Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence?

Kam A. Newman, Mojtaba Akhtari and Sheda Heidarian

## Abstract

Myelodysplastic syndromes are heterogeneous group of clonal hematologic malignancies characterized by peripheral blood cytopenias secondary to the ineffective hematopoiesis. ADs are frequently reported in MDS, the incidence ranging from 10 to 30%, and particularly ADs are more frequently seen at CMML. ADs may prone patient to MDS, especially when immune suppressors such as azathioprine are used for the underlying AD. Both innate and adaptive immune systems, and different cytokines including interleukins, TNF-α, and C-X-C motif chemokine 10 (CXCL10) contribute in immune dysregulation of MDS. Vasculitis, seronegative rheumatoid arthritis, SLE, Behçet's disease, RP, and AIHA are just some of the ADs occurring concomitantly with MDS. Although hematopoietic growth factors are recommended by the American Society of Clinical Oncology (ASCO), it has been recognized from several case reports that treatment of the underlying MDS may resolve the associated autoimmune disorders. The heterogeneity and complexity of pathology, clinical manifestations, response to therapy, and prognosis of MDS and its immune dysregulation make the prognosis of MDS with autoimmune diseases a matter of debate. Better understanding of the immune dysregulation of MDS in the molecular level may help to design prospective, double blind clinical trials to find the best treatment options for autoimmune disorders associated with MDS.

Keywords: autoimmune disorders (ADs), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), Behçet's disease, systemic lupus erythematosus (SLE), azathioprine, azacitidine, tumor necrosis factor alpha (TNF-α), regulatory T-cells (Treg), autoimmune hemolytic anemia (AIHA), vasculitis, chronic inflammatory demyelinating polyneuropathy (CIDP), neutrophilic dermatosis, Henoch-Schonlein purpura, relapsing polychondritis (RP), granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA), polyarteritis nodosa (PAN)

### 1. Introduction

Myelodysplastic syndromes (MDS) are characterized by peripheral blood cytopenias secondary to the ineffective hematopoiesis, and represent a heterogeneous group of clonal hematologic malignancies in which abnormal multipotent progenitor cells are involved. As a result, there is an increased risk of bleeding diathesis and anemia requiring frequent transfusions, infections, and progression to acute myeloid leukemia [1–4]. It is a very well-known fact that a large spectrum of genetic mutations is involved in MDS pathogenesis that may affect clinical outcome and response to the treatment. These genetic mutations may control cell cycle by affecting key proteins of spliceosome, DNA repair, kinase signaling, tumor suppressor genes, and transcription factors, changing bone marrow micro environment, resulting in hypercellular bone marrow with peripheral cytopenias through enhanced programmed cell death (PCD) and bone marrow dysfunction [5, 6]. To overcome programmed cell death, hematopoietic growth factors such as erythropoiesis stimulating agents (ESAs) and granulocyte colony stimulating factor (G-CSF) are the 1st step in management of the low-grade MDS recommended by the American Society of Clinical Oncology (ASCO) to reduce early apoptosis [1].

There are several reports regarding therapy related MDS in population with autoimmune disorders who underwent disease modifying antirheumatic drugs (DMARDs) therapy. In a retrospective case-control study of 40,011 patients with 27 kinds of autoimmune disorders, 311 patients met the inclusion criteria, 86 of them had MDS, and found azathioprine exposure has increased 7 fold myeloid neoplasms in a median of 8 years. In this study, methotrexate, and mycophenolate mofetil did not elevate the risk of myeloid neoplasms [21]. However, there is a case report regarding association of low-dose oral methotrexate therapy with MDS in a rheumatoid arthritis patient [22]. In another study, from 370 rheumatologic patients who received azathioprine for at least 1 year, 59 patients underwent bone marrow examination and 2 of them found to have MDS. This study revealed that risk of secondary MDS is 100 fold higher in patients who received azathioprine for their rheumatologic disorders. Chromosomal examination of the patients with MDS secondary to the azathioprine showed abnormalities of chromosome 7 in majority of them (8 out of 10) [23]. There is also evidence that MDS patients who have autoimmune disorders might respond to hypomethylating agents such as

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence?

It is a very well-known fact that about 10–30% of MDS patients may present with a variety of autoimmune or laboratory manifestations or develop an autoimmune disorder. These manifestations are polymorphic and include leukocytoclastic vasculitis, clubbing, peripheral neuropathy, autoimmune hemolytic anemia, polyarthritis, myositis, acute or systemic vasculitis, Raynaud's phenomenon, polyarteritis nodosa, vitiligo, iritis, colonic ulcerations, pulmonary involvement, and reported autoimmune disorders include rheumatoid arthritis, Sjogren's disease, giant cell arteritis, polymyalgia rheumatica, relapsing polychondritis, Behçet's disease, and systemic lupus erythematosus. Although autoimmune manifestations are mostly seen during the course of MDS, autoimmune disorders may occur before MDS diagnosis. Laboratory manifestations of MDS include hypergammaglobulinemia, hypogammaglobulinemia, monoclonal gammopathy, positive direct antiglobulin test (DAT), positive ANA, rheumatoid factor, cryoglobulinemia, and

Several studies support that autoimmune disorders may occur in the setting of MDS, and treating MDS with immunosuppressors may improve the autoimmune disorder. Although there were several case reports of MDS preceding autoimmune disorders, the first comprehensive retrospective study in 1986 on 104 MDS patients revealed two patients had pernicious anemia, two had hypothyroidism, and one had both pernicious anemia and hypothyroidism [23]. Later, in a retrospective study in 1994, five patients with MDS reviewed and revealed polyarthritis with positive rheumatoid factor (RF) and necrotizing vasculitis [25]. In another retrospective study in 1995, 221 patients with MDS reviewed and found 30 patients with autoimmune disorders, and categorized patient to three categories of acute systemic vasculitis or autoimmune disorder, chronic or isolated autoimmune phenomena, and classic connective tissue disorders. Skin vasculitis, arthritis, and fever were among

A case series in 2002 showed various autoimmune paraneoplastic disorders including vasculitis, pyoderma gangrenosum, Coombs negative autoimmune

azacitidine and decitabine [24].

DOI: http://dx.doi.org/10.5772/intechopen.80710

anti-double-stranded DNA.

33

2. Rheumatologic manifestations of MDS

3. Autoimmune disorders in myelodysplastic syndrome

the most common autoimmune manifestations [26].

Thrombopoietic stimulating agents (TSAs), ESAs, G-CSF, antithymocyte globulin (ATG) [7], lenalidomide [8], and hypomethylating agents are some of the nontransplantation options for management of the MDS patients suggesting that immune dysregulation plays a pivotal role in MDS pathogenesis [1]. Although its etiology is not clear, it has been shown that natural killer (NK) cell activity and its response to chemokines is decreased in MDS, and natural killer cells will be progressively more dysfunctional with MDS progression [9]. It has been shown that although dysfunctional regulatory T-cells (Treg), cells in charge of suppressing T helper (Th) activity, contribute in early stages of MDS, Th expands in the later stages of MDS, and there function is significantly reduced with treatment [10].

Tumor necrosis factor alpha (TNF-α) level is higher in bone marrow and peripheral blood plasma of MDS patients, and may reflect an unfavorable outcome [11, 12]. Study shows that plasma level of 19 cytokines are significantly altered compared with normal individuals, among all of them, C-X-C motif chemokine 10 (CXCL10) and interleukin 6 were associated with shortened survival [13]. The relationship between shorter survival and interleukin 6 levels is very well known, and high producing genotypes of both TNF-α and interleukin 6 are highly associated with transfusion dependency for both anemia and thrombocytopenia, and severity of the bicytopenias [14]. Interferon regulatory factor-1 (IRF-1), a transcriptional activator of interferon system, has anti oncogenic properties, inhibits tumor formation, and regulates innate immune response. It has been shown that IRF-1 mRNA is 10 fold decreased in MDS patients, while it is increased in MDS patients with autoimmune disorders, showing that IRF-1 may promote inflammation and autoimmunity and has a protective roll in MDS patient's [15].

Although it has been reported that MDS is significantly associated with autoimmune disorders, it may occur secondary to the autoimmune disorders per se [16] or exposure to the therapeutic agents used for treatment of autoimmune disorders. A retrospective study in Sweden on 1662 MDS patients and 42,878 matched controls revealed that underlying autoimmune disorder increased risk of MDS by 2.1 with highest risks observed with prior autoimmune hemolytic anemia (AIHA), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA) and aplastic anemia. It was speculated that chronic stimulation of the immune system may act as a trigger and prone the patient to MDS [17]. In a retrospective study of 2471 patients, it was found that MDS occurred subsequent to autoimmune disorders, most commonly rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polyarteritis nodosa, discoid lupus erythematosus, and pernicious anemia were associated with MDS [18]. In a case control study of 80 for MDS patients, it was found that there is strong and statistically significant evidence that MDS occurred after autoimmune disorders with Grave's disease and Hashimoto's thyroiditis were among the most important disorders [19]. There is a case report of limited granulomatosis with polyangiitis (GPA) treated with corticosteroids, who did develop myelodysplastic syndrome, papillary thyroid carcinoma, and gastric adenocarcinoma [20].

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence? DOI: http://dx.doi.org/10.5772/intechopen.80710

There are several reports regarding therapy related MDS in population with autoimmune disorders who underwent disease modifying antirheumatic drugs (DMARDs) therapy. In a retrospective case-control study of 40,011 patients with 27 kinds of autoimmune disorders, 311 patients met the inclusion criteria, 86 of them had MDS, and found azathioprine exposure has increased 7 fold myeloid neoplasms in a median of 8 years. In this study, methotrexate, and mycophenolate mofetil did not elevate the risk of myeloid neoplasms [21]. However, there is a case report regarding association of low-dose oral methotrexate therapy with MDS in a rheumatoid arthritis patient [22]. In another study, from 370 rheumatologic patients who received azathioprine for at least 1 year, 59 patients underwent bone marrow examination and 2 of them found to have MDS. This study revealed that risk of secondary MDS is 100 fold higher in patients who received azathioprine for their rheumatologic disorders. Chromosomal examination of the patients with MDS secondary to the azathioprine showed abnormalities of chromosome 7 in majority of them (8 out of 10) [23]. There is also evidence that MDS patients who have autoimmune disorders might respond to hypomethylating agents such as azacitidine and decitabine [24].

#### 2. Rheumatologic manifestations of MDS

It is a very well-known fact that about 10–30% of MDS patients may present with a variety of autoimmune or laboratory manifestations or develop an autoimmune disorder. These manifestations are polymorphic and include leukocytoclastic vasculitis, clubbing, peripheral neuropathy, autoimmune hemolytic anemia, polyarthritis, myositis, acute or systemic vasculitis, Raynaud's phenomenon, polyarteritis nodosa, vitiligo, iritis, colonic ulcerations, pulmonary involvement, and reported autoimmune disorders include rheumatoid arthritis, Sjogren's disease, giant cell arteritis, polymyalgia rheumatica, relapsing polychondritis, Behçet's disease, and systemic lupus erythematosus. Although autoimmune manifestations are mostly seen during the course of MDS, autoimmune disorders may occur before MDS diagnosis. Laboratory manifestations of MDS include hypergammaglobulinemia, hypogammaglobulinemia, monoclonal gammopathy, positive direct antiglobulin test (DAT), positive ANA, rheumatoid factor, cryoglobulinemia, and anti-double-stranded DNA.

#### 3. Autoimmune disorders in myelodysplastic syndrome

Several studies support that autoimmune disorders may occur in the setting of MDS, and treating MDS with immunosuppressors may improve the autoimmune disorder. Although there were several case reports of MDS preceding autoimmune disorders, the first comprehensive retrospective study in 1986 on 104 MDS patients revealed two patients had pernicious anemia, two had hypothyroidism, and one had both pernicious anemia and hypothyroidism [23]. Later, in a retrospective study in 1994, five patients with MDS reviewed and revealed polyarthritis with positive rheumatoid factor (RF) and necrotizing vasculitis [25]. In another retrospective study in 1995, 221 patients with MDS reviewed and found 30 patients with autoimmune disorders, and categorized patient to three categories of acute systemic vasculitis or autoimmune disorder, chronic or isolated autoimmune phenomena, and classic connective tissue disorders. Skin vasculitis, arthritis, and fever were among the most common autoimmune manifestations [26].

A case series in 2002 showed various autoimmune paraneoplastic disorders including vasculitis, pyoderma gangrenosum, Coombs negative autoimmune

acute myeloid leukemia [1–4]. It is a very well-known fact that a large spectrum of genetic mutations is involved in MDS pathogenesis that may affect clinical outcome and response to the treatment. These genetic mutations may control cell cycle by affecting key proteins of spliceosome, DNA repair, kinase signaling, tumor suppressor genes, and transcription factors, changing bone marrow micro environment, resulting in hypercellular bone marrow with peripheral cytopenias through enhanced programmed cell death (PCD) and bone marrow dysfunction [5, 6]. To overcome programmed cell death, hematopoietic growth factors such as erythropoiesis stimulating agents (ESAs) and granulocyte colony stimulating factor (G-CSF) are the 1st step in management of the low-grade MDS recommended by the American Society of Clinical Oncology (ASCO) to reduce early apoptosis [1].

Recent Developments in Myelodysplastic Syndromes

Thrombopoietic stimulating agents (TSAs), ESAs, G-CSF, antithymocyte globulin (ATG) [7], lenalidomide [8], and hypomethylating agents are some of the nontransplantation options for management of the MDS patients suggesting that immune dysregulation plays a pivotal role in MDS pathogenesis [1]. Although its etiology is not clear, it has been shown that natural killer (NK) cell activity and its response to chemokines is decreased in MDS, and natural killer cells will be progressively more dysfunctional with MDS progression [9]. It has been shown that although dysfunctional regulatory T-cells (Treg), cells in charge of suppressing T helper (Th) activity, contribute in early stages of MDS, Th expands in the later stages of MDS, and there function is significantly reduced with treatment [10]. Tumor necrosis factor alpha (TNF-α) level is higher in bone marrow and peripheral blood plasma of MDS patients, and may reflect an unfavorable outcome [11, 12]. Study shows that plasma level of 19 cytokines are significantly altered compared with normal individuals, among all of them, C-X-C motif chemokine 10 (CXCL10) and interleukin 6 were associated with shortened survival [13]. The relationship between shorter survival and interleukin 6 levels is very well known, and high producing genotypes of both TNF-α and interleukin 6 are highly associated with transfusion dependency for both anemia and thrombocytopenia, and severity of the bicytopenias [14]. Interferon regulatory factor-1 (IRF-1), a transcriptional activator of interferon system, has anti oncogenic properties, inhibits tumor formation, and regulates innate immune response. It has been shown that IRF-1 mRNA is 10 fold decreased in MDS patients, while it is increased in MDS patients with autoimmune disorders, showing that IRF-1 may promote inflamma-

tion and autoimmunity and has a protective roll in MDS patient's [15].

and gastric adenocarcinoma [20].

32

Although it has been reported that MDS is significantly associated with autoimmune disorders, it may occur secondary to the autoimmune disorders per se [16] or exposure to the therapeutic agents used for treatment of autoimmune disorders. A retrospective study in Sweden on 1662 MDS patients and 42,878 matched controls revealed that underlying autoimmune disorder increased risk of MDS by 2.1 with highest risks observed with prior autoimmune hemolytic anemia (AIHA), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA) and aplastic anemia. It was speculated that chronic stimulation of the immune system may act as a trigger and prone the patient to MDS [17]. In a retrospective study of 2471 patients, it was found that MDS occurred subsequent to autoimmune disorders, most commonly rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polyarteritis nodosa, discoid lupus erythematosus, and pernicious anemia were associated with MDS [18]. In a case control study of 80 for MDS patients, it was found that there is strong and statistically significant evidence that MDS occurred after autoimmune disorders with Grave's disease and Hashimoto's thyroiditis were among the most important disorders [19]. There is a case report of limited granulomatosis with polyangiitis (GPA) treated with corticosteroids, who did develop myelodysplastic syndrome, papillary thyroid carcinoma,

hemolytic anemia, autoimmune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy (CIDP) with good response to immunosuppressive therapy [27]. In a retrospective review of 235 MDS patients autoimmune manifestations such as skin vasculitis (24%), noninfectious fever (13%), arthralgia and arthritis (13%), peripheral neuropathy (10%), and pulmonary infiltrates (8%) were more common than systemic vasculitis [28]. In a cohort of 1408 patients with MDS, 391 (28%) had autoimmune disorders, with hypothyroidism (44%), as the most prevalent, and idiopathic thrombocytopenic purpura (12%), rheumatoid arthritis (10%), and psoriasis (7%) were among the common manifestations of autoimmune diseases [29].

3.2 Behçet's disease

DOI: http://dx.doi.org/10.5772/intechopen.80710

general BD population [51].

3.3 Inflammatory arthritis

mia with excess blast (RAEB) [53].

MDS has been reported [60–62].

3.5 Immunological abnormalities

3.4 Miscellaneous

35

A multisystem, chronic inflammatory disease of unknown etiology, Behçet's disease (BD) is characterized by recurrent oral and genital ulcers, uveitis, arthritis, and vascular involvement of several organs including pulmonary, central nervous system and gastrointestinal tract. In a retrospective study of 805 BD patients, 16 patients had MDS, from which 43.8% had BD prior to MDS, 18.7% diagnosed after MDS and 37.5% had concurrent BD and MDS. It has been shown that trisomy 8 has been accumulated in all of BD patients with MDS, and these patients more likely to be female, older age, and have fever and ileocecal ulcerations [44]. In a retrospective study of 46 MDS patients, 8 patients had trisomy 8, 5 of them had multiple intestinal ulcers, a common feature of BD. Two of the MDS patients with trisomy 8 and multiple intestinal ulcers were treated with granulocyte-colony stimulating factor (G-CSF), aggravating their symptoms, suggesting G-CSF should be used cautiously in this subgroup of MDS patients [45]. There is several case reports of BD associated with MDS [46–49]. In a case report of two patients with BD and MDS, it has been suggested that PET/CT may help diagnosis of both BD and MDS with high uptake by bone marrow in MDS patients and genital and gastrointestinal aphthous ulcers in BD patients [50]. It has been suggested that the frequency of gastrointestinal involvement is more common in MDS-associated BD patients than

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence?

There are several case reports and small series of inflammatory arthritis and MDS co-occurrence. In a retrospective study of 28 MDS patients, 8 had acute seronegative inflammatory arthritis with good response of arthritis to steroids [52]. In a French multicenter retrospective study of 22 patients with MDS, 77% of patients had polyarthritis, and 68% had symmetric joint involvement. Radiologic erosions are rare, and MDS associated arthritis is more frequent in refractory ane-

There are several case reports of relapsing polychondritis (RP) presenting as a paraneoplastic disorder in the setting of MDS [54, 55]. In a retrospective study of hematological changes in 19 patients with relapsing polychondritis, MDS was found in three RP patients [56]. Autoimmune hemolytic anemia has been reported in association with MDS [57–59]. Association of systemic lupus erythematosus and

It is a very well-known fact that a spectrum of immunological abnormalities occur in MDS. In a retrospective study of 104 MDS patients, 12.5% had monoclonal gammopathy, 19% had low immunoglobulin levels, 32% had polyclonal rise in serum immunoglobulin level, and 8.1% had positive direct antiglobulin test (DAT) [25]. In a case series of 142 patients with MDS and CMML, 23.2% had non-organ specific autoantibody ANA as the most frequent serologic finding [25]. Thrombocytopenia is a common finding in MDS, and can be seen in up to two third of the patients. In a study of 54 MDS patients with no treatment of transfusions, direct platelet immunofluorescence test for platelet associated IgG was positive in 28 patients. Patients with higher amount of platelet associated IgG, had significantly higher mean platelet volume (MPV), thrombocytopenia and worse outcome [63].

In a retrospective study of 67 MDS patients with autoimmune diseases, neutrophilic dermatosis was the most common autoimmune disease (35.8%), followed by Behçet's disease (14.9%), and rheumatoid arthritis (13.4%) [30].

#### 3.1 Vasculitis

The association between MDS and vasculitis is rare, but more common than solid tumors, and has been described for decades. Cutaneous vasculitis presents by palpable purpura mainly in lower extremities that involves small vessels and is characterized by perivascular inflammation and vessel wall damage by infiltrating neutrophils. Although both cutaneous and systemic vasculitis has been reported in MDS patients, at times they can be seen together in MDS patients. For instance, in a case series of 6 biopsy proven cutaneous vasculitis patients with MDS, 3 patients had evidence of systemic vasculitis [31]. In one case, MDS patient with biopsy proven cutaneous vasculitis developed acute myeloid leukemia within 4 months of vasculitis diagnosis [32]. Henoch-Schonlein purpura, a small vessel vasculitis with IgA dominant immune deposits has been described in MDS patients [33].

The association of MDS and polyarteritis nodosa (PAN) type medium-vessel vasculitis has been reported [34]. In a retrospective study of 8 patients with chronic myelomonocytic leukemia (CMML), with vasculitis involved the medium-vessel, fulfilling the criteria for classic PAN, the presentation was non-specific, and patients developed atypical manifestations [35]. There is a case report of 43-yearold man who qualified for a diagnosis of PAN and developed systemic vasculitis at the time of chronic myelomonocytic leukemia (CMML) diagnosis [36]. There is a report of two cases with CMML who presented with PAN-like systemic vasculitis with bilateral perirenal hemorrhage and negative antineutrophil cytoplasmic antibody with improvement of vasculitis with systemic steroids [37].

Although most MDS associated vasculitis described as leukocytoclastic vasculitis, published case reports documented large vessel vasculitis as autoimmune complication of MDS. Aortitis has been reported as an autoimmune manifestation of an MDS patient at presentation [38]. There is a report of two MDS cases that presented with acute large vessel vasculitis with rapid improvement with systemic steroids [39]. In a retrospective analysis of 271 temporal arteritis patients, it was found that 20 patients had malignancy, of which 11 patients had MDS, favoring a relationship between large vessel vasculitis and MDS [40]. There is a case report of Takayasu's arteritis diagnosed shortly after diagnosis of MDS, with progression to AML regardless of improvement of vasculitis with immunosuppressive treatment [41]. There is a case report of a 71-year-old woman presenting with fever, neck pain, anemia, and thrombocytopenia, with positive positron emission tomography (PET)/CT scan of the aorta and carotid arteries with negative temporal artery biopsy who received the diagnosis of MDS after a bone marrow aspiration analysis [42, 43].

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence? DOI: http://dx.doi.org/10.5772/intechopen.80710

### 3.2 Behçet's disease

hemolytic anemia, autoimmune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy (CIDP) with good response to immunosuppressive therapy [27]. In a retrospective review of 235 MDS patients autoimmune manifestations such as skin vasculitis (24%), noninfectious fever (13%), arthralgia and arthritis (13%), peripheral neuropathy (10%), and pulmonary infiltrates (8%) were more common than systemic vasculitis [28]. In a cohort of 1408 patients with MDS, 391 (28%) had autoimmune disorders, with hypothyroidism (44%), as the most prevalent, and idiopathic thrombocytopenic purpura (12%), rheumatoid arthritis (10%), and psoriasis (7%) were among the common manifestations of autoimmune

In a retrospective study of 67 MDS patients with autoimmune diseases, neutrophilic dermatosis was the most common autoimmune disease (35.8%), followed by

The association between MDS and vasculitis is rare, but more common than solid tumors, and has been described for decades. Cutaneous vasculitis presents by palpable purpura mainly in lower extremities that involves small vessels and is characterized by perivascular inflammation and vessel wall damage by

infiltrating neutrophils. Although both cutaneous and systemic vasculitis has been reported in MDS patients, at times they can be seen together in MDS patients. For instance, in a case series of 6 biopsy proven cutaneous vasculitis patients with MDS, 3 patients had evidence of systemic vasculitis [31]. In one case, MDS patient with biopsy proven cutaneous vasculitis developed acute myeloid leukemia within 4 months of vasculitis diagnosis [32]. Henoch-Schonlein purpura, a small vessel vasculitis with IgA dominant immune deposits has been described in MDS

The association of MDS and polyarteritis nodosa (PAN) type medium-vessel vasculitis has been reported [34]. In a retrospective study of 8 patients with chronic myelomonocytic leukemia (CMML), with vasculitis involved the medium-vessel, fulfilling the criteria for classic PAN, the presentation was non-specific, and patients developed atypical manifestations [35]. There is a case report of 43-yearold man who qualified for a diagnosis of PAN and developed systemic vasculitis at the time of chronic myelomonocytic leukemia (CMML) diagnosis [36]. There is a report of two cases with CMML who presented with PAN-like systemic vasculitis with bilateral perirenal hemorrhage and negative antineutrophil cytoplasmic anti-

Although most MDS associated vasculitis described as leukocytoclastic vasculitis, published case reports documented large vessel vasculitis as autoimmune complication of MDS. Aortitis has been reported as an autoimmune manifestation of an MDS patient at presentation [38]. There is a report of two MDS cases that presented with acute large vessel vasculitis with rapid improvement with systemic steroids [39]. In a retrospective analysis of 271 temporal arteritis patients, it was found that 20 patients had malignancy, of which 11 patients had MDS, favoring a relationship between large vessel vasculitis and MDS [40]. There is a case report of Takayasu's arteritis diagnosed shortly after diagnosis of MDS, with progression to AML regardless of improvement of vasculitis with immunosuppressive treatment [41].

body with improvement of vasculitis with systemic steroids [37].

There is a case report of a 71-year-old woman presenting with fever, neck

pain, anemia, and thrombocytopenia, with positive positron emission tomography (PET)/CT scan of the aorta and carotid arteries with negative temporal artery biopsy who received the diagnosis of MDS after a bone marrow aspiration

Behçet's disease (14.9%), and rheumatoid arthritis (13.4%) [30].

Recent Developments in Myelodysplastic Syndromes

diseases [29].

3.1 Vasculitis

patients [33].

analysis [42, 43].

34

A multisystem, chronic inflammatory disease of unknown etiology, Behçet's disease (BD) is characterized by recurrent oral and genital ulcers, uveitis, arthritis, and vascular involvement of several organs including pulmonary, central nervous system and gastrointestinal tract. In a retrospective study of 805 BD patients, 16 patients had MDS, from which 43.8% had BD prior to MDS, 18.7% diagnosed after MDS and 37.5% had concurrent BD and MDS. It has been shown that trisomy 8 has been accumulated in all of BD patients with MDS, and these patients more likely to be female, older age, and have fever and ileocecal ulcerations [44]. In a retrospective study of 46 MDS patients, 8 patients had trisomy 8, 5 of them had multiple intestinal ulcers, a common feature of BD. Two of the MDS patients with trisomy 8 and multiple intestinal ulcers were treated with granulocyte-colony stimulating factor (G-CSF), aggravating their symptoms, suggesting G-CSF should be used cautiously in this subgroup of MDS patients [45]. There is several case reports of BD associated with MDS [46–49]. In a case report of two patients with BD and MDS, it has been suggested that PET/CT may help diagnosis of both BD and MDS with high uptake by bone marrow in MDS patients and genital and gastrointestinal aphthous ulcers in BD patients [50]. It has been suggested that the frequency of gastrointestinal involvement is more common in MDS-associated BD patients than general BD population [51].

### 3.3 Inflammatory arthritis

There are several case reports and small series of inflammatory arthritis and MDS co-occurrence. In a retrospective study of 28 MDS patients, 8 had acute seronegative inflammatory arthritis with good response of arthritis to steroids [52]. In a French multicenter retrospective study of 22 patients with MDS, 77% of patients had polyarthritis, and 68% had symmetric joint involvement. Radiologic erosions are rare, and MDS associated arthritis is more frequent in refractory anemia with excess blast (RAEB) [53].

### 3.4 Miscellaneous

There are several case reports of relapsing polychondritis (RP) presenting as a paraneoplastic disorder in the setting of MDS [54, 55]. In a retrospective study of hematological changes in 19 patients with relapsing polychondritis, MDS was found in three RP patients [56]. Autoimmune hemolytic anemia has been reported in association with MDS [57–59]. Association of systemic lupus erythematosus and MDS has been reported [60–62].

#### 3.5 Immunological abnormalities

It is a very well-known fact that a spectrum of immunological abnormalities occur in MDS. In a retrospective study of 104 MDS patients, 12.5% had monoclonal gammopathy, 19% had low immunoglobulin levels, 32% had polyclonal rise in serum immunoglobulin level, and 8.1% had positive direct antiglobulin test (DAT) [25]. In a case series of 142 patients with MDS and CMML, 23.2% had non-organ specific autoantibody ANA as the most frequent serologic finding [25]. Thrombocytopenia is a common finding in MDS, and can be seen in up to two third of the patients. In a study of 54 MDS patients with no treatment of transfusions, direct platelet immunofluorescence test for platelet associated IgG was positive in 28 patients. Patients with higher amount of platelet associated IgG, had significantly higher mean platelet volume (MPV), thrombocytopenia and worse outcome [63].

#### 4. Prognosis

It has been suggested that appearance of skin vasculitis in MDS patients may reflect acute myeloid leukemia transformation. In a prospective study of 157 MDS patients for a median of 44 months, 15 patients (9.55%) experienced skin lesions, and neutrophilic dermatosis (7, 4.46%), specific lesions (5, 3.18%), cutaneous vasculitis (2, 1.27%) and Behçet's disease (1, 0.63%) were reported. This study revealed that neutrophilic dermatosis was more prevalent in MDS patients, may confer the higher risk of acute myeloid leukemia transformation [64]. In another study of 84 newly diagnosed MDS patients, correlation of cutaneous findings with immunologic parameters and prognostic features of MDS examined, and revealed that 21 patients had skin lesions at presentation, and skin manifestations were a significant predictor of the high-risk MDS subgroup [65].

TNF-α antagonists, and their efficacy is much less in autoimmune disorders associated with MDS than autoimmune disorders without MDS. Overall, response rate to 5-azacitidine in MDS-associated autoimmune disorders was 67% in favor of a cau-

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence?

Myelodysplastic syndromes are a heterogeneous group of progressive clonal hematopoietic stem cell disorders characterized by a varying degree of peripheral cytopenia, and increased probability of transformation to acute myeloid leukemia. MDS and particularly CMML are frequently associated with a variety of autoimmune disorders that can be diagnosed concomitantly with MDS or before or after MDS. The heterogeneity and complexity of pathology, clinical manifestations, response to therapy, and prognosis of MDS and its immune dysregulation makes the prognosis of MDS with autoimmune diseases a matter of debate. Prospective, randomized studies

The authors would like to thank Mr. Dixon Bennet for his technical assistance.

\*, Mojtaba Akhtari<sup>2</sup> and Sheda Heidarian<sup>3</sup>

Residency Program, Mike and Jan Salta Health Center, Rancho Mirage, CA,

3 President Elect, Medical Staff, Eisenhower Health, Rancho Mirage, CA,

\*Address all correspondence to: knewman@eisenhowerhealth.org

provided the original work is properly cited.

2 Clinical Medicine, Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, USC/Norris Cancer Center, Los Angeles, CA, United States

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Eisenhower Rheumatology Specialty Clinic, Eisenhower Health, Internal Medicine

are required to confirm the autoimmune diseases role in MDS prognosis.

sality relationship between MDS and autoimmune disorders [72].

DOI: http://dx.doi.org/10.5772/intechopen.80710

6. Conclusion

Acknowledgements

Disclosure

None.

Author details

Kam A. Newman<sup>1</sup>

United States

United States

37

In a retrospective study of 153 MDS patients, 12% had autoimmune diseases, and 63% has at least one immunological abnormality in test results. In this study, the survival of patients without autoimmune diseases was better than patients with autoimmune disease [66]. However, in a 4 year prospective study of 70 MDS patients, 53 patients without and 13 patients with autoimmune disease, there was no particular difference concerning prognosis between two groups. And patients with autoimmune diseases were not statistically different in survival compared with MDS patients without autoimmune disease [67].

#### 5. Treatment

Autoimmune disorders associated with MDS may predate or occur after MDS diagnosis, and their treatment many be associated with significant side effects in MDS patients. It has been recognized from several case reports that treatment of the underlying MDS may resolve the associated autoimmune disorders. In a transfusion dependent MDS patient who was receiving G-CSF and erythropoietin, neutrophilic dermatosis did not improve with G-CSF withholding. Two months after starting 5 azacitidine, a hypomethylating agent, the skin rash completely resolved, and did not recur after 2 years [68]. In another case series of 3 MDS patients with autoimmune disorders, 5-azacitidine improved both MDS and autoimmune disorders although long term steroid could not be tapered [69].

In a retrospective study of 123 MDS patients with autoimmune disorders, 118 patients (96%) were treated with steroids, and 48% of patients were required a second line treatment for refractory disease or relapse. Although autoimmune disorder treatment did not improve MDS, MDS treatment with 5-azacitidine improved the autoimmune disorder in 9 out of 11 (80%) of patients [70]. In another retrospective study of 123 MDS/CMML patients with autoimmune disorders, 28 patients received at least 5 cycles of azacitidine, 20 of them did not respond to steroids. In 86% of MDS/CMML patients, clinical autoimmune syndromes improved by azacitidine, and prednisone dose tapered in 64% of patients [71].

The overall effect of biologic medications efficacy in MDS patients who presented with autoimmune disorder is not clear. As of today, there is only one retrospective study of MDS patients with autoimmune disorders and biologic medications. In this study of at least one biologic medication, 29 patients followed for at least 3 years. 89% of patients received a biologic after failure or intolerance of two disease modifying anti rheumatic agents (DMARDs), however, 11% of patients received biologics as a first line treatment. Except rituximab, a CD-20 blocker, mainly for vasculitis (58% response), there was partial or insufficient response to

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence? DOI: http://dx.doi.org/10.5772/intechopen.80710

TNF-α antagonists, and their efficacy is much less in autoimmune disorders associated with MDS than autoimmune disorders without MDS. Overall, response rate to 5-azacitidine in MDS-associated autoimmune disorders was 67% in favor of a causality relationship between MDS and autoimmune disorders [72].

## 6. Conclusion

4. Prognosis

5. Treatment

36

predictor of the high-risk MDS subgroup [65].

Recent Developments in Myelodysplastic Syndromes

MDS patients without autoimmune disease [67].

although long term steroid could not be tapered [69].

azacitidine, and prednisone dose tapered in 64% of patients [71].

The overall effect of biologic medications efficacy in MDS patients who presented with autoimmune disorder is not clear. As of today, there is only one retrospective study of MDS patients with autoimmune disorders and biologic medications. In this study of at least one biologic medication, 29 patients followed for at least 3 years. 89% of patients received a biologic after failure or intolerance of two disease modifying anti rheumatic agents (DMARDs), however, 11% of patients received biologics as a first line treatment. Except rituximab, a CD-20 blocker, mainly for vasculitis (58% response), there was partial or insufficient response to

It has been suggested that appearance of skin vasculitis in MDS patients may reflect acute myeloid leukemia transformation. In a prospective study of 157 MDS patients for a median of 44 months, 15 patients (9.55%) experienced skin lesions, and neutrophilic dermatosis (7, 4.46%), specific lesions (5, 3.18%), cutaneous vasculitis (2, 1.27%) and Behçet's disease (1, 0.63%) were reported. This study revealed that neutrophilic dermatosis was more prevalent in MDS patients, may confer the higher risk of acute myeloid leukemia transformation [64]. In another study of 84 newly diagnosed MDS patients, correlation of cutaneous findings with immunologic parameters and prognostic features of MDS examined, and revealed that 21 patients had skin lesions at presentation, and skin manifestations were a significant

In a retrospective study of 153 MDS patients, 12% had autoimmune diseases, and 63% has at least one immunological abnormality in test results. In this study, the survival of patients without autoimmune diseases was better than patients with autoimmune disease [66]. However, in a 4 year prospective study of 70 MDS patients, 53 patients without and 13 patients with autoimmune disease, there was no particular difference concerning prognosis between two groups. And patients with autoimmune diseases were not statistically different in survival compared with

Autoimmune disorders associated with MDS may predate or occur after MDS diagnosis, and their treatment many be associated with significant side effects in MDS patients. It has been recognized from several case reports that treatment of the underlying MDS may resolve the associated autoimmune disorders. In a transfusion dependent MDS patient who was receiving G-CSF and erythropoietin, neutrophilic dermatosis did not improve with G-CSF withholding. Two months after starting 5 azacitidine, a hypomethylating agent, the skin rash completely resolved, and did not recur after 2 years [68]. In another case series of 3 MDS patients with autoimmune disorders, 5-azacitidine improved both MDS and autoimmune disorders

In a retrospective study of 123 MDS patients with autoimmune disorders, 118 patients (96%) were treated with steroids, and 48% of patients were required a second line treatment for refractory disease or relapse. Although autoimmune disorder treatment did not improve MDS, MDS treatment with 5-azacitidine improved the autoimmune disorder in 9 out of 11 (80%) of patients [70]. In another retrospective study of 123 MDS/CMML patients with autoimmune disorders, 28 patients received at least 5 cycles of azacitidine, 20 of them did not respond to steroids. In 86% of MDS/CMML patients, clinical autoimmune syndromes improved by

Myelodysplastic syndromes are a heterogeneous group of progressive clonal hematopoietic stem cell disorders characterized by a varying degree of peripheral cytopenia, and increased probability of transformation to acute myeloid leukemia. MDS and particularly CMML are frequently associated with a variety of autoimmune disorders that can be diagnosed concomitantly with MDS or before or after MDS. The heterogeneity and complexity of pathology, clinical manifestations, response to therapy, and prognosis of MDS and its immune dysregulation makes the prognosis of MDS with autoimmune diseases a matter of debate. Prospective, randomized studies are required to confirm the autoimmune diseases role in MDS prognosis.

### Acknowledgements

The authors would like to thank Mr. Dixon Bennet for his technical assistance.

## Disclosure

None.

## Author details

Kam A. Newman<sup>1</sup> \*, Mojtaba Akhtari<sup>2</sup> and Sheda Heidarian<sup>3</sup>

1 Eisenhower Rheumatology Specialty Clinic, Eisenhower Health, Internal Medicine Residency Program, Mike and Jan Salta Health Center, Rancho Mirage, CA, United States

2 Clinical Medicine, Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, USC/Norris Cancer Center, Los Angeles, CA, United States

3 President Elect, Medical Staff, Eisenhower Health, Rancho Mirage, CA, United States

\*Address all correspondence to: knewman@eisenhowerhealth.org

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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myelodysplastic syndromes and chronic myelomonocytic leukaemia: A French multicentre retrospective study.

DOI: http://dx.doi.org/10.5772/intechopen.80710

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence?

Rheumatology (Oxford, England). 2016;

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[72] Mekinian A, Dervin G, Lapidus N, Kahn JE, Terriou L, Liozon E, et al. GFM, SNFMI, CRI and MINHEMON. Biologics in myelodysplastic syndromerelated systemic inflammatory and autoimmune diseases: French

multicenter retrospective study of 29 patients. Autoimmunity Reviews. 2017;

55(2):291-300

16(9):903-910

43

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[66] Okamoto T, Okada M, Mori A, Saheki K, Takatsuka H, Wada H, et al. Correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients. International Journal of Hematology. 1997;66(3):345-351

[67] Giannouli S, Voulgarelis M, Zintzaras E, Tzioufas AG, Moutsopoulos HM. Autoimmune phenomena in myelodysplastic syndromes: A 4-yr prospective study. Rheumatology (Oxford, England). 2004;43(5):626-632

[68] Raj K, Ho A, Creamer JD, du Vivier AW, Salisbury JR, Mufti GJ. Complete response of deep neutrophilic dermatosis associated with myelodysplastic syndrome to 5 azacytidine. The British Journal of Dermatology. 2007;156(5):1039-1041

[69] Pilorge S, Doleris LM, Dreyfus F, Park S. The autoimmune manifestations associated with myelodysplastic syndrome respond to 5-azacytidine: A report on three cases. British Journal of Haematology. 2011;153(5):664-665

[70] Mekinian A, Grignano E, Braun T, Decaux O, Liozon E, Costedoat-Chalumeau N, et al. Systemic inflammatory and autoimmune manifestations associated with

Myelodysplastic Syndrome and Autoimmune Disorders: Causal Relationship or Coincidence? DOI: http://dx.doi.org/10.5772/intechopen.80710

myelodysplastic syndromes and chronic myelomonocytic leukaemia: A French multicentre retrospective study. Rheumatology (Oxford, England). 2016; 55(2):291-300

[57] Oren H, Uçar C, Gülen H, Duman M, Irken G. Autoimmune hemolytic anemia occurring with myelodysplastic syndrome: Report of a pediatric case and review of the literature. Annals of Hematology. 2001;80(9):540-542

Recent Developments in Myelodysplastic Syndromes

[64] Farah C, Bulai Livideanu C, Jegu J, Paul C, Viraben R, Lamant L, et al. Prevalence and prognostic value of cutaneous manifestations in patients with myelodysplastic syndrome. Journal

Dermatology and Venereology. 2010;

[65] Dalamaga M, Karmaniolas K, Matekovits A, Migdalis I, Papadavid E. Cutaneous manifestations in relation to immunologic parameters in a cohort of primary myelodysplastic syndrome patients. Journal of the European Academy of Dermatology and Venereology. 2008;22(5):543-548

[66] Okamoto T, Okada M, Mori A, Saheki K, Takatsuka H, Wada H, et al. Correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients. International Journal of Hematology.

[67] Giannouli S, Voulgarelis M,

response of deep neutrophilic dermatosis associated with myelodysplastic syndrome to 5 azacytidine. The British Journal of Dermatology. 2007;156(5):1039-1041

Zintzaras E, Tzioufas AG, Moutsopoulos HM. Autoimmune phenomena in myelodysplastic syndromes: A 4-yr prospective study. Rheumatology (Oxford, England). 2004;43(5):626-632

[68] Raj K, Ho A, Creamer JD, du Vivier AW, Salisbury JR, Mufti GJ. Complete

[69] Pilorge S, Doleris LM, Dreyfus F, Park S. The autoimmune manifestations

[70] Mekinian A, Grignano E, Braun T, Decaux O, Liozon E, Costedoat-Chalumeau N, et al. Systemic inflammatory and autoimmune manifestations associated with

associated with myelodysplastic syndrome respond to 5-azacytidine: A report on three cases. British Journal of Haematology. 2011;153(5):664-665

of the European Academy of

24(10):1171-1175

1997;66(3):345-351

[58] Lin JT, Wang WS, Yen CC, Chiou TJ, Liu JH, Hsiao LT, et al. Myelodysplastic syndrome complicated by autoimmune hemolytic anemia: Remission of refractory anemia following mycophenolate mofetil. Annals of Hematology. 2002;81(12):

[59] Sokol RJ, Hewitt S, Booker DJ. Erythrocyte autoantibodies, autoimmune haemolysis, and

[60] Ng HS, Ng HW, Sinniah R, Feng PH. A case of systemic lupus erythematosus with sideroblastic

erythroleukaemia. Annals of the Rheumatic Diseases. 1981;40(4):

[61] Jiménez-Balderas FJ, Morales-Polanco MR, Gutierrez L. Acute sideroblastic anemia in active systemic lupus erythematosus. Lupus. 1994;3(3):

[62] Montoro J, Gallur L, Merchán B, Molero A, Roldán E, Martínez-Valle F, Villacampa G, Navarrete M, Ortega M, Castellví J, Saumell S, Bobillo S, Bosch F, Valcárcel D. Autoimmune disorders are common in myelodysplastic syndrome patients and confer an adverse impact on outcomes. Ann Hematol. 2018;97(8):

[63] Gilli SC, de Souza Medina S, de Castro V, Fernandes LG, Saad ST. Platelet associated IgG may be related with thrombocytopenia in patients with myelodysplastic syndromes. Leukemia

Research. 2012;36(5):554-559

anaemia terminating in

myelodysplastic syndromes. Journal of Clinical Pathology. 1989;42(10):

723-726

1088-1091

422-426

157-159

1349-1356

42

[71] Fraison JB, Mekinian A, Grignano E, Kahn JE, Arlet JB, Decaux O, et al. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leukemia Research. 2016;43:13-17

[72] Mekinian A, Dervin G, Lapidus N, Kahn JE, Terriou L, Liozon E, et al. GFM, SNFMI, CRI and MINHEMON. Biologics in myelodysplastic syndromerelated systemic inflammatory and autoimmune diseases: French multicenter retrospective study of 29 patients. Autoimmunity Reviews. 2017; 16(9):903-910

**45**

**Chapter 4**

**Abstract**

**1. Introduction**

Immune Cells

*and Meenakshi Singh*

Immune Dysregulation in MDS:

Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder affecting individuals over the age of 60 years. It is characterized by ineffective hematopoiesis and extensive apoptosis of hematopoietic cells. MDS patients are at a high risk of transforming in to acute myeloid leukemia. The main cause of apoptosis and escape from immune surveillance in MDS is immune dysregulation caused by a number of factors such as aberrant cytokine production and influence of various immune cells. In the past decade various pro-inflammatory cytokines and a number of immune cells such as Natural Killer cells, regulatory T cells, cytotoxic T cells, mesenchymal stem cells, myeloid derived suppressor cells and dendritic cells have been implicated in immune dysregulation leading to MDS pathogenesis. In this review we focus on

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders with ineffective hematopoiesis, cytopenias and risk of transformation to acute myeloid leukemia (AML). Incidence of MDS is higher in older individuals (>70 years of age) [1, 2]. The severity of MDS could range from indolent disease in which no blood transfusion is required, to borderline AML. An individual can get MDS either de novo, secondary to other myeloid disorders or MDS related to therapy. There are several point mutations associated with MDS [3–5]. Few of the individuals carrying these point mutations have a risk of developing MDS in the future but the factors involved in progression of the disease have not yet been identified [6]. MDS is a multifactorial disorder arising due to factors such as genetic alterations, epigenetic changes, gene transcription dysregulation and immune dysregulation [7]. This chapter is a review of the current data available indicating the role of immune cells in immune dysregulation related to MDS pathogenesis.

The Role of Cytokines and

the current data available on the role of these immune factors.

dendritic cells, mesenchymal derived stem cells

**Keywords:** myelodysplastic syndrome, cytokines, natural killer cells,

*Selma D'Silva, Sunil B. Rajadhyaksha* 

## **Chapter 4**
