Introduction
Dermatomyositis is a chronic, inflammatory disease that involves the skin and muscles. It most frequently occurs in adults aged 50–60 with preponderance in females, but pediatric occurrence (juvenile dermatomyositis) with the highest incidence between 5 and 15 years of age was also observed [
1]. In addition to the classic adult and pediatric subtype of the disease, several other clinically important presentations, including paraneoplastic, drug-induced, hypomyopathic, and amyopathic variants, may be distinguished [
2]. The disease is characterized by skeletal muscle weakness most commonly involving the proximal muscles of the upper and lower extremities and characteristic cutaneous lesions—flat-topped, erythematous to violaceous papules and plaques found over the metacarpophalangeal and both proximal and distal interphalangeal joints (formerly known as Gottron sign). Other typical dermatological features include bilateral lilac discoloration of the eyelids and eyelid area (heliotrope rash) and red, maculopapular well-demarcated rash on the chest wall (the V sign, shawl sign) [
3]. The diagnosis of the disease is based on the presence of typical clinical symptoms and supported by the EULAR/ACR criteria [
4]. Muscle biopsy is not required to confirm the diagnosis in patients with skin lesions typical of dermatomyositis [
4].
The pathogenesis of dermatomyositis is multifactorial and still incompletely elucidated. The important role of genetic and environmental factors including infections, vitamin D deficiency, exposure to ultraviolet radiation, and drugs is emphasized. The literature indicates both autoimmune and nonimmune mediators in the pathogenesis of dermatomyositis. The particular role of autoimmune processes was suggested in the development of certain symptoms of the disease [
5]. It is hypothesized that muscle damage is mediated by humoral factors (antibodies and the complement system) directed against the endothelial cells of endomysial capillaries. Two mechanisms are proposed for the induction of immune response. The first mechanism is associated with the overexpression of myositis-specific autoantigens in the inflamed muscles. The second mechanism is connected with the procurement of adjuvant activity by autoantigens [
5]. Moreover, studies showed atypical signaling through the interferon pathway as an important pathological hallmark of the disease [
6].
The presence of circulating autoantibodies is one of characteristic laboratory findings associated with autoimmunity in dermatomyositis. They may be detected in 40–80% of patients with the disease [
1,
7‐
9]. They are classified into two subgroups: myositis-specific and myositis-associated autoantibodies [
10]. Myositis-specific antibodies are detected in particular clinical syndromes within the spectrum of inflammatory myopathies, including dermatomyositis, polymyositis, and other rare subtypes such as necrotizing myopathy and inclusion body myositis [
11]. Myositis-specific antibodies include antibodies directed against aminoacyl-tRNA synthetases (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS, anti-Ha, and anti-Zo), type 5 protein associated with melanoma (anti-MDA5), nuclear helicase (anti-Mi-2), signal recognition particle (anti-SRP), transcriptional intermediary factor 1 (anti-TIF1), nuclear matrix protein 2 (anti-NXP2), and SUMO-1 activating enzyme (anti-SAE) [
1]. Studies revealed that the average incidence of myositis-specific antibodies amounted to 50% in dermatomyositis and polymyositis patients [
12].
Anti-PM/Scl, anti-Ku, anti-Ro, anti-La, anti-U1-RNP, and anti-U3-RNP are the most common myositis-associated antibodies and may be found in 20% of patients with myositis [
12]. They are also commonly detected in other systemic autoimmune diseases, mainly overlap syndromes [
13].
As regards dermatomyositis, especially myositis-specific antibodies are clinically important biomarkers facilitating and supporting the correct diagnosis of the disease [
14]. Their presence is associated with a characteristic clinical phenotype and may be useful in predicting and monitoring the disease as well as the response to treatment [
15]. Idiopathic inflammatory myopathies are a group of diseases associated with an increased risk of malignancy. The latest literature data revealed that such an association was especially strong in patients with dermatomyositis [
16]. Moreover, a higher incidence of malignancy was observed in males and in advanced-age patients with the disease [
17]. The relationship between an increased risk of malignancy and the presence of certain disease-specific autoantibodies has been extensively studied in recent years. There is a hypothesis that there are mechanisms selecting the target antigens of MSA out of thousands of proteins in cells of patients. There is a possibility that the production of certain autoantibodies, especially cancer-associated autoantibodies, is triggered by the formation of cryptic epitopes resulting from a mutation of the target antigens, e.g., mutation in a gene encoding TIF-1 protein triggers production of anti-TIF1 antibodies. The cryptic epitopes which may be created by the changing of the pattern of protein disassembly as a result of amino acids mutations are presented on the surface of antigen-presenting cells by class I or II major histocompatibility complex (MHC). The crucial step toward triggering autoimmune response is recognizing the MHC-peptide complex as changed and impaired. Immunological tolerance to the epitopes may be incomplete and the cryptic epitopes expressed on antigen-presenting cells in some specific conditions may generate an autoimmune response [
18].
The aim of this review is to summarize the current data regarding the link between malignancy and the presence of specific antibodies in patients with dermatomyositis.
Dermatomyositis and Malignant Diseases
An association between dermatomyositis and malignancy was reported in numerous studies. The first case described in 1916 by Stertz was related to gastric cancer detected in a patient with idiopathic inflammatory myopathy [
19]. The increased risk of cancer is associated with both dermatomyositis and other types of autoimmune myopathies. However, it is significantly higher in dermatomyositis with the incidence of malignancy ranging from 5.5 to 42% [
20,
21]. A recent meta-analysis of 5 studies involving 4538 patients showed that the risk of cancer increased 4.66-fold in patients with the disease compared to the general population [
17].
Malignant diseases may be diagnosed simultaneously, before or after the diagnosis of dermatomyositis. Malignant tumors are detected after the diagnosis of the disease in the vast majority of cases. The greatest risk of cancer was reported to occur within 12 months following the diagnosis of the disease (SIR of malignancy of 17.29). It is still increased 5 years after the diagnosis (SIR of malignancy of 1.37) [
17].
A wide variety of cancers were reported in dermatomyositis. A significantly increased risk of cancer of lymphatic and hematopoietic system (SIR 22.72), lung (SIR 19.74), ovary (SIR 5.39), and no increased risk of stomach and prostate cancer was reported in a meta-analysis by Olazagasti et al. [
22]. The location of neoplastic processes may depend on ethnicity, sex, and genetic background. According to the analysis of 2 large cohorts of patients with dermatomyositis, the most frequently reported malignancies were breast cancer (24.5%), hematologic malignancies (17.0%), colorectal cancers (9.4%), and prostate cancer (9.4%) [
23]. Studies conducted in the Asian population showed that the nasopharynx was the most common location of malignancy with the incidence of 22.5–62.5% of all cancers [
24,
25] (Table
1).
Table 1
Types of malignant diseases detected with the highest incidence in patients with dermatomyositis
Lymphatic and hematopoietic | |
Lung | |
Ovary | |
Prostate | |
Colon | |
Breast | |
Stomach | |
Nasopharynx | |
Numerous factors were also reported to be associated with a higher risk of cancer in patients with dermatomyositis. Although the disease occurs with female preponderance, a higher risk of malignancy was reported in males with a standardized incidence ratio (SIR) of cancer at 5.29 compared to 4.56 in females. The risk of malignancy was also higher in a group of patients beyond 44 years of age [
17]. In contrast to adult patients, a higher risk of cancer was not found in patients with juvenile dermatomyositis [
26]. In addition to older age and male sex, dysphagia, cutaneous necrosis, and some laboratory markers including accelerated erythrocyte sedimentation rate, increased C-reactive protein, or total creatine kinase concentrations were identified as the most important predictive factors of malignancy [
16]. Conversely, the presence of interstitial lung disease, Raynaud’s phenomenon, and arthritis or arthralgia were associated with a lower risk of malignancy in dermatomyositis [
27]. According to the literature, the meaningful role of certain specific autoantibodies was emphasized as factors associated with a higher risk of cancer in patients with dermatomyositis (Table
2). It is unclear if autoantibodies have a role in the pathogenesis of cancer [
28]. They might be an epiphenomenon that arises in response to the impaired or mutant proteins of cancer cells [
29]. Undoubtedly, autoantibodies may help in the early detection of malignancy [
30].
Table 2
Prevalence of autoantibodies and percentage of patients with a certain type of autoantibodies who present with a malignant disease in dermatomyositis
Anti-TIF1-γ | Transcription intermediary factor 1 | | |
Anti-NXP2 | Nuclear matrix protein 2 | | |
Anti-SAE | Small ubiquitin-like modifier activating enzyme | | |
Anti-ARS | Aminoacyl-tRNA synthetases | | |
All types of autoantibodies | – | | |
Conclusion
Cancer is one of the most common causes of mortality in patients with dermatomyositis [
60]. Malignancies are detected after the diagnosis of the disease in the majority of cases [
23]. Early cancer detection is essential for improving the prognosis of patients. Therefore, malignancy screening is crucial in dermatomyositis. Compared to the general population, the risk of malignancy in patients with dermatomyositis is 4.66-fold higher with an even higher risk in males and patients over 44 years of age [
17]. A significantly increased risk of malignancy (SIR 17) was reported within the first 12 months after the diagnosis of the disease [
17]. The detection of some specific antibodies may be an important tool in the identification of patients with dermatomyositis at a high risk of developing malignancy. Anti-TIF1-γ antibodies, especially co-occurring with anti-TIF1-ɑ and anti-NXP-2 antibodies have the strongest association with the development of neoplasms in patients with the disease. The presence of anti-SAE and other autoantibodies may also be correlated with an increased risk of cancer. Nevertheless, future research is essential to confirm the reports.
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