Introduction
Idiopathic inflammatory myopathy (IIM) is a group of chronic acquired autoimmune diseases characterized by symmetrical muscle weakness in the proximal extremities, elevated serum myosin, and abnormal findings in electromyography and muscle biopsy. IIM includes mainly dermatomyositis (DM) and polymyositis (PM), as well as rare types such as clinically amyopathic dermatomyositis (CADM), inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and juvenile myositis (JM) [
1,
2].
The association between IIM and malignancies has been observed for decades: Stertz first reported an association between DM and cancer in 1916 [
3]. A population-based study in Sweden found a more than twofold risk of cancer in PM/DM compared to the general population [
4]. More and more scholars subsequently found a higher risk of malignant tumors in IIM patients [
5‐
8]. Some types of PM/DM are even proposed as a paraneoplastic skin disease. Most reviews are focused on risks in PM/DM for all types of malignancy. IIM could be combined with different types of cancers, such as lung cancer, nasopharyngeal cancer, ovarian cancer, breast cancer, stomach cancer, cervical cancer, etc. There were reviews about the relationship between IIM and site-specific cancer, such as nasopharyngeal [
9] and colorectal cancer [
10]. Melanoma is occasionally reported, but represents one of the most aggressive malignant tumors, dangerous for causing 90% of skin cancer mortality [
11]. No meta-analysis has been conducted to summarize the relationship between IIM and melanoma. Herein, we specifically wanted to investigate whether IIM is associated with a higher incidence of melanoma.
Methods
Data sources and searches
Two independent authors (Luo and Xia) searched three English databases (PubMed, Embase, Web of Science) and three Chinese databases (CNKI, VIP, and Wanfang) for studies on IIM related to tumors published up to October 2023. A combination of MeSH terms and free words was used. The search strategy combined terms ‘idiopathic inflammatory myopathy,’ ‘dermatomyositis,’ ‘polymyositis,’ or ‘myositis’ with ‘cancer,’ ‘malignancy,’ ‘tumor,’ ‘tumour,’ ‘neoplasm,’ or ‘carcinoma.’ The term ‘melanoma’ was then searched in all the full texts. This meta-analysis was performed according to the guidelines specified by PRISMA [
12] and registered on INPLASY under registration
https://doi.org/10.37766/inplasy2023.11.0031.
Study selection
The following inclusion criteria were applied: 1) written in English or Chinese; 2) type of study: cohort study reporting estimates with corresponding confidence intervals (CIs); 3) study population: patients with IIM combined with tumors; 4) outcome indicators: occurrence of tumors as one of the observed outcomes. Studies were excluded if 1) the study population was a repetitive population; 2) specific raw data indicators were unavailable; 3) the type of literature was a conference, case report, review, lecture, abstract, and so on.
Two authors (Luo and Xia) independently read all literature sources and full texts. A pre-designed extraction Microsoft Excel file was used for the following information: first author, year of publication, type of study, region, period of study, number of people followed, diagnostic criteria, risk estimate such as relative risk ratio (RR), hazard ratio (HR), or standardized incidence ratio (SIR), with corresponding 95% confidence interval (95% CI). In case of any disputes, mutual discussion was organized with a third researcher.
Assessment of research quality
The Newcastle–Ottawa Scale (NOS) was used for the quality assessment of non-randomized controlled studies. Eight items were categorized into three dimensions, which include selection, comparability, and outcome.
Statistical analysis
The extracted data were processed using Stata software (version 16.0; Stata Corp LLC, College Station, TX, USA). The measure of interest was regarded as a continuous variable. The confidence intervals for each effect size were used with a 95% CI. We plotted a funnel plot to show the publication bias of studies: symmetry indicated no publication bias, and asymmetry publication bias requiring further examination by Begg’s correlation test and Egger’s linear regression.
The heterogeneity test was done by means of Q statistic and I2 test. Regarding the Q test, if P > 0.05, there was homogeneity among the studies; conversely, if P ≤ 0.05, there was heterogeneity. The size of heterogeneity was then quantitatively analyzed according to I2 test: if I2 < 50%, it indicated less heterogeneity in the included studies within the acceptable range; conversely, if I2 ≥ 50%, there was more heterogeneity. The corresponding effect model was selected according to the result. If P > 0.05 and I2 < 50%, the fixed effects model was used; on the contrary, if the heterogeneity was large (P ≤ 0.05 or I2 ≥ 50%), the random effects model was used for meta-analysis. The following subgroup analyses were performed if the original articles provided enough data: 1) sex, 2) age, 3) subtypes of IIM.
Sensitivity analysis was performed to assess the robustness and reliability of the combined results of meta-analysis. In this study, each single study was excluded one by one. If the effect on the combined effect size is small after eliminating a single study, it means that the results are stable and reliable; if the effect on the combined effect size is large after eliminating a single study, it means that the results are unreliable and further analysis is needed.
Discussion
Idiopathic inflammatory myopathy (IIM) is a group of heterogeneous inflammatory diseases characterized by symmetrical muscle weakness in the proximal extremities. The subtypes include polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), juvenile dermatomyositis (JDM), immune-mediated necrotizing myopathy (IMNM), and amyopathic dermatomyositis (ADM). Estimates of IIM prevalence range from 0.5 to 9.3 cases/million [
15‐
17].
Epidemiological studies have shown that patients with DM have an increased risk of developing malignant neoplasms compared to the general population, with overall standardized incidence ratios (SIRs) ranging from 3.8 to 7.7 [
18,
19]. The incidence of malignant tumors among DM patients varies widely in different literature, mostly ranging from 5% to 52%. The differences may be related to race, age, gender, and length of follow-up. In a word, the etiology and pathogenesis process are complex and still unclear. Among the connective tissue diseases, DM has been regarded as having the highest incidence of malignant tumors, with various types involving all organs. The site of malignancy has been reported as the ovary, lung, or gastrointestinal tract in Western countries and the nasopharynx in Southeast Asia, Southern China, and Northern Africa [
20]. Some data show that DM is highly correlated with lung, nasopharyngeal, and colon cancer in men, and breast and ovarian cancer in women, with SIRs ranging from 8.2 to 32 [
4,
7,
21,
22]. Nasopharyngeal cancer is the most prevalent in the Far East, North Africa, and the south of the country, but rare in Caucasians [
23]. Chinese authors reported lung cancer to have the highest incidence in DM [
24]. Population-based studies have demonstrated that PM carries a less elevated risk of cancer compared to DM [
4,
21].
PM and DM are often reported in association with various malignancies, without including rare subtypes such as IBM. Thus, we did not consider IIM as a topic at first. However, as one of our final included articles followed up IIM patients, we expanded the scope from PM/DM to IIM to have a comprehensive view of myositis. In our study, the pooled overall RR/HR was 3.08 (95% CI 0.79–5.37) and the SIR was 6.30 (95% CI 1.59–11.02), which is consistent with existing research findings.
Strengths
Melanoma has not been frequently investigated with IIM. To the best of our knowledge, this is the first meta-analysis that takes into account this most dangerous type of skin cancer. The included cohort studies are more reliable compared to case–control studies. The four studies were reported in different decades and regions, making results more representative. Table
1 showed the diagnosed criteria in each study. Moreover, the time of development of cancer was also considered, which means that all the melanoma cases were observed after the diagnosis of IIM, not before.
Limitations
The first limitation of the study is that the number of included studies is not large. Due to the small number of 19 melanoma cases observed, there was no definite age and gender information, so we could not perform further subgroup analyses. At our initial plan, Chinese studies were searched due to the large population; however, there seemed to be a lack of high-quality cohort studies in China.
Conclusion
In this systematic review, through meta-analysis, we present the higher risk of melanoma in IIM. More high-quality cohort studies in China are needed to gain a broader view of the association.
Declarations
For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.
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