Impact of cancer on the mortality of patients with idiopathic inflammatory myopathies by flexible parametric multistate modelling.

BACKGROUND: Patients with idiopathic inflammatory myopathies (IIM) have an increased risk of cancer, but their cancer-related disease burden remains unclear. OBJECTIVES: To explore how cancer might impact the mortality of patients with IIM and examine the associated prognostic factors for cancer and death. METHODS: We identified patients with IIM diagnosed between 1998 and 2020 and ascertained their cancer and death records via linkage to the Swedish healthcare and population registers. Transition hazards from IIM diagnosis to cancer and death were estimated in multistate models using flexible parametric methods. We then predicted the probability of having cancer or death, and the duration of staying alive at a given time from IIM and cancer diagnoses from a crude model. We also explored prognostic factors for progression to cancer and death in a multivariable model. RESULTS: Of 1826 IIM patients, 310 (17%) were diagnosed with cancer before and 306 (17%) after IIM diagnosis. In patients diagnosed with cancer after IIM, the 5-year probability of death from cancer and from other causes was 31% and 18%, respectively, compared to 7% and 15% in patients without cancer after IIM. We reported several factors associated with risk of progression to cancer and death. Specifically, patients with first cancer after IIM who were older at IIM diagnosis, had cancer history, dermatomyositis and a cancer diagnosis within 1 year following IIM faced a greater cancer-specific mortality. CONCLUSION: We observed a substantial increase in mortality from cancer, compared to before, rather than other causes after a cancer diagnosis following IIM, suggesting an unmet medical need for effective cancer management in IIM patients. This finding, along with the identified prognostic factors, provides useful insight into future research directions for improving cancer management in IIM patients.

Familial autoimmunity in patients with idiopathic inflammatory myopathies.

BACKGROUND: Familial associations can be indicators of shared genetic susceptibility between two diseases. Previous data on familial autoimmunity in patients with idiopathic inflammatory myopathies (IIM) are scarce and inconsistent. OBJECTIVES: To investigate which autoimmune diseases (ADs) may share genetic susceptibility with IIM, we examined the familial associations between IIM and different ADs. METHODS: In this Swedish population-based family study, we assembled 7615 first-degree relatives (FDRs) of 1620 patients with IIM and 37,309 relatives of 7797 matched individuals without IIM. Via register linkages, we ascertained rheumatoid arthritis, other rheumatic inflammatory diseases (RIDs), multiple sclerosis, inflammatory bowel diseases (IBD), type 1 diabetes mellitus, autoimmune thyroid diseases (AITD), coeliac disease (CeD) and myasthenia gravis among the FDRs. We estimated the familial association between IIM and each AD using conditional logistic regression and performed subgroup analyses by kinship. RESULTS: Patients with IIM had significantly higher odds of having ≥1 FDR affected by other RIDs (adjusted odds ratio [aOR] = 1.40, 95% confidence interval [CI] 1.11-1.78) and greater odds of having ≥2 FDRs affected by CeD (aOR = 3.57, 95% CI 1.28-9.92) compared to the individuals without IIM. In the analyses of any FDR pairs, we observed familial associations for other RIDs (aOR = 1.34, 95% CI 1.14-1.56), IBD (aOR = 1.20, 95% CI 1.02-1.41), AITD (aOR = 1.10, 95% CI 1.02-1.19) and CeD (aOR = 1.37, 95% CI 1.08-1.74) while associations for other ADs were not statistically significant. CONCLUSION: The observed familial associations may suggest that IIM shares genetic susceptibility with various ADs, information that may be useful for clinical counselling and guiding future genetic studies of IIM.

Familial aggregation and heritability: a nationwide family-based study of idiopathic inflammatory myopathies.

OBJECTIVES: The magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM. METHODS: This is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM. RESULTS: We included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings. CONCLUSIONS: IIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.

Pregnancy outcomes in women with idiopathic inflammatory myopathy, before and after diagnosis-a population-based study.

OBJECTIVES: To examine pregnancy outcomes among births to women with idiopathic inflammatory myopathy (IIM) in relation to time of IIM diagnosis using population-based data. METHODS: This study used Swedish nationwide registers to identify all singleton births that occurred between 1973 and 2016 among women diagnosed with IIM between 1998 and 2016 and among women unexposed to IIM. We classified births according to the IIM status of the mother at time of delivery: post-IIM (n = 68), 1-3 years pre-IIM (n = 23), >3 years pre-IIM (n = 710) and unexposed to IIM (n = 4101). Multivariate regression models were used to estimate relative risks of adverse pregnancy outcomes in post-IIM births and pre-IIM births separately, in comparison with their non-IIM comparators. RESULTS: We found that post-IIM births had increased risks of caesarean section [adjusted relative risk (aRR) = 1.98; 95% CI: 1.08, 3.64], preterm birth (aRR = 3.35; 95% CI: 1.28, 8.73) and low birth weight (aRR = 5.69; 95% CI: 1.84, 17.55) compared with non-IIM comparators. We also noticed higher frequencies of caesarean section and instrumental delivery in 1-3 years pre-IIM births than in the non-IIM comparators. CONCLUSION: Women who gave birth after IIM diagnosis had higher risks of caesarean section, preterm birth and low birth weight. These results further underline the importance of special care and close monitoring of women with IIM. Higher frequencies of caesarean section and instrumental delivery in pre-IIM births highlight the need for future research on the influence of subclinical features of IIM on pregnancy outcomes.

Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.

STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.

Familial Co-Aggregation of Idiopathic Inflammatory Myopathies and Cancer: A Swedish Population-Based Study.

OBJECTIVE: To examine if idiopathic inflammatory myopathies (IIMs) share familial susceptibility with cancer, we estimated the familial co-aggregation of these diseases. METHODS: This Swedish population-based family study with data from national registers included 8,460 first-degree relatives of patients with IIM and 41,127 relatives of matched individuals without IIM. We modeled the adjusted odds ratios (ORs) of familial co-aggregation of IIM and cancer using conditional logistic regressions and adjusted for sex and birth year of index individuals and their first-degree relatives. We examined the associations for cancer overall and stratified by several factors of interest. We also performed exploratory analyses for specific cancer types. RESULTS: We observed no statistically significant familial associations between IIM and cancer overall. However, there was a familial association in male relative pairs of patients with dermatomyositis (adjusted OR for familial association 1.39 [95% confidence interval (95% CI) 1.15-1.68]). The association remained statistically significant after controlling for multiple testing. Moreover, this finding was consistent between kinships. Familial co-aggregation of IIM and cancer diagnosed before 50 years of age was only observed in offspring. In exploratory analyses, only the familial associations for myeloid malignancies (adjusted OR 2.27 [95% CI 1.43-3.60]) and liver cancer (adjusted OR 2.01 [95% CI 1.21-3.33]) in male relative pairs remained significant after controlling for multiple testing. CONCLUSION: We found little evidence of shared familial susceptibility as a major pathologic mechanism contributing to the co-occurrence of IIM and cancer overall. There could be subsets of patients and cancer types for which familial factors including genetics and shared environments are of more importance, but these findings need replication.

Environmental Risks for Inflammatory Myopathies.

This is an up-to-date review on external environmental factors for adult-onset idiopathic inflammatory myopathies (IIMs). Environmental factors with suggestive evidence including ultraviolet radiation, smoking, infectious agents (viruses in particular), pollutants, medications (ie, statin) and vitamin D deficiency are discussed. We also discuss the potential implications of environmental factors in IIM development, identify current challenges, and provide insight into future investigations.

Reproductive Pattern in Women with Idiopathic Inflammatory Myopathy: A Population-based Study.

OBJECTIVE: To examine the reproductive pattern of women with idiopathic inflammatory myopathy (IIM) compared to the general population. METHODS: Population-based, nationwide registers were used to identify offspring of women with IIM and comparators. RESULTS: Women with IIM in general had similar reproductive patterns as the comparators, whereas in those diagnosed between 26 and 45 years of age, there was an overall trend for fewer children as well as a higher proportion of nulliparity and a lower fertility rate in women with dermatomyositis than their comparators. CONCLUSION: Reproductive attention should be paid to patients with IIM diagnosed during the childbearing period.

Prevalence of depressive symptoms in primary school students in China: A systematic review and meta-analysis.

BACKGROUNDS: Depression in children and adolescents is usually under-recognized. The findings of epidemiological studies on depressive symptoms in primary school students are inconsistent across studies. This study reports a systematic review and meta-analysis on the prevalence of depressive symptoms in primary school students in China. METHODS: Literature search was performed in both international (PubMed, PsycINFO, EMBASE) and Chinese (China National Knowledge Internet, WANFANG Data and Chinese Biological Medical Literature) databases. The random-effects model was used to analyze data. RESULTS: Twenty-seven studies involving 42,374 subjects were included. The pooled prevalence of depressive symptoms in Chinese primary school students was 17.2% (95% CI: 14.3%-20.5%). Subgroup analyses found that the prevalence significantly varied between geographic regions, with western China reporting the highest prevalence. Meta-regression analyses found that year of survey and study quality were significantly associated with the prevalence of depressive symptoms. CONCLUSIONS: Given the high prevalence of depressive symptoms and its negative health outcomes, preventive measures, regular screening and effective treatments need to be implemented for this population.

Prevalence of depressive symptoms in children and adolescents in China: A meta-analysis of observational studies.

Depressive symptoms are common in children and adolescents. The prevalence of depressive symptoms in children and adolescents in China vary significantly across studies. A meta-analysis of the prevalence of depressive symptoms in children and adolescents in China was conducted. Literature search was performed in both English (PubMed, PsycINFO and EMBASE) and Chinese (China National Knowledge Internet, WANFANG Data and SinoMed) databases. Random-effects model was used to synthesize the prevalence of depressive symptoms. Eighteen studies covering 29,626 participants were identified and analyzed. All these studies used the same measurement to identify depressive symptoms. The reported point prevalence of depressive symptoms ranged between 4% and 41% in the studies; the pooled prevalence of depressive symptoms was 19.85% (95% confidence interval: 14.75%-24.96%). In the subgroup analyses the prevalence of depressive symptoms was significantly associated with the region where the study was conducted: 17.8% in eastern, 23.7% in central, 22.7% in western, and 14.5% in northeast regions of China (P < 0.001). Considering the adverse impact of depressive symptoms on health outcomes, regular screening and effective interventions should be implemented in this population.

Prevalence of major depressive disorder in children and adolescents in China: A systematic review and meta-analysis.

BACKGROUND: Prevalence figures of major depressive disorder (MDD) in children and adolescents across various epidemiological studies have been inconclusive. This is a systematic review and meta-analysis of the pooled prevalence of MDD and its associated factors in children and adolescents in China. METHOD: A systematic review and literature search were conducted covering PubMed, PsycINFO, EMBASE and Chinese databases (China National Knowledge Internet, WANFANG Data and SinoMed) to identify studies reporting the prevalence of MDD in children and adolescents in China. The pooled prevalence estimates and associated factors were examined using the Comprehensive Meta-Analysis program, Version 2. RESULTS: Fourteen studies involving 82,592 subjects were included in this meta-analysis. The pooled point prevalence of MDD in Chinese children and adolescents was 1.3% (95% CI: 0.8%-2.0%). Subgroup and meta-regression analyses revealed that diagnostic criteria, age, year of survey and study quality were significantly associated with the prevalence of MDD. CONCLUSIONS: The point prevalence of MDD in children and adolescents in China is similar to worldwide figures. Further national epidemiological studies with the view of developing effective intervention strategies should be considered.

Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds.

Inactivation of the p53 transcription factor by mutation or other mechanisms is a frequent event in tumorigenesis. One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation. In this work, a library of organometallic iridium(III) compounds were synthesized and evaluated for their ability to disrupt the p53/hDM2 protein-protein interaction. The novel cyclometallated iridium(III) compound 1 [Ir(eppy)2(dcphen)](PF6) (where eppy = 2-(4-ethylphenyl)pyridine and dcphen = 4, 7-dichloro-1, 10-phenanthroline) blocked the interaction of p53/hDM2 in human amelanotic melanoma cells. Finally, 1 exhibited anti-proliferative activity and induced apoptosis in cancer cell lines consistent with inhibition of the p53/hDM2 interaction. Compound 1 represents the first reported organometallic p53/hDM2 protein-protein interaction inhibitor.