Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study.

Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes. Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations. Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases. Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.

Toxic metals and pediatric clinical immune dysfunction: A systematic review of the epidemiological evidence.

BACKGROUND: Children are at high risk for exposure to toxic metals and are vulnerable to their effects. Significant research has been conducted evaluating the role of these metals on immune dysfunction, characterized by biologic and clinical outcomes. However, there are inconsistencies in these studies. The objective of the present review is to critically evaluate the existing literature on the association between toxic metals (lead, mercury, arsenic, and cadmium) and pediatric immune dysfunction. METHODS: Seven databases (PubMed (NLM), Embase (Elsevier), CINAHL (Ebsco), Web of Science (Clarivate Analytics), ProQuest Public Health Database, and ProQuest Environmental Science Collection) were searched following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in February 2024. Rayaan software identified duplicates and screened by title and abstract in a blinded and independent review process. The remaining full texts were reviewed for content and summarized. Exclusions during the title, abstract, and full-text reviews included: 1) not original research, 2) not epidemiology, 3) did not include toxic metals, 4) did not examine an immune health outcome, or 5) not pediatric (>18 years). This systematic review protocol followed the PRISMA guidelines. Rayaan was used to screen records using title and abstract by two blinded and independent reviewers. This process was repeated for full-text article screening selection. RESULTS: The search criteria produced 7906 search results; 2456 duplicate articles were removed across search engines. In the final review, 79 studies were included which evaluated the association between toxic metals and outcomes indicative of pediatric immune dysregulation. CONCLUSIONS: The existing literature suggests an association between toxic metals and pediatric immune dysregulation. Given the imminent threat of infectious diseases demonstrated by the recent COVID-19 epidemic in addition to increases in allergic disease, understanding how ubiquitous exposure to these metals in early life can impact immune response, infection risk, and vaccine response is imperative.

Evaluating the effectiveness of the Charlson Comorbidity Index in predicting immune checkpoint inhibitor-related adverse events.

Aims: Our study aimed to evaluate the effectiveness of the Charlson Comorbidity Index (CCI) in predicting immune-related adverse events (irAEs) in solid tumor patients receiving immunotherapy. Patients & methods/materials: The CCI score at the time of initiation of immunotherapy was calculated in 164 solid tumor patients receiving immunotherapy and the correlation between the CCI score and immune toxicity was evaluated. Results: A significant relationship was found between CCI score and irAEs in lung cancer and renal cell cancer patients. In malignant melanoma, no significant relationship was found between the CCI score and the occurrence of irAEs. Conclusion: We argue that CCI can be used to predict irAEs, but we believe that a specific comorbidity index that includes autoimmune diseases should be developed.

The aim of our study was to find a scale that can predict which patients are most likely to develop side effects of immunotherapy drugs, which work by stimulating the immune system. We evaluated whether the Charlson Comorbidity Index ­ a scale which already exists to predict the mortality of patients with serious conditions ­ was able to predict whether people with cancer experienced negative side effects from immunotherapy drugs. We found that it may be useful to predict these negative reactions in patients receiving immunotherapy to treat lung and kidney cancer. This means that the Charlson Comorbidity Index might be useful for patients with these types of cancers, to help predict whether they will experience negative side effects. This could help doctors and patients to take better precautions and be more prepared in the event that these side effects do occur.

Immune-mediated diseases and risk of incident cardiovascular diseases: a prospective cohort study.

OBJECTIVES: Disorders of immune system may impact cardiovascular health; however, comprehensive study is lacking. We aimed to analyse the association of total and 20 individual immune-mediated diseases (IMDs) with risk of incident cardiovascular disease (CVD). METHODS: In this prospective cohort study, 414 495 participants (55.6% women; mean age 55.9 years) from UK Biobank with baseline assessment at 2006-10 were included. Among them, 21 784 participants had prevalent IMDs. Information on IMDs at baseline and incidence of CVDs during follow-up were recorded. Cox proportional hazard models were used to estimate the association between IMDs and CVDs risk. RESULTS: During the median follow-up of 12.1 years, there were 6506 cases of CVDs in participants with IMDs (29.9%) and 77 699 cases in those without IMDs (19.8%). After multivariable adjustment, participants with IMDs were significantly associated with an increased risk of total CVD [hazard ratio (HR) 1.57; 95% CI 1.52-1.61]. Among the 20 IMDs, 16 showed significant associations with CVD (all P < 0.0025 after Bonferroni correction), with HR ranging from 1.34 (1.16-1.54) for celiac disease to 2.75 (2.10-3.61) for SLE. Participants with any IMD exposure had a higher risk of all individual CVD events, with HR ranging from 1.34 (1.14-1.58) for cerebral hemorrhage to 1.80 (1.54-2.11) for pericardium diseases. IMD duration <5, 5-10 and >10 years was associated with 55%, 59% and 56% increased risk of total CVD, respectively. CONCLUSION: Total and individual IMDs were associated with an increased risk of overall CVDs. It is important to consider primary prevention of CVD in patients with IMD and dysregulation of immune system in the cardiovascular health.

Inborn Errors of Immunity and Efforts to Diagnose Affected Children in the Absence of Training and Specialty Practice in Clinical Immunology in Ethiopia: a Brief Report.

Four in five children with inborn errors of immunity globally remain undiagnosed. These figures are disproportionally high in low-income countries like Ethiopia. Apart from the inclusion of basic overviews of these disorders in to postgraduate pediatric curricula, little effort has been placed in to establishing clinical immunology training programs. This report summarizes the existing epidemiology of inborn errors of immunity in Ethiopia, unique presentations in Ethiopian children, challenges faced in diagnosing them, and efforts to improve their management.

Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy.

INTRODUCTION: Biomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments. METHODS: We carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). RESULTS: Homozygosity at one or more HLA-I loci, but not HLA-II, was associated with a reduced risk of irAE (relative risk (RR) = 0.61, 95% CI 0.33-0.95, P = 0.035) especially pneumonitis or any grade 3 toxicity. Patients with HLA-A03 supertype had a higher risk of developing irAE (RR = 1.42, 95% CI 1.02-2.01, P = 0.039). The occurrence of any irAE was significantly associated with improved CBR (RR = 1.48, P < 0.0001), PFS (HR = 0.45, P = 0.0003) and OS (HR = 0.34, P < 0.0001). CONCLUSIONS: Homozygosity at one or more HLA-I loci may serve as biomarker to predict patients who are unlikely to experience severe irAEs among patients with NSCLC and treated with anti-PD1/PDL1, but less likely to derive clinical benefit. Patients with HLA-I homozygous might benefit from additional therapy.

Cardiovascular Implications of Immune Disorders in Women.

Immune responses differ between men and women, with women at higher risk of developing chronic autoimmune diseases and having more robust immune responses to many viruses, including HIV and hepatitis C virus. Although immune dysregulation plays a prominent role in chronic systemic inflammation, a key driver in the development of atherosclerotic cardiovascular disease (ASCVD), standard ASCVD risk prediction scores underestimate risk in populations with immune disorders, particularly women. This review focuses on the ASCVD implications of immune dysregulation due to disorders with varying global prevalence by sex: autoimmune disorders (female predominant), HIV (male-female equivalent), and hepatitis C virus (male predominant). Factors contributing to ASCVD in women with immune disorders, including traditional risk factors, dysregulated innate and adaptive immunity, sex hormones, and treatment modalities, are discussed. Finally, the need to develop new ASCVD risk stratification tools that incorporate variables specific to populations with chronic immune disorders, particularly in women, is emphasized.

Immune-Mediated Diseases Associated With Cancer Risks.

IMPORTANCE: Immune regulation is important for carcinogenesis; however, the cancer risk profiles associated with immune-mediated diseases need further characterization. OBJECTIVE: To assess the prospective association of 48 immune-mediated diseases with the risk of total and individual cancers and the prospective association of organ-specific immune-mediated diseases with the risk of local and extralocal cancers. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study used data from the UK Biobank cohort study on adults aged 37 to 73 years who were recruited at 22 assessment centers throughout the UK between January 1, 2006, and December 31, 2010, with follow-up through February 28, 2019. EXPOSURES: Immune-mediated diseases. MAIN OUTCOMES AND MEASURES: The association of immune-mediated diseases with risk of cancer was assessed with multivariable hazard ratios (HRs) and 95% CIs after adjusting for various potential confounders using time-varying Cox proportional hazards regression. Heterogeneity in the associations of organ-specific immune-mediated diseases with local and extralocal cancers was assessed using the contrast test method. RESULTS: A total of 478 753 participants (mean [SD] age, 56.4 [8.1] years; 54% female) were included in the study. During 4 600 460 person-years of follow-up, a total of 2834 cases of cancer were documented in 61 496 patients with immune-mediated diseases and 26 817 cases of cancer in 417 257 patients without any immune-mediated diseases (multivariable HR, 1.08; 95% CI, 1.04-1.12). Five of the organ-specific immune-mediated diseases were significantly associated with higher risk of local but not extralocal cancers: asthma (HR, 1.34; 95% CI, 1.14-1.56), celiac disease (HR, 6.89; 95% CI, 2.18-21.75), idiopathic thrombocytopenic purpura (HR, 6.94; 95% CI, 3.94-12.25), primary biliary cholangitis (HR, 42.12; 95% CI, 20.76-85.44), and autoimmune hepatitis (HR, 21.26; 95% CI, 6.79-66.61) (P < .002 for heterogeneity). Nine immune-mediated diseases were associated with an increased risk of cancers in the involved organs (eg, asthma with lung cancer [HR, 1.34; 95% CI, 1.14-1.57; P < .001] and celiac disease with small intestine cancer [HR, 6.89; 95% CI, 2.18-21.75; P = .001]); 13 immune-mediated diseases were associated with an increased risk of cancer in the near organs (eg, Crohn disease with liver cancer: [HR, 4.01; 95% CI, 1.65-9.72; P = .002]) or distant organs (eg, autoimmune hepatitis with tongue cancer [HR, 27.75; 95% CI, 3.82-199.91; P = .001]) or in different systems (eg, idiopathic thrombocytopenic purpura with liver cancer [HR, 11.96; 95% CI, 3.82-37.42; P < .001]). CONCLUSIONS AND RELEVANCE: In this cohort study, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers. The associations for individual immune-mediated diseases were largely organ specific but were also observed for some cancers in the near and distant organs or different systems. Our findings support the role of local and systemic immunoregulation in cancer development.

Clinical outcomes and temporal trends of immunological and non-immunological rare diseases in adult kidney transplant.

BACKGROUND: Rare diseases (RDs) encompass many difficult-to-treat conditions with different characteristics often associated with end-stage renal disease (ESRD). However, data about transplant outcomes in adult patients are still lacking and limited to case reports/case series without differentiation between immunological/non-immunological RDs. METHODS: Retrospective analysis among all adult kidney transplanted patients (KTs) with RDs (RDsKT group) performed in our high-volume transplantation center between 2005 and 2016. RDs were classified according to the Orphanet code system differentiating between immunological and non-immunological diseases, also comparing clinical outcomes and temporal trends to a control population without RDs (nRDsKT). RESULTS: Among 1381 KTs, 350 patients (25.3%) were affected by RDs (RDsKTs). During a f/up > 5 years [median 7.9 years (4.8-11.1)], kidney function and graft/patient survival did not differ from nRDsKTs. Considering all post-transplant complications, RDsKTs (including, by definition, patients with primary glomerulopathy except on IgA nephropathy) have more recurrent and de-novo glomerulonephritis (14.6% vs. 9.6% in nRDsKTs; p = 0.05), similar rates of de-novo cancers, post-transplant diabetes, dysmetabolism, hematologic disorders, urologic/vascular problems, and lower infectious episodes than nRDsKTs (63.7% vs 72.7%; p = 0.013). Additional stratification for immunological and non-immunological RDsKTs or transplantation periods (before/after 2010) showed no differences or temporal trends between groups. CONCLUSIONS: Kidney transplant centers are deeply involved in RDs management. Despite their high-complex profile, both immunological and non-immunological RDsKTs experienced favorable patients' and graft survival.

Social Stressors, Arboviral Infection, and Immune Dysregulation in the Coastal Lowland Region of Ecuador: A Mixed Methods Approach in Ecological Perspective.

Aedes aegypti, the mosquito that transmits arboviral diseases such as dengue (DENV), chikungunya (CHIKV), and Zika viruses (ZIKV), is present in tropical and subtropical regions of the world. Individuals at risk of mosquito-borne disease (MBD) in the urban tropics face daily challenges linked to their socio-environment conditions, such as poor infrastructure, poverty, crowding, and limited access to adequate healthcare. These daily demands induce chronic stress events and dysregulated immune responses. We sought to investigate the role of socio-ecologic risk factors in distress symptoms and their impact on biological responses to MBD in Machala, Ecuador. Between 2017 and 2019, individuals (≥ 18 years) with suspected arbovirus illness (DENV, ZIKV, and CHIKV) from sentinel clinics were enrolled (index cases, N = 28). Cluster investigations of the index case households and people from four houses within a 200-m radius of index home (associate cases, N = 144) were conducted (total N = 172). Hair samples were collected to measure hair cortisol concentration (HCC) as a stress biomarker. Blood samples were collected to measure serum cytokines concentrations of IL-10, IL-8, TNF-α, and TGF-ß. Univariate analyses were used to determine the association of socio-health metrics related to perceived stress scores (PSS), HCC, and immune responses. We found that housing conditions influence PSS and HCC levels in individuals at risk of MBD. Inflammatory cytokine distribution was associated with the restorative phase of immune responses in individuals with low-moderate HCC. These data suggest that cortisol may dampen pro-inflammatory responses and influence activation of the restorative phase of immune responses to arboviral infections.

Risk of Thromboembolic Events and Associated Risk Factors, Including Treatments, in Patients with Immune-mediated Diseases.

PURPOSE: This study assessed the association between thromboembolic events (TEs) and immune-mediated diseases (IMDs) and characterized the risk profile of TEs among patients with IMDs. METHODS: An administrative claims database (2014-2018) was used to identify adults with ≥2 diagnoses on different dates for ≥1 IMD (IMD cohort; ankylosing spondylitis, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus); patients without an IMD diagnosis were assigned to the non-IMD cohort. Patients in the IMD cohort were matched 1:1 to patients in the non-IMD cohort on age, sex, and index date. Incremental risk of TE (ie, deep vein thrombosis [DVT], pulmonary embolism [PE], myocardial infarction [MI], and ischemic stroke [IS]) was assessed using adjusted incidence rate ratios (aIRRs) to control for covariates in both cohorts. Risk factors for TEs were assessed in the IMD cohort and included age, female sex, comorbidities, baseline TEs, non-IMD treatments, and IMD treatments. FINDINGS: A total of 182,431 patients were included in each cohort (mean age, [51.3] years; 64.3% female). A higher proportion of patients in the IMD cohort versus the non-IMD cohort had ≥1 baseline TE (4.1% vs 2.7%; P < 0.0001). The IMD cohort had a 1.80 (95% CI, 1.68-1.92; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. After adjustments, patients in the IMD cohort had a 1.49 (95% CI, 1.40-1.59; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. Similar results were observed across individual TEs (DVT: aIRR = 1.78; PE: aIRR = 1.66; MI: aIRR = 1.17; IS: aIRR = 1.35; all P < 0.05). Risk factor profiles varied by TE. The greatest risk factor was respective TE during baseline (eg, patients with baseline DVT had 41.1 times the rate of DVT during the study period vs patients without baseline DVT; P < 0.001). Comorbidities, such as cardiovascular diseases, type 2 diabetes, and peripheral vascular disease, were associated with increased rates of MI (IRR = 2.60, 1.30, and 1.54, respectively; all P < 0.05) and IS (IRR = 1.53, 1.54, and 1.24, respectively; all P < 0.05). Janus kinase inhibitors were associated with an increased rate of PE (IRR = 2.52; P < 0.05) and nonsignificant, numerically higher rates of DVT (IRR = 1.23; P = NS) and IS (IRR = 1.82; P = NS). Sphingosine 1-phosphate receptor modulators were associated with decreased rates of TEs (DVT: IRR = 0.61, P = NS; PE: IRR = 0.30, P = NS; MI: IRR = 0.54, P = NS; IS: IRR = 0.33, P < 0.05). IMPLICATIONS: The risk of TEs was higher among patients with IMD versus patients without IMD; several factors may affect this risk.

Iatrogenic immune-mediated neuropathies: diagnostic, epidemiological and mechanistic uncertainties for causality and implications for clinical practice.

Acute and chronic immune-mediated neuropathies have been widely reported with medical intervention. Although causal relationship may be uncertain in many cases, a variety of drugs, several vaccination types, surgical procedures and bone marrow transplants have been reported as possible cause or trigger of a putative immune-mediated response resulting in acute and chronic neuropathies. We conducted a systematic review of the literature from 1966 to 2020 on reported cases of possible iatrogenic immune-mediated neuropathies. We determined in each case the likelihood of causality based on frequency of the association, focusing primarily on clinical presentation and disease course as well as available ancillary investigations (electrophysiology, blood and cerebrospinal fluid and neuropathology). The response to immunotherapy and issue of re-exposure were also evaluated. We also considered hypothesised mechanisms of onset of immune-mediated neuropathy in the specific iatrogenic context. We believe that a likely causal relationship exists for only few drugs, mainly antitumour necrosis factor alpha agents and immune checkpoint inhibitors, but remains largely unsubstantiated for most other suggested iatrogenic causes. Unfortunately, given the lack of an accurate diagnostic biomarker for most immune-mediated neuropathies, clinical assessment will often override ancillary investigations, resulting in lower levels of certainty that may continue to cast serious doubts on reliability of their diagnosis. Consequently, future reports of suspected cases should collect and exhaustively assess all relevant data. At the current time, besides lack of evidence for causality, the practical implications on management of suspected cases is extremely limited and therapeutic decisions appear likely no different to those made in non-iatrogenic cases.

Comparison of Adverse Events Among Home- vs Facility-Administered Biologic Infusions, 2007-2017.

Importance: Infusion reactions occur in 7% to 20% of patients receiving biologics. Home infusions are convenient and incur lower costs but may be associated with more adverse events; the safety of receiving biologic infusions for immune-mediated diseases at home remains unclear. Objective: To assess whether patients receiving home biologic infusions have increased adverse events requiring emergency department (ED) or hospital admission compared with patients receiving facility infusions. Design, Setting, and Participants: This retrospective cohort study used administrative claims data from a large national insurer for adult patients who received biologic infusions for immune-mediated disease between January 2007 and December 2017. Patients with hematologic malignant neoplasms or bone marrow transplantation were excluded. Data were analyzed from August 2019 to October 2020. Main Outcomes and Measures: ED or hospital admission on the same or next day after administration of a biologic infusion at home vs at a facility; secondary outcomes included discontinuation of the biologic after an ED or hospital admission and postinfusion mortality. Results: Of a total of 57 220 patients (mean [SD] age, 50.1 [14.8] years; 512 314 [68.1%] women) who received 752 150 biologic infusions (34 078 home infusions [4.5%] to 3954 patients and 718 072 facility infusions [95.5%] to 54 770 patients), patients who received home infusions were younger (mean [SD] age, 43.2 [13.2] vs 51.3 [14.8] years), more likely to be men (14 031 [41.2%] vs 225 668 [31.4%]), and had a lower Charlson comorbidity score compared with patients who received facility infusions (mean [SD] score, 0.5 [1.0] vs 1.1 [1.3]). Home infusions were associated with 25% increased odds of ED or hospital admission on the same or next day after the infusion (odds ratio [OR], 1.25; 95% CI, 1.09-1.44; P = .002) and 28% increased odds of discontinuation of the biologic after the ED or hospital admission (OR, 1.28; 95% CI, 1.08-1.51; P = .005). There was no difference in postinfusion mortality between home or facility infusions. The rates of adverse events were highest with home infusions of tocilizumab (48 of 481 infusions [10.0%]), vedolizumab (150 of 2681 infusions [5.6%]), and infliximab (1085 of 20 653 infusions [5.3%]), although the number of tocilizumab and vedolizumab infusions was low. Conclusions and Relevance: In this study, biologic infusions administered at home, compared with those administered at a facility, were associated with increased adverse events requiring escalation of care. Because the number of home infusions has increased and is expected to continue to rise, the safety implications of administering biologic infusions at home needs to be further assessed.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

BACKGROUND AND AIMS: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. RESULTS: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Association of Immune-Related Adverse Events and Efficacy Outcomes With Consolidation Pembrolizumab After Chemoradiation in Patients With Inoperable Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Many patients with non-small-cell lung cancer (NSCLC) treated with immunotherapy experience immune-related adverse events (irAEs). Patients with metastatic NSCLC who receive checkpoint inhibitors (CPI) and experience irAEs generally receive fewer cycles of CPI without decreased efficacy. However, the association between irAEs and efficacy outcomes in patients with locally advanced NSCLC treated with curative intent with CPI after chemoradiation has never been reported. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the Hoosier Cancer Research Network (HCRN) LUN 14-179 single-arm phase 2 trial of consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC. PATIENTS AND METHODS: A total of 92 eligible patients were enrolled from March 2015 to November 2016. Demographics, disease characteristics, and number of pembrolizumab cycles received were reported in patients with and without irAEs. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS). A log-rank test was used to compare groups. RESULTS: Any grade irAEs occurred in 55.4% of patients. There was no significant difference in number of pembrolizumab cycles received, TMDD, OS, or PFS in patients with and without irAEs. Patients who discontinued pembrolizumab early because of irAEs received significantly fewer cycles of pembrolizumab (5 vs 15, P = .0016) without a significant difference in TMDD, PFS, or OS. Similarly, patients who received immunosuppressive therapy received fewer numbers of cycles of pembrolizumab (4 vs 16, P < .001) without significantly reduced TMDD, PFS, or OS. CONCLUSION: irAEs due to pembrolizumab, regardless of grade or number of irAEs, were not associated with decreased efficacy outcomes. Furthermore, early discontinuation of pembrolizumab because of irAEs and/or treatment of irAEs with immunosuppressive therapy was not associated with a decrease in treatment efficacy.

Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database.

PURPOSE: To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs). METHODS: An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR). RESULTS: Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associated with ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs. CONCLUSION: ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable?

Neurological disorders and coronavirus 2019 (COVID-19) pandemic are two conditions with a recent well-documented association. Intriguing evidences showed that COVID-19 infection can modify clinical spectrum of manifested neurological disorders but also it plays a crucial role in the development of future diseases as long-tem consequences. In this viewpoint review, we aimed to assess the vulnerability to SARS-CoV-2 infection and development of COVID-19 among neurological disorders. With this in mind, we tested the hypothesis that age rather than neuropathology itself could be decisive in neurodegenerative diseases such as Parkinson's disease, whereas neuropathology rather than age may be critical in neuroimmunological diseases such as Multiple Sclerosis. Highlighting the role of potential susceptibility or protection factors from this disastrous infection, we also stratify the risk for future neurodegeneration.

Trends in Optic Neuritis Incidence and Prevalence in the UK and Association With Systemic and Neurologic Disease.

Importance: Epidemiologic data on optic neuritis (ON) incidence and associations with immune-mediated inflammatory diseases (IMIDs) are sparse. Objective: To estimate 22-year trends in ON prevalence and incidence and association with IMIDs in the United Kingdom. Design, Setting, and Participants: This cohort study analyzed data from The Health Improvement Network from January 1, 1995, to September 1, 2019. The study included 10 937 511 patients 1 year or older with 75.2 million person-years' follow-up. Annual ON incidence rates were estimated yearly (January 1, 1997, to December 31, 2018), and annual ON prevalence was estimated by performing sequential cross-sectional studies on data collected on January 1 each year for the same period. Data for 1995, 1996, and 2019 were excluded as incomplete. Risk factors for ON were explored in a cohort analysis from January 1, 1997, to December 31, 2018. Matched case-control and retrospective cohort studies were performed using data from January 1, 1995, to September 1, 2019, to explore the odds of antecedent diagnosis and hazard of incident diagnosis of 66 IMIDs in patients compared with controls. Exposures: Optic neuritis. Main Outcomes and Measures: Annual point prevalence and incidence rates of ON, adjusted incident rate ratios (IRRs) for risk factors, and adjusted odds ratios (ORs) and adjusted hazard ratios (HRs) for 66 IMIDs. Results: A total of 10 937 511 patients (median [IQR] age at cohort entry, 32.6 [18.0-50.4] years; 5 571 282 [50.9%] female) were studied. A total of 1962 of 2826 patients (69.4%) with incident ON were female and 1192 of 1290 92.4%) were White, with a mean (SD) age of 35.6 (15.6) years. Overall incidence across 22 years was stable at 3.7 (95% CI, 3.6-3.9) per 100 000 person-years. Annual point prevalence (per 100 000 population) increased with database maturity, from 69.3 (95% CI, 57.2-81.3) in 1997 to 114.8 (95% CI, 111.0-118.6) in 2018. The highest risk of incident ON was associated with female sex, obesity, reproductive age, smoking, and residence at higher latitude, with significantly lower risk in South Asian or mixed race/ethnicity compared with White people. Patients with ON had significantly higher odds of prior multiple sclerosis (MS) (OR, 98.22; 95% CI, 65.40-147.52), syphilis (OR, 5.76; 95% CI, 1.39-23.96), Mycoplasma (OR, 3.90; 95% CI, 1.09-13.93), vasculitis (OR, 3.70; 95% CI, 1.68-8.15), sarcoidosis (OR, 2.50; 95% CI, 1.21-5.18), Epstein-Barr virus (OR, 2.29; 95% CI, 1.80-2.92), Crohn disease (OR, 1.97; 95% CI, 1.13-3.43), and psoriasis (OR, 1.28; 95% CI, 1.03-1.58). Patients with ON had a significantly higher hazard of incident MS (HR, 284.97; 95% CI, 167.85-483.81), Behçet disease (HR, 17.39; 95% CI, 1.55-195.53), sarcoidosis (HR, 14.80; 95% CI, 4.86-45.08), vasculitis (HR, 4.89; 95% CI, 1.82-13.10), Sjögren syndrome (HR, 3.48; 95% CI, 1.38-8.76), and herpetic infection (HR, 1.68; 95% CI, 1.24-2.28). Conclusions and Relevance: The UK incidence of ON is stable. Even though predominantly associated with MS, ON has numerous other associations with IMIDs. Although individually rare, together these associations outnumber MS-associated ON and typically require urgent management to preserve sight.

Review: Extragastric diseases and Helicobacter pylori.

The involvement of Helicobacter pylori infection in many extra-gastroduodenal manifestations remains a fascinating field of investigation. However, for several of these supposed associations, the potential pathogenic mechanism remains unclear. The present review highlights the main associations of H pylori with extra-gastroduodenal manifestations reported during the last year. We searched for the most relevant studies on this topic, published between April 2019 and March 2020, identified using the term "Helicobacter" in the MEDLINE/Pubmed database. Consistent data emerged from studies investigating metabolic syndrome and ischaemic cardiovascular diseases. Other reported fields of investigation were hepatology, especially focused on non-alcoholic steatohepatitis, neurology, including Parkinson's disease and Alzheimer's disease, as well as dermatology. Inflammatory bowel disease (IBD), that comprises Crohn's disease and ulcerative colitis, may originate from a dysregulation of the host's immune response to commensal bacteria in individuals with genetic predisposition. The reduction of biodiversity and other specific imbalances in the faecal microbiome composition of IBD patients compared to that of healthy controls support this hypothesis. In this context, an inverse correlation between H pylori infection and IBD prevalence has been confirmed. Similar results were found in patients with kidney diseases and allergic manifestations. There are indications of the possible involvement of H pylori infection in metabolic syndrome and ischaemic cardiovascular diseases. However, due to a series of factors linked to study designs and the multifactorial pathogenesis of some diseases, further studies are needed.