MDS is a heterogeneous hematological malignancy characterized by thrombocytopenia with a high risk of transformation to acute myeloid leukemia. Therapeutic measures for this disease include transfusion to stimulate hematopoiesis and iron chelation therapy, demethylation therapy, immunosuppressive therapy,and hematopoietic stem cell transplantation.Patients with MDS frequently present with immune abnormalities, which include asymptomatic isolated abnormalities of serum immunogenic parameters (e.g., antinuclear antibody positivity, rheumatoid factor positivity), nonspecific autoimmune inflammation (e.g., noninfectious fever, polyarthralgia), and autoimmune diseases (e.g., RA, hypothyroidism, vasculitis)[8].
Autoimmune diseases and MDS can occur sequentially or simultaneously. Abnormal inflammation in patients with autoimmune diseases can cause clonal evolution, disturbances in bone marrow growth, and lead to the development of myeloid tumors. In contrast, abnormal inflammation in the bone marrow microenvironment of patients with MDS can activate the adaptive immune response and trigger autoimmune disease. Most patients have autoimmune diseases before they are diagnosed with MDS[9–10]. Patients can have autoimmune disease even before they have progressed to a state of MDS. The prevalence of clonal hematopoiesis of undetermined significance (CHIP), a precursor disease to MDS, is higher in patients with autoimmune diseases.A German study recruited 200 patients with non-hematologic diseases and found a significant correlation between CHIP and autoimmune diseases[11]. The prevalence of clonal hematopoiesis in patients with RA and anti-neutrophil cytoplasmic antibody-associated vasculitis was 17% and 30.4%, respectively[12–13]. In addition, patients with ulcerative colitis have been found to have slightly higher levels of CHIP than the general population.The inflammatory environment of the intestinal tract in patients promotes CHIP with a unique mutational profile, particularly clones with DNMT3A and PPM1D mutations[14].
Patients with autoimmune diseases combined with MDS may be associated with shared genetic susceptibility, chronic immune stimulation and immune dysregulation,and immunosuppressive drug use[15]. Autoimmune diseases and hematologic malignancies share common signaling pathway abnormalities, such as the tumor suppressor gene TP53 and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin cellular pathway signaling. The role of inflammation in cancer development and progression is complex. The family of transcription factors NF-κB plays a crucial role in inflammation and innate immunity.Constitutive activation of NF-κB in patients with chronic inflammatory diseases promotes tumor development[16]. In addition, neutrophils release reactive oxygen species during inflammation to kill pathogens.This innate immune response may lead to DNA damage and produce genetic mutations that can trigger tumorigenesis[17]. The role of the immune system in MDS has been highly investigated. In low-risk MDS, dysfunctional T-cell responses and innate immune activation induce apoptosis of hematopoietic precursor cells[18]. The age-dependent accumulation of somatic mutations is thought to underlie the age-related nature of MDS[19].The increase in systemic inflammation associated with aging has been termed " inflammageing". Elevated levels of the pro-inflammatory cytokines TNFα, IL-1β, and IL-6 activate chronic inflammation and cause damage to hematopoietic stem cells[20–21].
Patients with autoimmune diseases combined with MDS are more common in young women[9, 22]. Most studies have shown no difference in the distribution of MDS histologic subtypes between patients with and without autoimmune disease. However, some studies suggest that different MDS subtypes may have different etiologies.Patients with autoimmune diseases may be predisposed to develop specific subtypes of MDS. The main MDS subtypes associated with autoimmune diseases are MDS with multilineage dysplasia (MDS-MLD), MDS with single-lineage dysplasia (MDS-SLD), and MDS with excess blasts (MDS-EB)[9, 23–24]. In addition, MDS with trisomy 8 is often associated with behcet’s disease. Connective tissue disease is more common in patients with low-risk MDS[9, 25].
There is controversy about the impact of autoimmune diseases on the survival prognosis of MDS patients, which may be related to the specific type of autoimmune disease. Three multicenter case-control studies in France showed that MDS patients with a combination of systemic inflammatory and autoimmune diseases, giant cell arteritis, and vasculitis did not have a significant difference in overall survival (OS) compared with MDS patients without immune abnormalities.But patients with MDS-associated vasculitis had a lower rate of progression to acute leukemia compared with control subjects[9, 26–27]. A Spanish study found shorter survival in this subset of patients with MDS combined with autoimmune disease, especially in low-risk MDS patients[10]. This can be explained by the fact that patients with MDS combined with autoimmune diseases have more severe immune dysregulation, which leads to more severe bone marrow failure and disease progression[28].Conversely, it has been shown that MDS patients combined with autoimmune disease appears to have a better survival benefit. Recently,a US study retrospectively analyzed 15,277 patients with MDS from the SEER Medicare database, of whom 2,442 (16%) had pre-existing autoimmune disease, which reduced the risk of death by 11%.In low-risk MDS, the presence of pre-existing autoimmune disease was associated with an increased risk of leukemic transformation[29]. Another case-control study showed that this group of patients with MDS combined with autoimmune disease had better OS and lower leukemic transformation rates[4]. It has been hypothesized that the reason for this may be that autoimmune-driven tumor clones have unique mutational or cytogenetic risk profiles and are less aggressive.
Observational studies and RCTs have limitations.They require the collection of a certain number of cases and long-term follow-up.MR studies can elucidate causality through the genetic variant susceptibility loci of the disease. This is the first two-sample MR study on the causal effect of autoimmune diseases on MDS. The MR results showed that patients with RA, MS, MG, and HT had an elevated risk of developing MDS of 18.6%, 24.7%, 32.6%, and 51.9%, respectively. Our study did not find a causal relationship between other types of autoimmune diseases and MDS. The present study also has some limitations. First, the population participating in this study was predominantly European.So we should be cautious in applying this finding to other populations. Secondly,despite the fact that the genetic tools we chose were strongly predictive of exposure,it is still possible that the hypotheses about correlation and exclusion limits may not have been fully validated. It has also been reported that long term use of Immunosuppressive and biological agents also increases the risk of MDS.Due to the lack of GWAS associated with specific treatments of autoimmune diseases, it is not possible to validate a causal relationship through MR studies.Relevant studies can be carried out in the future.