Autoimmune phenomena in myelodysplastic syndromes: a 4-yr prospective study

S. Giannouli, M. Voulgarelis, E. Zintzaras1, A. G. Tzioufas and H. M. Moutsopoulos

Department of Pathophysiology, Medical School, National University of Athens, 1Biomathematics Laboratory, Medical School, University of Thesssaly, Larisa, Greece.

Correspondence to: H. M. Moutsopoulos, Department of Pathophysiology, Medical School, National University of Athens, M. Asias 75, Goudi 11527 Athens, Greece. E-mail: hmoutsop{at}med.uoa.gr


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To determine the clinical aspects and evolution of autoimmune inflammatory manifestations (AIMs) in patients with myelodysplastic syndrome (MDS) and ascertain the prognostic implications of these manifestations in MDS.

Methods. Seventy patients diagnosed for MDS were enrolled in a prospective cohort study of 4-yr duration. Thirteen patients with AIMs were identified (group A). The remaining 57 MDS patients without AIMs constituted the control group (group B). Demographic, clinical features, laboratory data, treatment and outcome of all these cases were recorded.

Results. On comparing features between the two groups we were unable to identify any particular difference (P >= 0.05) concerning bone marrow blast count [odds ratio (OR) = 0.68], international prognostic scoring system (IPSS) (OR = 1.36), favourable cytogenetic abnormalities (OR = 0.52), leukaemic transformation (OR = 1.30) and survival (P = 0.76). Furthermore there was a significant difference in survival between low vs non-low IPSS patients for both groups (P<0.01).

Conclusion. In a 4-yr prospective study the prognosis of MDS patients with AIMs appeared to be closely related to the IPSS subcategory of the underlying haematological malignancy and not to the autoimmune process.

KEY WORDS: Myelodysplastic syndrome, Vasculitis, Relapsing polychondritis, Arthritis, Autoimmunity.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Primary myelodysplastic syndromes (MDS) are clonal disorders of haematopoietic stem cells characterized by ineffective and dysplastic haematopoiesis and peripheral cytopenias. A distinct subset of MDS patients manifests overt autoimmune inflammatory manifestations (AIMs), the underlying pathogenesis and prognostic significance of which still remain controversial. The estimated incidence of AIMs in myelodysplasia has increased by 10% in previous studies [14]. Clinical manifestations of such phenomena may include systemic vasculitic syndrome, skin vasculitis, arthritis, peripheral polyneuropathy, inflammatory bowel disease and even classical connective tissue disorders such as relapsing polychondritis [2]. All these previous studies were retrospective and included even less well-described cases concerning cytogenetic analysis, prognostic factors, MDS-associated therapy, overall survival and evolution of myelodysplasia. The present study is a prospective analysis of a cohort of 70 MDS patients evaluated and followed up in our department over the last 4 yr. During this study 13 patients with the diagnosis of MDS-associated AIMs were identified. We describe the disease characteristics, the clinical course and the evolution of these 13 patients. We also review the incidence, nature, course and the response to therapy of these manifestations in comparison with our findings. Finally we discuss potential pathophysiological mechanisms involved in this phenomenon, highlighting the recent studies performed in our department.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Among 70 MDS patients diagnosed at the Department of Pathophysiology, Medical School of Athens, over a period of 4 yr (from January 1999 to July 2003), 13 MDS patients developed AIMs (group A). The remaining 57 MDS patients without AIMs constituted the control group (group B). Medical history, date of diagnosis of MDS, as well as date of presentation of AIMs were recorded. Patients with a history of genotoxic therapy for a previous malignancy were excluded. All patients who participated in our prospective cohort study were fully informed of the aim of this study and provided written consent for their participation and their agreement that the results of this study may well be presented or published, solely in the interests of science, provided that their anonymity is maintained. We also confirm that this study was approved and authorized by the Scientific Board of Athens University Medical School, Clinical–Pathological Division (President Professor D. Kelekis) and conforms to standards defined by our university authorities.

Diagnostic procedures
Bone marrow aspirates, biopsies and cytogenetic data from all patients were obtained after written informed consent. Neither chemotherapy nor immunosuppression had been administered prior to the first bone marrow collection. Dysplastic changes and dyspoiesis in bone marrow aspirates were defined according to the criteria of Bennett et al. [5]. Mild megaloblastic changes without dyspoiesis in other cell lines were not considered sufficient for a diagnosis of MDS. MDS patients were classified according to the French–American–British (FAB) classification and were also categorized as low-, intermediate- or high-risk MDS, according to the International Prognostic Scoring System (IPSS) [5, 6]. The criteria proposed by the FAB group for subclassification of these disorders are morphological and include the numbers of myeloblasts and ring sideroblasts in the bone marrow, the percentage of the blasts and the monocytes in the blood and the presence of Auer rods. Based on these parameters, five subtypes were recognized: refractory anaemia, refractory anaemia with ring sideroblasts, refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation and chronic myelomonocytic leukaemia. Furthermore, the IPSS proposes several groups of risk on the basis of clinical and cytogenetic variables. Karyotypic analysis of all samples by means of GTG banding was performed. Haematological response was defined according the proposal of the International Working Group (IWG) for evaluating effects of treatment in MDS patients [7]. The criteria of the American College of Rheumatology Subcommittee on Classification of Vasculitis were used for defining vasculitis [8]. The diagnosis of relapsing polychondritis was based on the characteristic clinical features as described by McAdam et al. [9]. Clinical examination, haematological and biochemical parameters, serum electrophoresis and antibodies against hepatitis B and C viruses and cytomegalovirus were recorded. The autoantibody profile, including detection of antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), rheumatoid factor (RF), total haemolytic complement (C3, C4) and cryoglobulins was also monitored. Histological examinations of all the involved tissues were performed. Survival time, and time of progression to acute myelogenous leukaemia (bone marrow blasts more than 30% of the total nucleated marrow cells) when it occurred, were recorded in all patients.

Statistical analysis
Characteristics, which were continuous variables, were compared using the Mann–Whitney U-test. For establishing binary variables, odd ratios (OR) with corresponding 95% confidence intervals (C.I.) were calculated. The association between the two groups of patients and IPSS was tested using the {chi}2 test. The survival difference between the two groups was tested using Kaplan–Meier curves and the log-rank test. Where P was less than 0.05 then the differences were considered significant. The analysis was performed using the statistical package Statistica v.6.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Comparative features of group A and B patients
On comparing features between the two groups of MDS patients with and without AIMs we were unable to identify any particular difference in regard to MDS subtype and cytogenetic abnormalities (favourable or not) (Table 1). Furthermore, no correlation between FAB classification and IPSS grade with predisposition to development of AIMs was observed. However, group A patients had a lower age at MDS diagnosis compared with group B (median age 67 yr, min.–max. 51–80 vs 74, min.–max. 43–89, P = 0.03).


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TABLE 1. Summary statistics [mean ± S.D., median (min.–max.) and %] for the characteristics of myelodysplastic syndrome (MDS) with and without autoimmune inflammatory manifestations (AIMs). The significant levels (P) and the odds ratios with the corresponding 95% C.I.s [OR (upper, lower limit)] for the differences between the two groups of patients are shown

 
The two groups of patients were not statistically different in survival (P = 0.76). The median survival time of group A and group B patients was 39 and 26 months respectively, with corresponding lower quartiles of 11 and 8 months respectively (Fig. 1). The two groups had the same pattern in survival differences, dependent on the IPSS levels. The survival curves between low vs non-low IPSS patients were significantly different for both groups (P<0.01) (Fig. 2). Finally, the leukaemic transformation did not differ statistically between the two groups [OR = 1.30 with 95% C.I. (0.24, 7.07)].



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FIG. 1. Survival curves for myelodysplastic syndrome (MDS) patients with and without autoimmune inflammatory manifestations (AIMs) (P = 0.76). The median survival time for MDS patients with AIMs and for MDS patients without AIMs are 38.93 and 25.98 months respectively.

 


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FIG. 2. Survival curves for myelodysplastic syndrome (MDS) patients with autoimmune inflammatory manifestations (AIMs) and MDS patients without AIMs for the different IPSS levels. In both groups there is significant difference between low vs non-low IPSS levels (P<0.01).

 
Characteristics of MDS patients with AIMs
Demographic and clinical characteristics of MDS patients with AIMs, subdivision according to FAB classification and IPSS system, as well as haematological and cytogenetic data are indicated in Table 2. Prior exposure to agents predisposing to myelodysplasia was not reported. The estimated prevalence of AIMs in our cohort of MDS patients was 18.5%. Seven male and six female patients with ages ranging from 51 to 80 yr were detected. Six patients were of high risk, three were of intermediate and four were of low risk according to the IPPS for MDS. Eleven patients were anaemic (haemoglobin < 11 g/dl), 11 were thrombocytopenic (platelet count < 150 x 109/l) and nine leucopenic (WBC < 4 x 109/l). Six patients had refractory anaemia (RA), one refractory anaemia with ring sideroblasts (RARS), two refractory anaemia with excess of blasts (RAEB), two refractory anaemia with excess of blasts in transformation (RAEB-T) and two chronic myelomonocytic leukaemia (CMML). Clonal abnormalities were identified in six patients and included 5q–, +8, –5, –7, deletion 20q and deletion 3q.


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TABLE 2. Demographic, haematological and cytogenetic data of myelodysplastic patients with autoimmune inflammatory manifestations

 
Description of AIMs features
The AIMs detected in group A patients are shown in Table 3. The AIMs detected fell into the following patterns: systemic vasculitis, skin vasculitis, isolated autoimmune manifestations like autoimmune thrombocytopenia, polyarthritis and colonic ulcerations and classic connective tissue disorders such as relapsing polychondritis and Sjögren’s syndrome. The majority of our patients manifested vasculitic overlap syndromes with leucocytoclastic vasculitis being the most common manifestation. Two of our patients (cases 1 and 2) developed acute vasculitic syndrome, manifested with an acute onset of fever, leucocytoclastic vasculitis, pleural effusions, non-infectious pulmonary infiltrates and peripheral neuropathy. Serological abnormalities, included hyper- or hypogammaglobulinaemia, direct Coombs test positivity, monoclonal paraproteinaemia, antimitochondrial autoantibodies, autoantibodies against thyroid peroxidase and thyroglobulin, antinuclear antibodies and the presence of rheumatoid factor. Evidence of autoimmune disease prior to the diagnosis of MDS was found in four patients; MDS antedated AIMs in one patient and the remainder developed AIMs during the course of the haematological disorder. AIMs which were presented prior to the diagnosis of myelodysplasia (cases 6, 7, 11 and 12) included symmetric polyarthritis, temporal arteritis, glomerulonephritis and Sjögren’s syndrome respectively (Table 4). There was not any association between MDS therapy and the onset of AIMs.


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TABLE 3. Autoimmune inflammatory manifestations in myelodysplastic patients

 

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TABLE 4. Treatment and outcome of myelodysplasia-associated autoimmune inflammatory manifestations

 
Follow-up, treatment and survival of MDS/AIMs patients
The average follow-up time from MDS diagnosis to the last visit or the patient’s death was 18 months. More than 60% of the group A patients and 50% of the group B patients were followed up for at least 2 yr. AIMs responded to immunosuppressive therapy in 7/11 patients treated (Table 4). Nine patients received prednisolone at the initial dose of 60 mg/day. Although the effect was dramatic, with symptoms and signs vanishing within weeks, flares of the AIMs were recorded in two patients (cases 1 and 8) after the prednisolone dosage had been tapered to 30 mg/day. Although combinational therapy with cyclosporin and azathioprine was added respectively, the clinical response was not sustained in these patients. The clinical picture of AIMs activity was not linked to the severity of the peripheral cytopenias. In this regard, while AIMs were generally steroid sensitive no haematological responses to immunosuppressive therapy was observed in our patients except one (Table 4). This fact further indicates that the peripheral cytopenias of group A patients with refractory anaemia (cases 6, 8, 9, 12 and 13), were due to the myelodysplastic process than being related with flares of the autoimmune disease. Furthermore, two patients progressed to acute myeloid leukaemia.

In group B patients, without AIMs, the median survival times for low-, intermediate- and high-risk subcategories according to IPSS were 18, 10 and 7.5 months respectively. Furthermore the median survival time in this group of patients was similar between intermediate- and high-risk subcategories (P = 0.27), statistically lower than that of the low-risk subcategory (P<0.01). In this regard the management of the haematological disorder in all our MDS patients, whether with or without AIMs, was based on the patient’s prognostic subgrouping according to IPSS, with low-risk patients being treated only with haematopoietic growth factors and red cell transfusions, while high- and intermediate-risk patients received AML induction therapy or allogeneic bone marrow transplantation [10]. Among MDS patients with AIMs categorized in the high-risk group according to the IPPS, one patient received AML-related chemotherapy (case 1), two topotecam (cases 4 and 5) and one underwent allogeneic bone marrow transplantation (case 3). The rest of the patients were treated with blood cells and platelet transfusions, deferoxamine subcutaneous infusions and erythropoietin and granulocyte colony-stimulating factor (G-CSF) administration. Causes of death in group A included respiratory failure secondary to alveolar haemorrhage (one), cerebral haemorrhage (one), sepsis (two) and acute cardiovascular heart disease (CVHD) following allogeneic bone marrow transplantation (one).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Although MDS encompasses a heterogeneous group of haematological disorders, abnormal haematopoiesis and immune system dysfunction constitute common underlying aspects beyond its clinical diversity. The association of myelodyspasia and immunological abnormality disorders has been reviewed by Hamblin [1, 11] who first described two cases of autoimmune haemolytic anaemia in 104 patients with MDS. Since then this association has been further highlighted in the medical literature by sporadic case reports and several retrospective studies [24, 1217]. Clinical manifestations of such phenomena may include an acute systemic vasculitic syndrome, skin vasculitis, fever, arthritis, pulmonary infiltrates, peripheral polyneuropathy, inflammatory bowel disease, glomerulonephritis and even classical connective tissue disorders such as relapsing polychondritis. On the other hand, asymptomatic immunological abnormalities, first recognized by Mufti et al. [18], have also been reported in these patients. In these studies AIMs frequently respond to immunosuppressive agents, including steroids. Haematological responses to steroid therapy have also been occasionally reported [2]. These retrospective studies establish a link between MDS and AIMs and highlight interesting clinical aspects of this association. These studies, however, did not take into consideration the IPSS prognostic category and thus did not lead to firm conclusions regarding the exact clinical significance, the true prognosis and the survival of these MDS/AIMs patients. The IPPS is a product of pooled data from previous scoring systems predicting survival and evolution to acute myelogenous leukaemia in MDS patients, and is therefore a useful tool for the analysis of clinical significance and prognosis of AIMs in MDS. Our work is the first prospective study of a cohort of 70 patients, in which every single case is well documented clinically. We also provide all the relevant information, including IPSS prognostic category, cytogenetic analysis, treatment, evolution of the haemopathy, transformation to acute leukaemia and overall survival.

The incidence of AIMs in previous studies has been estimated at between 10 and 12% [14]. In a large Japanese single-institution study of 153 MDS patients, carried out by Okamoto et al. [19], 12% developed AIMs while 63% showed an abnormality in at least one immunological laboratory test. Billstrom et al. [4] identified the same incidence of AIMs in a retrospective study of 82 MDS patients. Ten per cent of 162 MDS patients displayed several rheumatic manifestations in the retrospective review of Castro et al. [3]. The estimated prevalence of AIMs in our cohort was 18.5%, higher than any previously reported, but our data could be potentially biased by the fact that our department is a reference centre for autoimmune rheumatic diseases. No gender predominance was identified, but AIMs developed in younger MDS cases as previously suggested. We did not find any significance in the distribution of MDS subtype between the two groups of patients with and without AIMs, being in agreement with Okamoto et al. [19]. It the study of Castro et al. [3], the RAEB subcategory displayed the greatest number of AIMs cases, but the largest number of patients in this study was in this subcategory. In our cohort study four patients presented AIMs before the development of MDS. To our knowledge MDS following certain rheumatic diseases is a rare phenomenon and may be caused by long-term immunodysfuction and prolonged use of immunosuppressant agents such as azathioprine. However, in our cases the short duration of the collagen diseases, the fact that no patients received azathioprine and the absence of chromosome aberrations, typically associated with therapy-related MDS, does not support the aforementioned scenario. Cytogenetic data were collected from all the patients enrolled in our study, revealing no difference in the incidence of clonal abnormalities between the groups with and without AIMs (46% and 35% respectively). Furthermore, the prevalence of favourable cytogenetic findings (normal, 5q–, 20q–, or –Y) does not differ statistically between the two groups [OR = 0.73 with 95% C.I. (0.20, 2.75)]. This is in disagreement with Billstrom et al. [4] who reported a greater than expected incidence of cytogenetic abnormalities in their MDS patients with AIMs (88% vs 49% in MDS without AIMs), even suggesting that an abnormal caryotype per se predisposes to AIMs [4]. These results could be interpreted by the fact that secondary MDS (therapy-related) patients were included in their study, whilst being excluded by us. In secondary MDS abnormal karyotypes are evident in almost all patients [20]. It is further well known that these patients have a poorer prognosis than those with primary MDS; so omitting these patients from our study prevents us from misinterpreting data.

It is worthy of note that patients with AIMs were not statistically different in survival from patients without AIMs, a finding that contrasts to previously published data [2, 4, 14, 19]. Ascertaining the prognostic significance of the coexisting autoimmune disorder in MDS could prove problematic and this is due to the fact that the underlying haematological disease is also remarkably heterogeneous in regard to prognosis. In an attempt to overcome this problem all our patients were classified according to the IPSS. IPSS is a prognostic model for MDS generated by multivariate analysis, combining several prognostic features such as the percentage of marrow blasts, the degree of various cytopenias and the presence of chromosomal abnormalities. No correlation between IPSS grade with predisposition to development of AIMs was observed. It should be emphasized that while the survival and prognosis of MDS patients were not influenced by the presence of AIMs, IPSS was an important prognostic parameter in MDS patients with AIMs. The fact that all the deaths in group A patients were due to myelodysplasia-related complications and occurred in the high-risk IPSS category further confirms our conclusions. On the other hand the severity of the AIMs varies significantly, reflecting their clinical diversity. The acute systemic vasculitic syndrome in MDS carries an adverse prognosis, being associated with rapid clinical deterioration and high mortality [15]. As only two of our patients developed this syndrome, the prognostic significance of this specific clinical entity could not be assessed in our study.

MDS is known to be associated with significant abnormalities related to the immune system. Decreased NK cell activity, abnormalities in antibody-dependent cell killing, impaired mitogenic response, diminished CD4 cell numbers and functional abnormalities of the B-cell subset, including hyper- or hypogammaglobulinaemia have all been detected in MDS [1]. These immunological alterations may not only account for some of the AIMs in MDS, but might also constitute an essential component in the pathogenesis of the ineffective haematopoiesis and resultant cytopenia of MDS in general [18, 21, 22]. Several investigators reported improvement of the haematological status of MDS patients with AIMs following immunosuppression treatment, implying an association between the activity of AIMs and the degree of bone marrow failure [2325]. In our study the clinical activity of AIMs did not parallel the severity of peripheral cytopenias, whilst the haematological responses to immunosuppressive therapy with steroids and agents with mild immunomodulatory effect were generally poor.

Interferon regulatory factor-1 (IRF-1) is a transcriptional activator of the interferon-beta gene linking immune response and oncogenesis [2628]. A recent study carried out by our department revealed that IRF-1 appears to be involved in the pathogenesis of AIMs in MDS [29]. We found that MDS patients with AIMs displayed elevated IRF-1 levels in their bone marrow mononuclear cells compared with MDS patients without AIMs. In this regard the absence of expression of IRF-1 which is also involved in vascular cell adhesion molecule 1 (VCAM-1) expression and nitric oxide synthase production [28] appears to protect against the development of the vasculitic syndrome in MDS patients without AIMs [30, 31]. The heterogeneity of clinical manifestations and prognosis among the different categories of MDS patients parallels the complexity regarding their pathogenetic events. In these complex genetic alterations the deregulation of IRF-1 gene seems to be a critical oncogenic event in MDS patients without AIMs. However, the finding of IRF-1 expression in MDS patients with AIMs argues against the causative role of the IRF-1 inactivation in this specific group of patients, indicating another underlying mechanism of leukaemic transformation. In conclusion a distinct subset of MDS patients manifests overt AIMs, the pathogenesis of which still remains unknown. However, the prognosis and the mortality of these patients appear to be closely related to the underlying haematological disorder. The IPSS index can be applied to these patients enabling a safer and more efficient approach.

The authors have declared no conflicts of interest.


    Acknowledgments
 
The present study was supported by research funding from the General Secretariat of Research and Development and from Genesis Hellas Co.


    Notes
 
This paper is dedicated to the memory of the late M. Tsakopoulos, MD, Professor of Experimental Physiology.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 24 September 2003; Accepted 19 December 2003





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