are named as the rheumatic diseases (RD) which are chronic, relapsing, and inflammatory multisystem disorders of unknown cause. Chronic myelogenous leukemia (CML) constitute the clonal diseases that originate from a transformed stem cell, involve all myeloid lineages, and the affected cells have both proliferative and S. Senel (&) Department of Internal Medicine Turgut Ozal Medical Center, Inonu University Faculty of Medicine, 44069 Malatya, Turkey E-mail:
[email protected] Tel.: +90-422-3410660 Fax: +90-422-3410728 E. Kaya Æ I. Aydogdu Æ M. A. Erkurt Æ I. Kuku Department of Internal Medicine Turgut Ozal Medical Center, Hematology, Inonu University Faculty of Medicine, 44069 Malatya, Turkey
A 33-year-old woman admitted to our outpatient department. While she was under treatment for recurrent oral aphthae, genital ulceration, arthralgias, and folliculitis on the lover limbs with diagnose of BD since 1997. Four years after, diagnosis of BD, hyperleukocytosis, thrombocytosis, and splenomegaly was developed. She also had an HLA-B5 (+), HLA-B7 (+) phenotype, and the skin pathergy test was positive using the standardized method. Chronic phase (CP) of CML confirmed by splenomegaly, peripheral blood (PB) findings. Bone-marrow aspiration was compatible with CML and Ph1 was negative with the giemsa banding method. The PB counts revealed: hemoglobin level 7.7 g/dl, platelets 548·103 ll 1, and white blood cell count 198.2·103 ll 1, and the peripheral smear revealed: 2% blasts, 2% promyelocytes, 8% myelocytes, 10% metamyelocytes, 6% bands, 68% neutrophils, 2% lymphocytes, and 2% monocytes. Other routine laboratory tests were unremarkable, except for an increased level of lactic dehydrogenase(1,013 U/l; normal range of 230–460 U/l) and Vitamine B12>1,200 pg/ml (180–900). LAP score was lower (1,200 pg/ml, and LAP score was lower than 20%, as concordant with CML. With the presence of the Ph1 and bone-marrow aspiration, clinical findings were compatiple with CP of CML and treatment of hydroxyurea initiated. Seven months after diagnosis, she was readmitted to the emergency service with fatigue, dyspnea, and productive cough. On admission, the laboratory findings were Hb: 9.6 g/dl, Wbc: 39·103 ll 1 Trb: 531·103 ll 1, LDH: 564
859
U/l, BUN: 70 mg/dl, creatinin: 8.0 mg/dl, total protein: 6.1. Results of albumine: 2.1 mg/dl, urine Na: 113 mEq/ l, and proteinurea 4.5 g/day showed nephrotic syndrome. ANA and Anti-Scl-70 were positive Anti-dsDNA was negative. On physical examination, blood pressure was 56/37 mmHg; pulse rate was 122 min, fever was 37.8C, splenomegaly, symmetric skin thickening of proximal, distal extremity and face, a velcro rale was slightly audible in the bilateral lower lung. Reynaud’s phenomenon, telangiectasia, and arthralgias were established. On further searching, both pericardial and pleural effusions were documented by echocardiography and high-resolution computed tomography. Also, the spyrometric test showed restrictive pulmonary disease due to pulmonary fibrosis and the esophageal manometry showed low esophageal sphincter dysmotility. Besides CML, dcSSc was also diagnosed with intersitial pneumonia, acute renal failure with nephrotic syndrome, pulmonary fibrosis, and specific characteristic skin lesions.
Discussıon With a 10-year follow-up time between 1994 and 2004, in our hematology department, we described four patients (Table 1) who have had both RD and hematopoetic malignencies. When we reviewed, there was no documented patient series like this in English literature. All of the patients were women, aged were between 24 and 65 years, and all had died of their diseases. Three of them were in CP; one was in A-BP. Except the patient with SpA, other three patients did not receive the IFN therapy. The hematological, rheumatological and total median follow-up times were 2.5, 5.0, and 8.5 years, respectively. We have discussed patients according to enumeration. Case 1 is the seventh patient reported in the literature as CML within BD, who has reported previously because of large genital ulcer due to hydroxyurea treatment [6]. CML developed after 6 years after the diagnoses of BD. In the literature, Budak-Alpdogan described two patients with CML, who developed the characteristic features of BD during IFN treatment and another patient who had a diagnosis of BD preceding CML [7]. The immunological mechanisms underlying BD are not totally understood and immune abnormalities have especially been detected during the active phase
of the disease. The mononuclear cells obtained from the BD patients have an increased production of IL-2, TNFalpha, IL-6, and IL-8; and have high serum levels of IFH-gamma and soluble interleukin-2 receptor. These factors may provoke clonal transformation of stem cells and development of CML [8]. In case 2, the diagnosis of undifferentiated SpA was made 8 years after CML. The phase of CML was different with this patient. She had been treated with IFN for 1 year and it is known that autoimmune side effects of Interferon are infrequent but may be hazardous and irreversible [9]. Sacchi and Talpaz reported an incidence of 2% of connective tissue diseases in their cohort of 581 CML patients [10]. Abe et al. reported a patient in whom diagnosis of RA was made while treated for CML with IFN [11]. Besides, the well known side effect of IFN on rheumatologic symptoms, the A-BP may trigger development of spondylarthropathy and it is also possible that the diagnosis of SpA can be related to IFN’s infrequent autoimmune side effect, as an underlying cause of undifferentiated SpA. The patient with RA had been treated with MTX (nearly for 10 years), hydroclorokin sulfate (for 1 year), prednisolon, and leflunomid (for 1 year). Diagnosis of CML was made after a 12-years history of RA. She was medicated with hydroxyurea for CML. The possibility of the side effect of MTX as a cause of CML can be discussed because of long-term use. Pointud et al. reported similar case in a patient with seropositive RA that acute myeloid leukemia developed after receiving weekly MTX for 33 mounts (total dose of 690 mg) [12]. Another two patients with RA, who developed CML and AML after short-term low-dose use of MTX was reported by Dubin Kerr et al. [13]. Choi et al. reported development of acute erythroleukemia in a rheumatoid arthritis patient after 60 months use of low-dose methotrexate therapy (total dose 1702.5 mg) [14]. Also, JobDeslandre et al. reported two cases with rheumatoid polyarthritis and Gougerot–Sjogren syndrome, who developed CML, without use of MTX [15]. Miyachi et al. reported the last case; an 80-year-old man who developed CML after 5-year history of RA [16]. This patient was reported to be treated with non-steroidal anti-inflammatory drug and gold sodium thiomalate. Kotter et al. reported two cases of seropositive RA developed after IFN therapy for CML and hairy cell leukemia [17]. Case 3 is the fourth patient in English literature who was diagnosed with CML after RA. Some
Table 1 Summary of the four patients with rheumatologic diseases and CML Phase of CML Case no. Gender/age Karyotype Ph1 First diagnosis Treatment
Second diagnosis Time between diagnoses
CP A-BP CP CP
CML SpA CML dcSSc
1 2 3 4
F/33 F/24 F/58 F/65
46 46 46 46
XX XX XX XX
( ) (+) (+) U
BD CML RA CML
Col/S IFN/HDU MTX/LEF/S/HCQ HDU
6 years 8 years 12 years 7 months
BD Behcet’s disease, SpA spondyloarthritis, RA rheumatiod arthritis, dcSSc diffuse cutaneous sytemic sclerosis, CP chronic phase, A-BP accelerated-blastic phase U unstudied, Col colchicine, HDU hydroxurea, S steroid, LEF leflunomid, HCQ hydroxychloroquine
860 Table 2 Summary of the reported cases of RA, SSc, and CML in literature Authors
First diagnosis
Treatment
Second diagnosis
Kotter et al. [17] Miyachi et al. [16] Dubin Kerr et al. [13] Job-Deslandre et al. [15] Abe et al. [11] Roumm and Medsger [22] Watanabe et al. [23] Wooten et al. [24] Beretta et al. [25]
CML RA RA RA/SS CML SSc SSc SSc CML
IFN GST/ NSAID MTX NA IFN NA NA NA IFN
RA CML CML CML RA CML CML CML SSc
BD Behcet’s disease, SpA spondyloarthritis, RA rheumatiod arthritis, SSc sytemic sclerosis, SS sjogren syndrome, GST gold sodium thiomalate, MTX methotrexate, IFN interferon, NA not available, NSAID nonsteroidal antiinflammatory drugs
studies suggest that MTX increases this risk of hematologic proliferative malignancies [18–19] whereas others do not [20–21]. Case 4 is the fifth patient in the literature who reported with CML and SSc. The other reported cases (Table 2) were those of Roumm and Medsger, Watanabe et al., Wooten et al., and Beretta et al. [22–25]. SSc has been described in association with a number of malignancies but only few cases of CML were documented. In most cases, the development of SSc preceded the discovery of malignancy by several years. In our case, there were 7 months between two diagnoses. She was having only the hydroxyurea regimen when the dcSSc diagnosis was made. The association between CML and SSc has not yet been elucidated. From the above results, an explanation may be that cytokines or other factors released from early neoplastic clones participate in the development of rheumatologic diseases, although this has not been proved yet. We thought that one of the reasons of increased diagnosis of RD is the achievement of prolonged survival in CML. It is unclear whether the development of CML in patients with RD or RD development after CML occurs by chance alone, is due to the underlying disease, or is facilitated by drugs. Whatever the cause is, it should be kept in mind that RD may develop in the course of CML and CML may be seen in RD patients, over several years within course of diseases.
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