Targeting ferroptosis in autoimmune diseases: Mechanisms and therapeutic prospects.

Ferroptosis is a form of regulated cell death that relies on iron and exhibits unique characteristics, including disrupted iron balance, reduced antioxidant defenses, and abnormal lipid peroxidation. Recent research suggests that ferroptosis is associated with the onset and progression of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). However, the precise effects and molecular mechanisms remain incompletely understood. This article presents an overview of how ferroptosis mechanisms contribute to the development and advancement of autoimmune diseases, as well as the involvement of various immune cells in linking ferroptosis to autoimmune conditions. It also explores potential drug targets within the ferroptosis pathway and recent advancements in therapeutic approaches aimed at preventing and treating autoimmune diseases by targeting ferroptosis. Lastly, the article discusses the challenges and opportunities in utilizing ferroptosis as a potential therapeutic avenue for autoimmune disorders.

Causal Relationship of Skin Microbiota on Psoriasis: A Mendelian Randomization Study.

Objective: Epidemiological investigations have indicated an association between skin microbiota imbalance and psoriasis, however, the causal relationship has not been confirmed through Mendelian randomization (MR). MR employed genetic instrumental variables (IVs) to evaluate the causal relationship between skin microbiota and psoriasis, providing new insights for potential treatments. Methods: Summary statistics for psoriasis and related traits were available from FinnGen R10 and United Kingdom Biobank (UKB) consortium. The genome-wide association studies (GWAS) on skin microbiota in three skin microenvironments came from two population-based German cohorts. Several selection processes were used to determine the optimal instrumental variables. Five MR methods were performed and different sensitivity analyses approaches yield robustness evidence under different assumptions. Results: 449 SNPs were employed as IVs for 53 bacterial genera, with F-statistics between 20.18 and 42.44, indicating no evidence of weak instrument bias. Bacteroides was associated with psoriasis from UKB in IVW (OR, 95% CI: 0.914, 0.869-0.961; P < 0.001, PB-H = 0.007). The taxon was also associated with psoriasis vulgaris (IVW: OR, 95% CI, 0.918, 0.872-0.967; P = 0.001, P B-H = 0.054) and psoriasis and related disorders (IVW: OR, 95% CI, 0.915, 0.875-0.957; P < 0.001, P B-H = 0.008). Consistent causal estimates were identified in terms of both magnitude and direction, indicating a protective effect of Bacteroides. Conclusion: The MR study found that Bacteroides in the antecubital fossa may protect against psoriasis, offering genetic proof that skin microbiota helps prevent the condition.

Effects of exogenous deoxyribonuclease I in collagen antibody-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with a high concentration of extracellular DNA (ecDNA). This could be a consequence of the inflammation, but the ecDNA could also be involved in the unknown etiopathogenesis of RA. Clearance of ecDNA is hypothesized to prevent the development of RA. This study aimed to analyze the effects of exogenous deoxyribonuclease I (DNase I) administration in an animal model of RA. METHODS: The collagen antibody-induced arthritis (CAIA) model of RA was induced in adult female DBA/1J mice. CAIA mice were treated with saline or DNase I (10 mg/kg) every 12 h for the whole duration of the experiment. Arthritic scores were assessed. Paw volume and temperature were assessed using a plethysmometer and a thermal camera, respectively. Plasma ecDNA and its subcellular origin were analyzed using fluorometry and real-time PCR. DNase activity was quantified with single radial enzyme diffusion method. RESULTS: The CAIA model was successfully induced as proved by a higher volume, temperature and the overall arthritis score in comparison to controls. The administration of DNase I resulted in a nearly two-fold increase in serum DNase activity. Still, it did affect neither plasma ecDNA, nor the arthritis score or other measures of joint inflammation. CONCLUSION: Our results suggest that exogenous DNase I does not prevent the development of CAIA in mice. Whether this is true for other animal models of arthritis or clinical RA requires further research. EcDNA does not seem to be involved in the pathogenesis of CAIA. Additional studies are also needed to elucidate the role of ecDNA in the development of RA, focusing especially on its origin and inhibition of ecDNA release.

Therapeutic potentials of adoptive cell therapy in immune-mediated neuropathy.

Immune-mediated neuropathy (IMN) is a group of heterogenous neuropathies caused by intricate autoimmune responses. For now, known mechanisms of different IMN subtypes involve the production of autoantibodies, complement activation, enhanced inflammation and subsequent axonal/demyelinating nerve damages. Recent therapeutic studies mainly focus on specific antibodies and small molecule inhibitors previously approved in rheumatoid diseases. Initial strategies based on the pathophysiologic features of IMN should be explored. Adoptive cell therapy (ACT) refers to the emerging immunotherapies in which circulating immunocytes are collected from peripheral blood and modified with killing and immunomodulatory capacities. It consists of chimeric antigen receptor-T cell therapy, T cell receptor-engineered T cell, CAR-Natural killer cell therapy, and others. In the last decade, ACT has demonstrated extraordinary potentials in treating cancers, infectious diseases and autoimmune diseases. Versatile combinations of targets, chimeric domains and effector cells greatly empower ACT to treat complicated immune disorders. In this review, we summarized the advances of ACT and envisioned suitable strategies for different IMN subtypes.

Does autoimmune diseases increase the risk of frailty? A Mendelian randomization study.

Background: The causality of autoimmune diseases with frailty has not been firmly established. We conducted this Mendelian randomization (MR) study to unveil the causal associations between autoimmune diseases with frailty. Methods: A MR analyses were performed to explore the relationships between autoimmune disease and frailty, using summary genome-wide association statistics. Results: Through a comprehensive and meticulous screening process, we incorporated 46, 7, 12, 20, 5, and 53 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for hypothyroidism, hyperthyroidism, rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), and overall autoimmune disease, respectively. Our analysis revealed that hypothyroidism (OR = 1.023, 95% CI: 1.008-1.038, p = 0.0015), hyperthyroidism (OR = 1.024, 95% CI: 1.004-1.045, p = 0.0163), RA (OR = 1.031, 95% CI: 1.011-1.052, p = 0.0017), T1D (OR = 1.011, 95% CI: 1.004-1.017, p = 0.0012), and overall autoimmune disease (OR = 1.044, 95% CI: 1.028-1.061, p = 5.32*10^-8) exhibited a positive causal effect on frailty. Conversely, there may be a negative causal association between MS (OR = 0.984, 95% CI: 0.977-0.992, p = 4.87*10^-5) and frailty. Cochran's Q test indicated heterogeneity among IVs derived from hypothyroidism, hyperthyroidism, T1D, and overall autoimmune diseases. The MR-Egger regression analyzes revealed an absence of horizontal pleiotropy in any of the conducted analyses. Conclusion: This study elucidates that hypothyroidism, hyperthyroidism, RA, T1D, and overall autoimmune disease were linked to an elevated risk of frailty. Conversely, MS appears to be associated with a potential decrease in the risk of frailty.

Sarcoidosis in a young adult: A rare sequelae of COVID-19 infection.

Key Clinical Message: This case illustrates sarcoidosis as a potential complication of COVID-19, highlighting the need for a comprehensive diagnostic approach, including histopathology and prolonged monitoring, to distinguish it from post-COVID fibrosis. Further research is crucial to elucidate these associations and understand their underlying mechanisms. Abstract: Severe Acute Respiratory Syndrome Coronavirus- 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus, causes COVID-19 and has been linked to autoimmune disorders. Sarcoidosis is a multi-system disease that is frequently triggered by infections. It is characterized by non-necrotizing granulomas in multiple organs. We present a case of sarcoidosis as rare sequelae of COVID-19. A 26-year-old man presented with mild COVID-19 symptoms, followed by prolonged fever and cough despite initial therapy, prompting a provisional diagnosis of post-COVID fibrosis. A subsequent assessment at a tertiary hospital revealed dyspnea, weight loss, and abnormal chest imaging, all of which were consistent with pulmonary sarcoidosis with pulmonary tuberculosis as a differential diagnosis. A biopsy taken during bronchoscopy confirmed pulmonary sarcoidosis and treatment with inhalation steroids resulted in symptom relief, which was followed by remission with oral steroid therapy. Sarcoidosis is a systemic disease of unknown etiology, characterized by non-necrotizing granulomas in multiple organs. It may be triggered by infections and involves an abnormal immune response. COVID-19 can potentially initiate sarcoidosis, with both sharing common immune mechanisms. Diagnosis involves imaging and biopsy, and treatment typically includes glucocorticoids and regular monitoring. This case report emphasizes the potential link between COVID-19 and autoimmune conditions like sarcoidosis, highlighting the need for a comprehensive diagnostic approach and long-term observation to distinguish between sarcoidosis and post-COVID fibrosis.

Survival after surgery for lung cancer among patients with autoimmune diseases.

PURPOSE: While patients with autoimmune diseases (ADs) are at high risk for developing specific malignancies, including lung cancer, ADs may protect against the development of cancer through increased immune cell activity in tumors. This study aimed to investigate whether the presence of ADs affects surgical outcomes and survival after surgery for lung cancer. METHODS: The medical records of 1236 patients who underwent surgery for non-small cell lung cancer between 2007 and 2018 were retrospectively reviewed. Perioperative and long-term outcomes were compared between patients with and without ADs using propensity score matching. RESULTS: Among the included patients, 115 with ADs and 1121 without ADs underwent surgery. Using 1-to-1 propensity score matching, 114 pairs were selected. Although there were no significant differences in the perioperative outcomes of the two groups, the overall and relapse-free survival rates were significantly lower in the group with ADs than in the group without ADs. CONCLUSIONS: Surgery for lung cancer can be performed without increasing the complications in patients with ADs. However, the long-term outcomes were significantly worse in patients with ADs than in those without ADs, suggesting that close follow-up for lung cancer and careful whole-body examination might be needed for patients with ADs.

Detection and differentiation of antinuclear antibodies in serum of dengue suspected patients with or without systemic autoimmune disease in Kolkata, India.

The pathophysiology of dengue may be influenced by antibodies released during infection. Several autoimmune diseases are accompanied by antinuclear antibodies (ANAs) but 8-10% of the general population have positive ANA tests. To test the hypothesis that an ANA-positive test indicates an immune dysregulated state that modifies the risk for certain clinical disorders in people with or without an autoimmune disease, we examined the various ANA profiles and their relationships to various autoimmune disorders, as well as the severity of these relationships, in patients infected with dengue fever. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) methods were used. Indirect immunofluorescence assay (IIFA) and line immunoassay (LIA) were performed to detect and differentiate the ANAs among dengue infected patients. Out of 135 dengue virus-positive patients, 94.07% were positive by ELISA and 5.93% positive by RT-PCR method. ANAs by IIFA and LIA were detected in 54.8% and 18.5% of the dengue positive patients, respectively, and 10.3% and 7.1% of the 126 dengue negative patients, respectively. This study showed that dengue was associated with an increased risk of autoimmune myositis and mixed connective tissue disease (MCTD), a rare complication of dengue. The risk of other autoimmune diseases did not seem to increase after DENV infection.

Cushing's syndrome developing myasthenia gravis with takotsubo cardiomyopathy after adrenalectomy: a case report.

BACKGROUND: Several cases of autoimmune disease onset after treatment for Cushing's syndrome have been reported. CASE PRESENTATION: Herein, we report a case of myasthenia gravis crisis in a 51-year-old woman 2 months after adrenalectomy for adrenal Cushing's syndrome accompanied by takotsubo cardiomyopathy. The resolution of excessive endogenous cortisol after adrenalectomy may have triggered the onset of previously latent myasthenia gravis. CONCLUSIONS: Observing the similarities in symptoms between myasthenia gravis and adrenal crisis, which can sometimes be challenging to differentiate, is essential. Moreover, the presence of takotsubo cardiomyopathy as a non-motor manifestation of myasthenic crisis must be noted.

Fetal and Maternal Outcomes in a Cohort of Patients With Primary Sjogren's Syndrome: An Observational Study.

Background Pregnant women with primary Sjogren's syndrome (PSS) have a high incidence of maternal and fetal complications due to immunological variations caused by maternal antibodies (anti-Sjogren's-syndrome-related antigen A (SSA) and anti-anti-Sjogren's-syndrome-related antigen B (SSB) crossing the placenta from the 12th week of gestation, mediating the tissue damage. A multidisciplinary approach is required in the management of such patients. Data regarding the effects of PSS on pregnancy are deficient in the Indian context. Methods This was a retrospective observational study on the maternal and fetal outcomes of PSS on a cohort of pregnant women treated at our tertiary care center between 2011 and 2020. Patients who satisfied the criteria for PSS were included, and patients with other associated autoimmune disorders were excluded. Maternal age, number of miscarriages, prior obstetric history, and maternal and fetal complications were recorded and statistically analyzed. Results There were 16 pregnancies in 10 women with PSS (incidence: 1/1,000 pregnancies/year) in our study. The mean gestational age of the mother at presentation was 31 ± 9.0 weeks. Oligohydramnios in five (11.8), intrauterine fetal demise (IUFD) in two (11.8), and first-trimester medical termination of pregnancy (MTP) in four (23.5) were noted. The weight of neonates was 2.3 ± 0.8 kg, and the mean duration of neonatal intensive care (NICU) stay was seven days. Fetal echo revealed congenital heart block (CHB), with six (50.0%) complete and one (8.3%) incomplete (p = 0.004). One baby needed a permanent pacemaker. Conclusion Maternal and fetal complications are high in our set of mothers with PSS. Early detection, regular follow-up, and a multidisciplinary approach may improve the outcome.

Maternal autoimmune disease and offspring risk of haematological malignancies: a case-control study.

Background: Autoimmune diseases are known to be associated with an increased risk of cancer. Whether maternal immune dysregulation can have an impact on the development of haematological malignancies in offspring remains uncertain. Therefore, we explored the association between offspring risk of haematological malignancies and maternal autoimmune disease using a real-world nationwide population-based study. Methods: In this case-control study, we identified 2172 children with haematological malignancies between 2004 and 2019 from Taiwan's National Health Insurance program and compared them with population-based controls without haematologic malignancies, who were matched with each individual at a ratio of 1:4. The medical information of the autoimmune mothers were obtained from the Taiwan Maternal and Child Health Database. Conditional logistic regression was used to estimate the odds ratio for haematologic malignancy in offspring. Furthermore, subgroup and stratified analyses were conducted. Findings: Among the rheumatologic diseases in our study, Crohn's disease was the most common disease both in the haematological malignancy group (1.1%) and the control group (0.9%). In multivariable analysis, the odds ratio for haematological malignancy in offspring with maternal autoimmune diseases was 1.2 (95% confidence interval [CI] 0.91-1.58). The overall risk of haematologic malignancy was not significantly higher when adjusted for specific risk factors, including neonatal age, maternal age, family income, urbanization, maternal occupation, birth weight, or maternal comorbidity, except for prematurity. When comparing different autoimmune diseases among haematological malignancies and the control group, maternal psoriatic arthritis/psoriasis had the highest adjusted overall risk for haematological malignancies (adjusted OR 2.11, CI 0.89-5), followed by ankylosing spondylitis (adjusted OR 1.45, CI 0.7-3), autoimmune thyroiditis (OR 1.26, CI 0.57-2.81), systemic lupus erythematosus (OR 1.21, CI 0.48-3.02), Crohn's disease (OR 1.19, CI 0.75-1.9), and Sjogren's syndrome (OR 1.18, CI 0.65-2.15), but no significance was reached in these analyses. Multivariable analysis of risk factors associated with haematological malignancy subtypes was done. It showed no associations between maternal autoimmune disease and childhood haematological malignancies. Interpretation: We found no significant relationship between maternal autoimmune disease and childhood haematological malignancies. The influence of maternal immune dysregulation on the next generation with respect to haematological malignancies development may be limited. Funding: There was no funding source for this study.

Biological function of type 1 regulatory cells and their role in type 1 diabetes.

The collapse of immune homeostasis induces type 1 diabetes (T1D). In T1D, uncontrolled immune attacks against islet ß cells reduce insulin secretion, resulting in hyperglycaemia and various complications. Type 1 regulatory (Tr1) cell therapy is a promising approach for the treatment of T1D. Tr1 cells are a subset of regulatory T (Treg) cells that are characterised by high interleukin-10 secretion and forkhead box protein P3 non-expression. Tr1 cells are reduced and have impaired function in patients with T1D. Immunotherapy is used to treat various diseases, and Treg cells have been applied to treat T1D in animal models and clinical trials. However, the safety and efficacy of Tr1 cells in treating diabetes and other diseases remain unclear. In this review, we aim to investigate the identification and biological function of Tr1 cells and related studies on immune diseases; additionally, we discuss the feasibility, limitations, and possible solutions of Tr1 cell therapy in T1D. This review shows that T1D is caused by an immune imbalance where defective Tr1 cells fail to control effector T cells, leading to the destruction of islet ß cells. However, Tr1 cell therapy is safe and effective for other immune diseases, suggesting its potential for treating T1D.

Mendelian randomization identifies causal associations between GWAS-associated bacteria and their metabolites and rheumatoid arthritis.

Background: Accumulating evidence suggests that an imbalance of gut microbiota is commonly observed in patients with rheumatoid arthritis (RA). However, it remains unclear whether gut microbiota dysbiosis is a cause or consequence of RA, and the mechanisms by which gut dysbiosis contributes to RA have not been fully understood. This study aimed to investigate the causal relationship between gut microbiota and metabolites with RA. Methods: A two-sample Mendelian randomization analysis was performed to estimate the causality of gut microbiota and metabolites on RA. A genome-wide association study (GWAS) of 211 gut microbiota and 217 metabolites was used as the exposure, whereas RA was treated as the outcome. Inverse variance weighted (IVW) was regarded as the primary approach for calculating causal estimates. MR Egger method, Weighted median method, Simple mode method, and weighted mode method were used for sensitive analysis. Metabolic pathway analysis was performed via the web-based Metaconflict 5.0. Additionally, an animal study was undertaken to evaluate the results inferred by Mendelian randomization. Result: This study indicated that six gut microbiota taxa (RuminococcaceaeUCG013, Erysipelotrichia, Erysipelotrichaceae, Erysipelotrichales, Clostridia, and Veillonellaceae) were estimated to exert a positive impact on RA. Conversely, seven gut microbiota taxa (Oxalobacter, Cyanobacteria, RuminococcaceaeUCG002, LachnospiraceaeUCG010, Christensenellaceae, Oxalobacteraceae, Anaerostipes) were estimated to exert a negative impact on RA. Three metabolites, namely indole-3-propionate (IPA), glycine and sphingomyelin (SM 16:1), were found to be linked to lower RA risk, while five metabolites (argininosuccinate, CE 20_4, TAG 58_8, PC 40_6, and LPC 20_4) were linked to higher RA risk. Additionally, four metabolic pathways were identified by metabolic pathway analysis. The collagen-induced arthritis (CIA) rats exhibited a higher relative abundance of Class_Clostridia and a lower abundance of Genus_Lachnospiraceae (p < 0.05) than the healthy controls. Conclusion: This study identified causal associations between specific gut microbiota, metabolites, and RA. These findings support the significant role of gut microbiota and metabolites in RA pathogenesis.

Agonist antibody to MuSK protects mice from MuSK myasthenia gravis.

Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.

Excess of severe autoimmune diseases in women with premature ovarian insufficiency: a population-based study.

STUDY QUESTION: Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis? SUMMARY ANSWER: Women with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis. WHAT IS KNOWN ALREADY: It has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%. STUDY DESIGN, SIZE, DURATION: This population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case-control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970-2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison's disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years. LIMITATIONS, REASONS FOR CAUTION: This study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher. WIDER IMPLICATIONS OF THE FINDINGS: Severe autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Impact of extrathyroidal autoimmune diseases on clinical features and the efficacy of Iodine-131 therapy in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of this study is to assess the impact of extrathyroidal autoimmune diseases (ADs) on the clinical characteristics and efficacy of iodine-131 (131I) therapy in patients with differentiated thyroid cancer (DTC). METHODS: Patients with DTC who were received 131I therapy simultaneously were classified into the combination group (n = 35) and noncombination group (n = 146) depending on the presence of ADs. The clinical characteristics, such as gender, age, tumor lesions, lymph node metastasis, distant metastasis, 131I therapy efficacy, and use of levothyroxine, were compared between the two groups. Statistical analysis was conducted using SPSS 26.0 and R 4.0.3. RESULTS: There was a statistically significant difference in age between the combination and noncombination groups (t = -2.872, p < .01), and the optimal cutoff value was 50.5 years. Propensity score matching was completed effectively on a total of 121 patients, using age as the matching factor, comprising 32 cases in the combination group and 80 cases in the noncombination group. The baseline demographic features of the two groups were equivalent after matching (p > .05), and there was no significant difference in the therapeutic efficacy of 131I between the two groups (p > .05). In the subgroup analysis involving patients aged great than 50.5 years, the levothyroxine/weight (µg/kg) was increased in the combination group, and the difference was statistically significant (p < .05). CONCLUSION: While extrathyroidal ADs may enhance the detection of DTC among elderly women, they have no impact on the clinical characteristics of thyroid cancer or the efficacy of 131I therapy. ADs may necessitate higher per-unit dosages of levothyroxine in patients with DTC, regardless of the clinical status. Consequently, it is not essential for nuclear medicine physicians to consider the presence of ADs when designing treatment plans for patients with DTC.

Histological differences related to autophagy in the minor salivary gland between primary and secondary types of Sjögren's syndrome.

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging.

Histopathologic spectrum of morphea: a single-center retrospective study.

Morphea is a rare autoimmune disease that often affects skin and subcutaneous tissues. The aim of this study was to determine the association between patient demographic parameters, lesion site, clinical subtype of morphea, and histological findings. Between 2016 and 2022, we investigated 78 patients with morphea at the Department of Pathology, Prof. Dr. Cemil Tascioglu City Hospital in Turkey. Case-specific hematoxylin and eosin stain slides were obtained from the pathology archive and assessed blindly by two pathologists. Flattening of rete ridges, location of inflammatory infiltrate, grade of inflammatory infiltrate, presence of plasma cells, presence of eosinophils, homogenization of dermal collagen, decrease of skin appendages, basal pigmentation and melanin incontinence were evaluated. Statistical analyses were performed using SPSS Statistics v.20 (IBM, Armonk, NY, USA). The most common clinical presentation was plaque type (87.5%), while histopathological findings included homogenization of dermal collagen (100%) and decrease of skin appendages (98.7%). Flattening of the rete ridges was observed in 46.2% of patients. Severity of the inflammatory infiltrate was found to be higher in these patients (p=0.028). Basal pigmentation was observed in 59% of patients. Line sign was more common in lower extremity lesions among all localizations (p=0.015). The histopathologic features of morphea are variable and confusing. Particularly, in cases with collagen homogenization, morphea should be considered in differential diagnosis with clinical correlation. In addition, the line sign could be helpful for identifying lesions located in the lower extremities.