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Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system. Different from other cell death subtypes, such as apoptosis, necroptosis, autophagy, and pyroptosis, ferroptosis has a unique association with the cellular iron load (but not the loads of other metals) and preserves its distinguishable morphological, biological, and genetic features. This review addresses how ferroptosis is initiated and how it contributes to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases. The mechanisms responsible for ferroptosis-associated events are discussed. We also cover the perspective of targeting ferroptosis as a potential therapeutic for patients with autoimmune diseases. Collectively, this review provides up-to-date knowledge regarding how ferroptosis occurs and its significance in autoimmune diseases.

Type I interferons (IFN-Is) are important players in the immunopathogenesis of systemic lupus erythematosus (SLE). Pathogenic events in patients with SLE are potent triggers of IFN-I induction, yet IFN-I may induce or initiate the immunopathogenesis leading to these events. Because blocking IFN-I is effective in some clinical manifestations of SLE patients, concerns about the efficacy of anti-IFN-I therapy in patients with lupus nephritis remain. Tissues from kidney biopsies of patients with lupus nephritis revealed infiltration of various immune cells and activation of inflammatory signals; however, their correlation with renal damage is not clear, which raises serious concerns about how critical the role of IFN-I is among the potential contributors to the pathogenesis of lupus nephritis. This review addresses several issues related to the roles of IFN-I in SLE, especially in lupus nephritis, including (1) the contribution of IFN-I to the development and immunopathogenesis of SLE; (2) evidence supporting the association of IFN-I with lupus nephritis; (3) therapies targeting IFN-I and IFN-I downstream signaling molecules in SLE and lupus nephritis; (4) findings challenging the therapeutic benefits of anti-IFN-I in lupus nephritis; and (5) a perspective associated with anti-IFN-I biologics for lupus nephritis treatment. In addition to providing clear pictures of the roles of IFN-I in SLE, especially in lupus nephritis, this review addresses the lately published observations and clinical trials on this topic.

Introduction Gout is the most common inflammatory arthritis worldwide and is the only type of chronic arthritis that potentially can be ‘cured’. However, data on gout incidence, prevalence and management, assessed at multiple time points in the same population, are sparse, particularly in Asian populations. The aim of this study was to describe trends in the epidemiology of gout in the general population of Taiwan. Methods The National Health Insurance Research Database was used to identify patients with gout and to estimate the prevalence and incidence of gout for each calendar year from 2005 to 2010. The pattern of gout management was also examined. Results Of 23,371,362 beneficiaries in 2010, there were 1,458,569 prevalent and 56,595 incident cases of gout, giving a prevalence of 6.24% (95% confidence interval (CI), 6.23% to 6.25%) and an incidence of 2.74 (95% CI, 2.72 to 2.76) per 1,000 person-years. The annual percentage change (APC) of the standardised prevalence was −0.7% (95% CI, −1.7% to 0.3%; P = 0.14), suggesting that the prevalence of gout was essentially the same throughout the study period. However, The APC of incidence was −13.4 (95% CI, −16.1 to −10.6) between 2005 and 2007 and −2.1 (95% CI, −10.4 to 7.1) between 2007 and 2010. Regions with the highest prevalence and incidence were eastern coastal counties and offshore islets, where indigenous people are clustered. Among prevalent gout cases in 2010, only 22.93% (95% CI, 22.87% to 23.00%) were prescribed urate-lowering treatment (ULT), which remained unchanged between 2005 and 2010 at an APC of 0.0 (95% CI, −3.8 to 4.0). Uricosuric agents were more commonly prescribed than xanthine oxidase inhibitors in Taiwan. Conclusions In Taiwan, 1 in 16 people have gout. Whereas the incidence has decreased recently, the prevalence remains unchanged. Management of gout in Taiwan is poor, with only one in five affected people being treated with ULT.

The association between the gut microbiota and the development of lupus is unclear. We investigated alterations in the gut microbiota after induction of lupus in a murine model using viral peptide of human cytomegalovirus (HCMV). Three treatment arms for the animals were prepared: intraperitoneal injection of HCMVpp65 peptide, adjuvant alone, and PBS injection. Feces were collected before and after lupus induction biweekly for 16S rRNA sequencing. HCMVpp65 peptide immunization induced lupus-like effects, with higher levels of anti-dsDNA antibodies, creatinine, proteinuria, and glomerular damage, compared with mice treated with nothing or adjuvant only. The Simpson diversity value was higher in mice injected with HCMVpp65 peptide, but there was no difference in ACE or Chao1 among the three groups. Statistical analysis of metagenomic profiles showed a higher abundance of various families ( Saccharimonadaceae , Marinifiaceae , and Desulfovibrionaceae ) and genera ( Candidatus Saccharimonas , Roseburia , Odoribacter , and Desulfovibrio ) in HCMVpp65 peptide-treated mice. Significant correlations between increased abundances of related genera ( Candidatus Saccharimonas , Roseburia , Odoribacter , and Desulfovibrio ) and HCMVpp65 peptide immunization-induced lupus-like effects were observed. This study provides insight into the changes in the gut microbiota after lupus onset in a murine model.

Background The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. Methods Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). Results A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI ] = 4.98 [2.07, 12.0], p <0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI ] = 5.45 [2.75, 10.8], p <0.001) patients. Conclusion Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

Objective To examine familial aggregation of gout and to estimate the heritability and environmental contributions to gout susceptibility in the general population. Methods Using data from the National Health Insurance (NHI) Research Database in Taiwan, we conducted a nationwide cross-sectional study of data collected from 22 643 748 beneficiaries of the NHI in 2004; among them 1 045 059 individuals had physician-diagnosed gout. We estimated relative risks (RR) of gout in individuals with affected first-degree and second-degree relatives and relative contributions of genes (heritability), common environment shared by family members and non-shared environment to gout susceptibility. Results RRs for gout were significantly higher in individuals with affected first-degree relatives (men, 1.91 (95% CI 1.90 to 1.93); women, 1.97 (95% CI 1.94 to 1.99)) and also in those with affected second-degree relatives (men, 1.27 (95% CI 1.23 to 1.31); women, 1.40 (95% CI 1.35 to 1.46)). RRs (95% CIs) for individuals with an affected twin, sibling, offspring, parent, grandchild, nephew/niece, uncle/aunt and grandparent were 8.02 (6.95 to 9.26), 2.59 (2.54 to 2.63), 1.96 (1.95 to 1.97), 1.93 (1.91 to 1.94), 1.48 (1.43 to 1.53), 1.40 (1.32 to 1.47), 1.31 (1.24 to 1.39), and 1.26 (1.21 to 1.30), respectively. The relative contributions of heritability, common and non-shared environmental factors to phenotypic variance of gout were 35.1, 28.1 and 36.8% in men and 17.0, 18.5 and 64.5% in women, respectively. Conclusions This population-based study confirms that gout aggregates within families. The risk of gout is higher in people with a family history. Genetic and environmental factors contribute to gout aetiology, and the relative contributions are sexually dimorphic.

ObjectivesRheumatoid arthritis (RA) may adversely influence pregnancy and lead to adverse birth outcomes. This study estimated the risk of adverse fetal–neonatal and maternal pregnancy outcomes in women with RA.DesignThis was a retrospective cohort study.SettingWe used both the National Health Insurance database and the Taiwan Birth Reporting System, between 2004 and 2014.ParticipantsWe identified 2 100 143 singleton pregnancies with 922 RA pregnancies, either live births or stillbirths, delivered by 1 468 318 women.Outcome measuresORs with 95% CIs for fetal–neonatal and maternal outcomes were compared between pregnancies involving mothers with and without RA using an adjusted generalised estimating equation model.ResultsCovariates including age, infant sex, Charlson Comorbidity Index, urbanisation, income, occupation, birth year and maternal nationality were adjusted. Compared with pregnancies in women without RA, pregnancies in women with RA showed that the fetuses/neonates had adjusted ORs (95% CI) of 2.03 (1.66 to 2.50) for low birth weight (n=123), 1.99 (1.64 to 2.40) for prematurity (n=141), 1.77 (1.46 to 2.15) for small for gestational age (n=144) and 1.35 (1.03 to 1.78) for fetal distress (n=60). Pregnancies in women with RA had adjusted ORs (95% CI) of 1.24 (1.00 to 1.52) for antepartum haemorrhage (n=106), 1.32 (1.15 to 1.51) for caesarean delivery (n=398), and 3.33 (1.07 to 10.34) for disseminated intravascular coagulation (n=3), compared with women without RA. Fetuses/neonates born to mothers with RA did not have a higher risk of being stillborn or having fetal abnormalities. Pregnant women with RA did not have increased risks of postpartum death, cardiovascular complications, surgical complications or systemic organ dysfunction.ConclusionsPregnancies in women with RA were associated with higher risks of multiple adverse fetal–neonatal and maternal outcomes; however, most pregnancies in these women were successful.

IntroductionUrine-soluble CD163 (usCD163) is released from alternatively activated macrophages involved in the resolution of inflammation in glomeruli and plays an important role in glomerulonephritis. This study explored the role of usCD163 in patients with systemic lupus erythematosus (SLE).Materials and MethodsusCD163 concentrations were measured cross-sectionally in 261 SLE patients in Taiwan. Clinical and laboratory data were collected, and SLE disease activity scores were calculated to assess the correlation with usCD163.ResultsSLE patients with high usCD163 levels tended to be younger, with a higher hospital admission rate, higher prednisolone dose, lower estimated glomerular filtration rate, higher urine protein creatinine ratio (UPCR), more pyuria and hematuria, higher levels of inflammatory markers, higher rates of anemia, neutropenia, and lymphopenia, lower complement 3 (C3) levels, higher anti-double-stranded DNA antibody (anti-dsDNA Ab) levels, and higher disease activity scores (p < 0.05). usCD163 levels were significantly higher in patients with active lupus nephritis (LN) than in those with extrarenal or inactive SLE and correlated with UPCR, disease activity, and anti-dsDNA Ab levels. SLE patients with high usCD163 levels tended to have a higher chronic kidney disease stage.Discussion and conclusionThe usCD163 level correlates with the severity of LN and disease activity in renal SLE.

Human cytomegalovirus (HCMV) has been linked to the triggering of systemic lupus erythematosus (SLE). We proposed that B cell epitope region of HCMV phosphoprotein 65 (HCMVpp65) 422–439 mimics an endogenous antigen and initiates lupus-like autoimmunity. Amino acid homology between HCMVpp65 422-439 and TAF9 134-144 (TATA-box binding protein associated factor 9, TAF9) was investigated using a similarity search in NCBI protein BLAST program (BLASTP). A murine model was used to confirm their antigenicity and ability to induce lupus-like symptoms. HCMVpp65 422-439 induced immune responses with the presence of specific antibodies against HCMVpp65 422-439 and TAF9 134-144 , as well as anti-nuclear and anti-double-stranded (ds)DNA antibodies that are characteristic of SLE. In addition, the majority of HCMVpp65 422-439 and TAF9 134-144 immunized mice developed proteinuria, and their renal pathology revealed glomerulonephritis with typical abnormalities, such as mesangial hypercellularity and immune complex deposition. Immunoglobulin eluted from the glomeruli of HCMVpp65 422-439 immunized mice showed cross-reactivity with TAF9 134-144 and dsDNA. Increased anti-TAF9 antibody activity was also observed in the sera from SLE patients compared with healthy people and disease controls. Molecular mimicry between HCMVpp65 peptide and host protein has the potential to drive lupus-like autoimmunity. This proof-of-concept study highlights the mechanisms underlying the link between HCMV infection and the induction of SLE.

This study aims to investigate the prevalence and predictive risk factors of malignancy in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 192 PM/DM patients followed up in a medical center between January 2000 and December 2013 were reviewed. Among the 192 patients, 33 patients (17.2 %) had associated cancer. Both PM and DM are significantly associated with cancer, although the risk of cancer appears to be somewhat higher among patients with DM (23.0 %) than among those with PM (8.9 %). Nasopharyngeal cancer (30.3 %) and breast cancer (18.2 %) comprised the most common malignant diseases associated with PM/DM. Univariate analysis showed that an older age at PM/DM onset, heliotrope rash, Gottron’s sign, dysphagia, and low creatine phosphokinase (CPK) level were associated with increased malignancy. Multivariate analysis revealed that independent predictors of malignancy in PM/DM were age >40 years at PM/DM onset (adjusted OR 3.44; 95 % CI 1.08–10.98; p  = 0.037) and heliotrope rash (adjusted OR 2.96; 95 % CI 1.04–8.43; p  = 0.042). During the follow-up period, 66 (34.4 %) patients died and the overall patient survival rates were 83.1 % at 1 year, 78.9 % at 2 years, 74.2 % at 5 years, and 65.5 % at 10 years. This study demonstrates a high frequency of malignancy (17.2 %) in DM/PM patients. Nasopharyngeal cancer and breast cancer were the most common cancer types in DM/PM patients in our study. Cancer screening should be offered to patients with newly diagnosed DM/PM. Moreover, all patients should be evaluated for the possibility of an underlying malignancy during treatment.