骨髓增生异常综合征合并自身免疫性疾病5例分析

目的　探讨骨髓增生异常综合征 (MDS)合并自身免疫性疾病的特点。方法　对 1997- 0 1～ 2 0 0 2 -0 6中山大学附属第二医院消化科 6 0例MDS患者的临床资料进行分析和随访观察。结果　 6 0例MDS患者中 ,5例合并自身免疫性疾病 ,其中格雷夫斯病 3例 ;合并自身免疫性疾病患者MDS的分型以环形铁粒幼细胞性难治性贫血 (RAS)最多见 (4例 )。结论　MDS可以合并格雷夫斯病 ,而体液免疫异常可能是MDS合并自身免疫性疾病的一个重要环节。FAB分型与是否合并自身免疫性疾病之间可能并无相关。     

Autoimmune diseases and myelodysplastic syndromes

Immune dysregulation and altered T‐cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50–70) for patients with autoimmune diseases versus 45 months (95% CI, 40–49) for those without (log‐rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66–0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. Am. J. Hematol. 91:E280–E283, 2016. © 2016 Wiley Periodicals, Inc.     

Large-vessel arteritis and myelodysplastic syndrome: report of two cases

Myelodysplastic syndrome (MDS) is frequently associated with autoimmune diseases such as polymyalgia, arthritis, and rarely, with systemic vasculitis. The pathogenesis of these autoimmune complications remains unknown, but there is increasing evidence of profound immune dysregulation in MDS. In the few cases reported so far, vasculitides associated with MDS affected mainly cutaneous vessels. Here we describe two cases of acute large-vessel vasculitis in association with MDS. The first patient is a 67-yr-old male presenting with a massive large-vessel arteritis as primary manifestation of refractory anemia with excess of blasts type 1 (RAEB-1). The second patient is a 60-yr-old male, who presented with acute thoracic aortitis after a 2-yr history of refractory anemia with ringed sideroblasts (RARS). Both patients received immunosuppressive treatment with steroids, leading to rapid improvement of systemic inflammatory symptoms, vessel wall injury and peripheral blood counts. Whereas the first patient displayed sustained favorable hematologic responses under long-term steroid therapy, there was a rapid transformation into secondary acute myeloid leukemia in the second patient. We conclude that large-vessel vasculitis should be added to the list of potential autoimmune complications in MDS. In this clinical setting, steroid therapy may alleviate inflammatory symptoms and result in beneficial hematologic responses.     

Behçet's disease with gastrointestinal involvement associated with myelodysplasia in a patient with congenital panhypopituitarism

Myelodysplastic syndromes (MDS) are hematologic disorders characterised by peripheral cytopenias and the hystologic features of hematologic dysplasia. Their association with autoimmune manifestations have been suggested by several authors: recently, the appearance of Behçet's disease during MDS has been reported. We describe the occurrence of MDS in a patient affected by Behçet's syndrome with gastrointestinal involvement and congenital panhypopituitarism.     

Manifestations systémiques et auto-immunes des syndromes myélodysplasiques

Myelodysplastic syndromes (MDS) can be associated with systemic or autoimmune diseases. Vasculitides (leucocytoclastic, periarteritis nodosa, micropolyangeitis, Wegener's granulomatosis), relapsing polychondritis, and Sweet's syndrome are the most commonly reported. Refractory anemia with excess of blasts (RAEB), transformed RAEB evolving to an acute leukemia, and chronic myelomonocytic leukemia (CMML) are preferentially associated with these vasculitides or systemic diseases. Corticosteroids are generally effective. Immunosuppressive drugs expose these patients to infectious complications and increase the risk of transformation into acute leukemia. Occurrence of relapsing polychondritis in a patient older than 60 years is associated with a myelodysplastic syndrome in 40% of the cases. Sweet's syndrome is associated in 10% of the cases with acute myeloid leukemia and MDS. Polyarthritis or oligoarthritis with systemic manifestations that include fever, skin rash, and more rarely serositis or haemolytic anemia can occur contemporarily to a MDS. Behçet's disease with intestinal involvement has been reported in patients presenting with trisomy 8 associated MDS. Pathogenic mechanisms underlying the association between MDS and autoimmune or systemic disorders remain to be elucidated.     

Clinical spectrum,outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20% of cases. Immune thrombocytopenia (ITP) is among the reportedly associated diseases, but large studies assessing the association are lacking. It is unclear whether patients with MDS or CMML and ITP have a particular phenotype or require particular management. We, therefore, analyzed the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison to: (i) patients with primary ITP without MDS/CMML and (ii) patients with MDS/CMML without ITP. Forty-one patients with MDS/CMML-associated ITP were included, of whom 26 (63%) had chronic ITP, 30 (73%) had low-risk myelodysplasia and 24 (59%) had CMML. An associated autoimmune disease was noted in ten (24%) patients. In comparison to patients with primary ITP, patients with MDS/CMML-associated ITP had a higher rate of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulins (56%). Patients with primary ITP were more likely to respond to intravenous immunoglobulins than were patients with MDS/CMML-associated ITP. Response rates to second-line therapies were not statistically different between patients with primary ITP or MDS/CMML-associated ITP. Four (10%) of the patients with MDS/CMML-associated ITP had multirefractory ITP whereas none of the primary ITP controls did so. After a median follow-up of 60 months, there was no difference in overall survival between patients with MDS/CMML-associated ITP or primary ITP. Leukemia-free-survival was significantly better in patients with MDS/CMML-associated ITP than in those with MDS/CMML without ITP. In conclusion, it appears that patients with MDS/CMML-associated ITP have a particular phenotype, with more severe bleeding than patients with primary ITP, a higher likelihood of multirefractory disease, but a similar response to primary ITP therapy except for intravenous immunoglobulins. Finally, compared to MDS/CMML patients without ITP, they are less likely to progress to having acute myeloid leukemia.     

Coomb’s阳性的MDS病例报道及MDS的诊断思考

MDS是血液科的常见疾病,疾病的本质是①髓系的发育异常,即无效造血,临床表现为一系或多系的血细胞减少;②高危演变为急性髓系白血病,在骨髓象表现为原始细胞增多。并且还需要排除其他可能引起血细胞减少的疾病,这使得临床上诊断有一定困难。随着对疾病本质的深入理解及新分子诊断技术的应用,可以寻找更多MDS的证据,目前对MDS的诊断水平已经大大提高。但是在临床上仍有一些起初表现不典型,诊断十分困难的MDS,为早期治疗造成困难,现报道我们临床上收治的以Coomb’s阳性的自身免疫性溶血为早期表现,疾病进展迅速的MDS患者,以加强我们对MDS的疾病认识。     

Myelodysplastic syndrome and aplastic anemia: distinct entities or diseases linked by a common pathophysiology?

It is often difficult to distinguish myelodysplastic syndrome (MDS) from severe aplastic anemia (SAA) because both can present with profoundly hypocellular bone marrows. The distinction matters because although both conditions are complicated by pancytopenia, the risk of progression to acute leukemia is much greater in MDS. This chapter reexamines the relationship between SAA and MDS. The clinical and morphological features and pathophysiology of AA (including moderate and severe forms of acquired AA) are compared with MDS and hypoplastic MDS, with particular reference to new observations implicating autoimmune processes in both conditions. SAA and hypoplastic MDS (HMDS) are discussed in the light of these findings and attempts to separate nonevolving bone marrow failure syndromes from marrow failure progressing to acute leukemia are reviewed. The weight of evidence supports a common pathophysiology and, more speculatively, a common etiology for at least some forms of AA and MDS.     

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

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 > or = 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.     

Dermatomyositis and myelodysplastic syndrome with myelofibrosis responding to methotrexate therapy

Dermatomyositis (DM) has not yet been reported as a complication of myelodysplastic syndrome (MDS). A 50-year-old man was diagnosed as having MDS because of the presence of anemia, the appearance of immature cells in peripheral blood, and the abnormal cellular morphology. A few months later, high fever, myalgia and erythema developed. Although DM symptoms were resistant to high-dose corticosteroid administration, methotrexate (MTX) therapy improved not only the symptoms of DM but also hematologic findings related to MDS. This indicates that immunosuppressive therapy including MTX administration can be useful for patients with MDS with autoimmune symptoms.     

Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia

T cell-mediated suppression of haematopoiesis is believed to play an important role in the pathophysiology of aplastic anaemia (AA) and in the pancytopenia of some myelodysplastic syndromes (MDS). Natural-killer T (NKT) cells belong to a unique lymphocyte subset that expresses an invariant T-cell receptor (TCR), consisting of Valpha24JalphaQ, and common NK cell surface markers. NKT cells have been hypothesized to play a role in immune regulation, and many human autoimmune conditions are associated with NKT cell deficiency. Here we investigate the role of NKT cells in AA and MDS patients. Flow cytometry demonstrated that NKT cells, unlike other T-lymphocyte subpopulations, were disproportionally decreased in AA and MDS marrow. When we compared variability within the CDR3 region of Valpha24 in CD4-CD8- T cells derived from AA and healthy individuals, the CDR3 size of Valpha24 cells showed a polyclonal distribution in AA patients, while in control subjects a typical oligoclonal or monoclonal pattern was found. Southern blot and sequence analysis of Valpha24 polymerase chain reaction products revealed that the NKT cell-specific JalphaQ region was predominant in control subjects, whereas it was not, or only very weakly, detected in AA and MDS patients. These results show that NKT cells are profoundly decreased in AA and MDS, and their deficiency may, as in other human autoimmune diseases, play a role in the local immune dysregulation in AA and MDS.     

A Rare Case of Ankylosing Spondylitis Coexisting with Relapsing Polychondritis,Antiphospholipid Syndrome,and Myelodysplastic Syndrome

Ankylosing spondylitis (AS) is rarely accompanied by other autoimmune diseases and/or hematologic disorders. We herein report a 46-year-old man with AS coexisting with relapsing polychondritis (RP), antiphospholipid syndrome (APS) and myelodysplastic syndrome (MDS). While receiving anti-TNF therapy for AS, the patient developed anemia and was diagnosed with MDS. After six months, he developed swelling and redness of the nose and both auricles. RP was diagnosed by an ear biopsy. Afterward, during the evaluation of a repeated fever, APS was diagnosed. This case of AS with multiple autoimmune diseases and hematologic malignancy successfully responded to a Janus kinase inhibitor (baricitinib).     

Cutaneous leukocytoclastic vasculitis and myelodysplastic syndrome with little or no evidence of associated autoimmune disorders-a case report and a brief review of the literature

Cutaneous leukocytoclastic vasculitis (CLV) is a necrotizing inflammatory disease of the small vessels in the dermis. Approximately 50% of cases with CLV are primary or idiopathic and the remainder may be associated with various diseases. Less than 1% CLV occurs in association with malignancies including leukemia, lymphoma, and myelodysplastic syndrome (MDS). The pathogenetic mechanism of CLV remains speculative and is generally believed to be related to autoimmune processes. We report here a 77-year-old white woman who presented with contemporaneous occurrence of CLV and MDS (WHO subtype RAEB-2). Autoantibodies and immune-complexes were not detected either in the serum or by direct immunofluorescense in the skin biopsy. The clinical course of MDS remained steady, but the cutaneous lesion resolved within 2 weeks with minimal or no specific therapy except corticosteroids. We suggest that absence of autoimmune phenomena and immune-complex in the skin lesions of CLV may be a hallmark of good prognosis.     

Ankylosing spondylitis in a patient with myelodysplastic syndrome: an association with HLA-B27 or coincidence?

The authors report an unusual case of myelodysplastic syndrome (MDS) associated with ankylosing spondylitis (AS). A 40-year-old-man with MDS presented with chronic low back pain for 6 years. Four years ago, MDS was diagnosed during routine blood analysis for the work-up of his articular complaints. His initial articular complaints were attributed to extramedullary manifestations of MDS. Persistent low back pain with increasing intensity finally led the patient to seek medical attention. Radiograph of the pelvis showed bilateral asymmetric sacroiliitis. A diagnosis of AS was established on the basis of modified New York criteria. Although various autoimmune phenomena associated with MDS have been described, this is the first report of AS in the setting of MDS. Causal relationship between these two disorders is currently unknown. Increased risk of hematological diseases as well as AS in individuals with a positive HLA-B27 provides a feasible explanation for this rare observation.     

Henoch–Schonlein purpura as a complication of a myelodysplastic syndrome

Henoch–Schonlein purpura (HSP) is considered as a small blood vessel systemic vasculitis. We describe a 78-year-old female, known to suffer from a myelodysplastic syndrome (MDS), who developed HSP with renal involvement. The ensuing decline in kidney function progressed to the point where the patient required dialysis. Surprisingly, renal biopsy did not show crescentic glomerulonephritis. MDS, essentially a hematological disorder of the elderly, has been associated with various autoimmune diseases including vasculitis, predominantly cutaneous. Our patient, however, is only the third reported in whom the combination of MDS with HSP was found. The occurrence of HSP in our patient with underlying MDS may represent a paraneoplastic phenomenon.     

Looking beyond VEXAS: Coexistence of undifferentiated systemic autoinflammatory disease and myelodysplastic syndrome

It has been established that individuals with myelodysplastic syndromes (MDS) have a higher frequency of systemic inflammatory disorders. On the other hand, patients with autoimmune diseases are at increased risk of MDS development. Both diseases can be associated with various genetic lesions and share diverse pathogenetic mechanisms. Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1, encompasses a range of inflammatory conditions involving multiple organs along with hematological pathologies, including MDS, as well as characteristic bone marrow vacuolization of myeloid and erythroid precursors. This novel syndrome drove further attention to complex associations between MDS and adult-onset inflammatory conditions. The present narrative literature review discusses the clinical presentation, pathophysiology, management of concurrent MDS and systemic inflammatory diseases in parallel to the clinical picture of VEXAS syndrome.     

Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy

The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.     

Isolated PACNS-like presentation of a systemic vasculitis complicating a myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are a series of haematological malignancies ranging from chronic refractory anaemia to leukaemia. There is increasing recognition of immunological abnormalities in patients with MDS, including few reports of cutaneous vasculitis; in no instance, a cerebral localization has been ascertained. Here, the case of a patient with MDS who presented exclusively with neurological signs that were considered indicative of a primary, isolated central nervous system vasculitis (PACNS) is reported. Although histological findings on brain tissue confirmed a small-vessel vasculitis, this had to be considered in the context of a systemic vasculitis. In fact, at autopsy, an involvement of skin, myocardium, lungs, liver, kidney and bone marrow was also found. An autoimmune vasculitis should be included in the differential diagnosis of acute-onset, isolated, cerebral symptoms complicating the course of MDS.     

MDS and GCA: a prognostic dilemma

Clinical Rheumatology - A number of autoimmune disorders, such as large vessel vasculitis, have been recognized in patients who have myelodysplastic syndrome (MDS) and myeloproliferative syndrome...     

Autoimmune manifestations associated with myelodysplastic syndrome predict a poor prognosis

We evaluated the clinical characteristics of autoimmune manifestations (AIMs) associated with myelodysplastic syndrome (MDS) to elucidate whether AIMs impacted MDS outcomes in Japan.This retrospective study including 61 patients who received a new diagnosis of MDS between January 2008 and December 2015 was conducted by the review of electronic medical records for the presence of AIMs within a 1-year period prior to or following the diagnosis of MDS.AIMs were identified in 12 of the 61 (20.0%) patients with MDS. The neutrophil counts and C-reactive protein levels in peripheral blood were significantly elevated in patients with AIMs, and the survival was shorter in those with AIMs compared to those without AIMs. Multivariate analysis demonstrated that the presence of AIMs and higher-risk disease according to the International Prognositic Scoring System (IPSS) were independent risk factors for increased mortality (hazard ratio, 4.76 and 4.79, respectively).This retrospective study revealed that the prognosis was poor in patients with MDS-associated AIMs. The treatment of MDS using the current algorithms is based on prognostic scoring systems such as IPSS. Treatment strategies for patients with MDS-associated AIMs should be reconsidered, even in those with low-risk MDS according to the IPSS.