History Of Autoimmune Disease Research Articles

Delayed immune-related adverse events in patients with advanced melanoma treated with immune checkpoint inhibitors.

12047 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of melanoma but can have serious or life-altering immune-related adverse events (irAEs). Most toxicities associated with ICIs occur within the first few months (mo) of treatment initiation, but delayed irAEs occurring 12 mo after ICI start are not well characterized. Further, clinical trials often have limited follow-up of AEs and thus, real world data is valuable. Methods: Patients (pts) ≥18 years with advanced melanoma who received ≥1 cycle of an ICI at BC Cancer from 2012-2019 with ≥12 mo of follow-up from time of ICI initiation were identified using the BC Cancer Registry and Pharmacy databases. Data on baseline clinicopathologic factors prior to the first cycle of ICI, and delayed irAE history and management were extracted. Delayed irAEs were graded using CTCAEv5. Results: In total, 530 pts treated with ≥1 cycle of an ICI were identified of which 309 pts had ≥12 mo of follow-up. Median follow-up for alive pts was 65.3 mo (13.0-143.5 mo). 96 (31%), 147 (48%), 19 (6%), and 47 (15%) pts received combination ICI (nivolumab/ipilimumab ± nivolumab maintenance), PD-1 inhibitor monotherapy (nivolumab or pembrolizumab), CTLA-4 inhibitor monotherapy (ipilimumab), and sequential CTLA-4 and PD-1 inhibitors, respectively. A total of 142 delayed irAEs were recorded in 94 (30%) pts. Median time to onset of delayed irAEs was 20.0 mo (12.2-80.6 mo). The most common delayed irAEs were dermatologic (27%), gastrointestinal (23%), and rheumatologic (20%). Most delayed irAEs were grade ≤2 (84%), but some were grade ≥3 (16%). Of individual delayed irAEs, 75 (51%) occurred on ICI treatment at time of onset, 39 (26%) after ≤3 mo of the last ICI cycle, and 34 (23%) after >3 mo of the last ICI cycle. 79 (56%) and 20 (14%) delayed irAEs were treated with systemic steroids and immunomodulators, respectively. Further, 12 (8%) delayed irAEs led to hospitalization, and 64 (45%) required subspecialty consultation. Pts with a history of autoimmune disease were more likely to have a delayed irAE (p=0.02), as were pts who achieved a partial or complete response (p=0.02). There was a trend towards a greater frequency of delayed irAEs in pts treated with PD-1 (37%) compared with combination (28%), CTLA-4 (11%), or sequential CTLA-4 and PD-1 (28%) (p=0.068). Conclusions: Delayed irAEs occurred in almost a third of pts with advanced melanoma treated with ICIs and followed for at least 1 year. Extended follow-up to monitor for delayed irAEs should be considered as many events required immunosuppressive therapy and rarely, may be life threatening. [Table: see text]

Update on GALLANT: A phase 2 study using metronomic gemcitabine, doxorubicin, and docetaxel plus nivolumab in previously treated sarcoma (NCT04535713).

e23569 Background: Metronomic dosing of gemcitabine, doxorubicin and docetaxel causes less severe side effects than standard chemotherapy for advanced sarcoma. Hypothesis: The addition of nivolumab to this regimen will have synergistic effects and improve treatment outcomes. Objectives: Primary objective: To assess progression-free survival (PFS); Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Methods: Inclusion criteria: Previously treated male and female subjects, > 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if the toxicity grade is <1. Results: Efficacy (n = 70). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. Best Overall Response = 14 PR, 47 SD, 9 PD. ORR = 20%; DCR (CR+PR+SD) was 87%. Median PFS was 8.2 (95% CI: 5.85-10.55) months; 6- month PFS rate of 59%. Median OS was 17.6 (95% CI: 13.53-21.67) months, with 6-month OS of 84%. Safety (n = 75): Grade 3/4 TRAEs include thrombocytopenia (n = 26), white blood cell count decreased (n = 17), neutropenia (n = 16), fatigue (n = 15), anemia (n = 13), nausea (n = 9), anorexia (n = 5), diarrhea (n = 2), emesis (n = 1), febrile neutropenia (n = 1), sepsis (n = 1), rectal bleeding (n = 1), transaminitis (n = 1), dizziness (n = 1), shortness of breath (n = 1). There were no unexpected adverse events reported. Conclusions: Taken together, the data suggests that nivolumab plus metronomic doses of gemcitabine, doxorubicin and docetaxel (1) may have synergistic activity, and (2) by indirect comparison, may be as effective as standard first line therapy for advanced sarcoma with manageable toxicity. Clinical trial information: NCT04535713 .

The dark side of herbal medicine - risks of Ashwagandha (Withania Somnifera) consumption

Introduction: Herbal medicine has been growing in popularity over the last few years. One of the most often used herbal remedy is Withania somnifera, more widely known as Ashwagandha Now known for its anti-stress, anti-inflammatory, antioxidant, anti-cancer, anti-anxiety properties it ranks as a cure-all. However, there is a rising amount of alarming reports regarding its safety. It has been observed that its effects are not always beneficial, and for some patients the risks of taking it may be greater than the promoted benefits. Aim of study: The aim of this paper is to evaluate possible risks connected to Withania Somnifera consumption based on available research articles and case reports. Materials and methods: This article is based on the literature found in the PubMed Database from the period of 2004-2024 with the use of keywords such as “Ashwagandha”; “Withania Somnifera”, “herbal medicine”;”complementary medicine”;“liver injury”; “thyrotoxicosis”; “adrenal insufficiency”;”autoimmune diseases”. Results: The outcomes of all the reviewed studies in this paper indicate that Withania Somnifera might cause a wide range of side effects. They include herb induced liver injury, endocrine complications such as thyrotoxicosis and adrenal insufficiency, acute graft rejection in a kidney transplant recipient and possible contribution to the onset of new autoimmune disease in patient with the history of autoimmune disorders. Conclusion: Further long-term research is needed on the Ashwaghanda’s benefits but particularly on its safety and potential side effects. The common education on the risks of taking herbal supplements should be carried out among health professionals and the rest of the society. Ashwagandha should not be used by patients with liver, endocrine and autoimmune disorders as well as transplant recipients.

Abstract CT287: LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715)

Abstract Background: Sarcoma cells are most immunogenic earlier in the course of the disease. Therefore, immune checkpoint inhibitors such as ipilimumab (ipi) and nivolumab (nivo), that promote sustained T-cell activation by suppressing T regs would be most effective when given as first line therapy, together with a tumoricidal agent, such as lurbinectedin, whose plausible mechanism of action is not only to destroy the cancer cells and expose the tumor neoantigens for immune recognition, but also to destroy growth promoting factors in the tumor microenvironment. In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. 15, 906, 2023). Lurbinectedin is a synthetic marine-derived agent and an analog of trabectedin. Therefore, we expect that lurbinectedin will be as effective as trabectedin when used together with ipi and nivo as first line therapy for advanced STS. Methods: Objective 1: Assess MTD of lurbinectedin. Objective 2: Evaluate PFS, OS, incidence and severity of adverse events; Correlative: Correlate response with ctDNA using Signatera. This is an open label, dose-seeking phase 1/2 study. The phase 1 part employs standard “cohort of three” design with a DLT window of 6 weeks. Treatment schedule: Ipi 1 mg/kg IV q 12 weeks; Nivo 3 mg/kg IV q 2 weeks; escalating doses of lurbinectedin from 2.6 mg/m2 to 3.2 mg/m2 IV q 3 weeks. Phase 2 part follows completion of phase 1 part wherein additional 28-34 participants will receive lurbinectedin at the MTD with fixed doses of Ipi and Nivo. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed. Citation Format: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla. LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT287.

COVID 19 vaccination as a trigger of acute genital ulcers in an immunocompromised adolescent—case study and literature review

Acute genital ulcers can affect females of all ages. In children, they often appear as an emergency and remain a diagnostic challenge for pediatricians, gynecologists and dermatologists. Prompt diagnosis and identification of disease- related factors help to implement appropriate treatment. Firstly, it is crucial to properly compile the past medical history of the patient. Past infectious, autoimmune, malignant or traumatic conditions, as well as vaccinations may contribute to the occurrence of acute genital ulcers. Moreover, new infectious agents, such as severe acute respiratory syndrome coronavirus 2 and vaccinations against Coronavirus disease of 2019, may play a significant role in the development of atypical clinical symptoms. Here we present a case of a 12-year-old girl with acute genital ulcers. Additional symptoms accompanying the ulcer included: abdominal pain, nausea, vomiting, dysuria, vulvar pain and fever. Blood test showed leukocytosis, especially neutrophilia and monocytosis and increased levels of c-reactive protein and procalcitonin. Serological tests for the most common infections were negative. Moreover, the patient had a history of autoimmune diseases. She had periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome, and IgA vasculitis, also known as Henoch-Schönlein purpura in her past medical history. Additionally, she was vaccinated against SARS-CoV-2 shortly before the lesions appeared.

Takotsubo Cardiomyopathy and Autoimmune Disorders: A Systematic Scoping Review of Published Cases.

Takotsubo cardiomyopathy (TCM) features transient left ventricular apical dysfunction or ballooning. The underlying mechanism remains elusive; however, evidence suggests the role of different physical and psychological stressors. We systematically reviewed patients presenting with TCM and autoimmunity to explore the link between the two conditions. We applied the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) to report this review. Using keywords related to autoimmune/immune-mediated diseases and TCM, we searched PubMed, Scopus, and WOS in March 2022. The final results were added to a data extraction sheet. Data were analyzed by SPSS version 26.0. Our search yielded 121 studies, including 155 patients. Females were considerably predominant. Most patients had a history of autoimmune disease, and almost a third had a history of cardiovascular disease. Dyspnea and chest pain were the most common chief complaints. More than 70% of patients had experienced physical stress. Myasthenia gravis, systemic lupus erythematosus, and multiple sclerosis were the most frequently reported autoimmune diseases. There were similarities in age and sex compared to classic TCM. TCM should be considered as a differential diagnosis for ACS, especially in patients with a positive background of autoimmunity. A precise reporting system is required for further studies.

Relationship between maternal obesity and first-trimester TSH in women with negative anti-TPO antibodies.

Obesity is associated with increased thyroid-stimulating hormone (TSH) in non-pregnant subjects, but this phenomenon has not been fully characterized during pregnancy. Our aim was to evaluate the impact of BMI on first-trimester TSH in a wide cohort of pregnant women with negative anti-thyroperoxidase antibodies (AbTPO) and its implications on uterine artery pulsatility index (UtA-PI), a marker of early placentation. The study included 2268 AbTPO-negative pregnant women at their first antenatal visit. Anamnestic data, BMI, TSH, anti-nuclear antibody (ANA) and extractable nuclear antigen (ENA) positivity and mean UtA-PI were collected. A total of 1693 women had normal weight, 435 were overweight and 140 were obese. Maternal age, ANA/ENA positivity, history of autoimmune diseases and familiar history of thyroid diseases were similar in the three groups. TSH was significantly higher in obese women (1.8 (IQR: 1.4-2.4) mU/L) when compared to normal weight (1.6 (IQR: 1.2-2.2) mU/L) and overweight (median: 1.6 (IQR: 1.2-2.2) mU/L) ones (P < 0.001). BMI was significantly related with the risk of having a TSH level ≥4 mU/L at logistic regression, independently from non-thyroid autoimmunity, smoking or familiar predisposition for thyroid diseases (OR: 1.125, 95% CI: 1.080-1.172, P < 0.001). A restricted cubic splines regression showed a non-linear relationship between BMI and TSH. Women with a TSH ≥4 mU/L had a higher UtA-PI, independently from BMI. Overweight/obesity is significantly related with TSH serum levels in AbTPO-negative pregnant women, independently from the other risk factors for hypothyroidism during pregnancy. The increase of TSH levels could be clinically relevant, as suggested by its association with abnormal UtA-PI, a surrogate marker of abnormal placentation.

Incidence and risk factors of immune-related adverse events induced by immune checkpoint inhibitors among older adults with non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) treatment has been linked to a variety of immune-related adverse events (irAEs), which can affect any organ system. The incidence and risk factors of irAEs have not been adequately evaluated among older adults with NSCLC. A cohort study was conducted using 1999-2019 SEER-Medicare data among beneficiaries aged ≥65 years with a diagnosis of NSCLC who received nivolumab, pembrolizumab, or atezolizumab. Incident irAEs were identified post-ICI initiation. Demographic, cancer-related characteristics, and clinical history risk factors of irAEs were evaluated with competing events considered. A total of 8175 older NSCLC patients were included (with 46.8% experiencing irAEs). Pneumonitis (16.5%), hypothyroidism (10.5%), arrhythmia (11.18%), and acute kidney injury (AKI) (5.8%) were the most common irAEs. The median time to first irAE was 82 days (IQR: 29-182 days). The earliest onset of irAE occurrence was for hematologic irAEs, while the latest were gastrointestinal, dermatologic, and musculoskeletal irAEs. Fine-Gray regression modeling revealed significantly greater hazards of irAE occurrence in patients who received pembrolizumab at index, did not have CNS metastases, had a history of autoimmune disorder, and had chemotherapy in combination with ICI. Race, socioeconomic status, previous radiation therapy, and comorbidity burden were found to be associated with the occurrence of certain type of irAEs. A significant proportion of older patients with NSCLC develop an irAE after receiving ICI treatment. Factors related to cancer and treatment as well as demographics contribute to the increased risk of irAEs. Close monitoring and prediction of irAE among older patients receiving ICI is warranted.

Differences in Outcomes of Hemophagocytic Lymphohistiocytosis (HLH) Based on Etiology: A Five Year Nationwide Analysis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, under-diagnosed, potentially lethal condition marked by dysregulated hyperinflammation and widespread multi-organ dysfunction. There is currently no literature describing the differences in HLH outcomes according to its commonly reported risk factors. Therefore, authors of this study aimed to identify potential differences in the outcomes of HLH among various etiologies as well as update literature on the prevalence of risk factors for HLH in the United States. Methods: Using weighted data from the Nationwide Inpatient Sample (NIS) database from 2016 to 2020, we assessed prevalence of known HLH risk factors (infection, malignancy, auto-immune, and inflammatory syndromes) and HLH outcomes (mortality, length of hospital stay, total healthcare charges, complications) stratified by HLH etiology (infection, malignancy, auto-immune, inflammatory). Baseline characteristics were analyzed using T-test for continuous variables and Chi-Square for categorical variables, and a multivariate regression analysis was used to estimate outcomes between races. Data analysis was performed using STATA® Version 17.0/SE Software, with statistical significance set at p &amp;lt; 0.05. Results: Among a total of 2,685 individuals admitted with a primary diagnosis of HLH, 52% (N=1,350) had an infection (27% bacterial, 28% viral,14% fungal, and 1% parasitic), 22% were with malignancy (N=525)(14% lymphoma, 2% leukemia, 3% plasma cell proliferation, 3% myeloproliferative disease, and 4% solid tumors), 16% had a history of autoimmune disease (N=380), and 7% had an inflammatory syndrome (N=175). 25% had no ICD-10 codes for common risk factors of HLH. Among patients with HLH and autoimmune disease, we noted a predominance of females (77%, p&amp;lt;0.001). Individuals with HLH and cancer had more comorbid conditions (Charlson index: 3 in 58%, p&amp;lt;0.001). Pertaining to outcomes, when compared to those with cancer, individuals with infection had a 3-fold increase in respiratory failure (adjusted Odds Ratio (aOR)=3.12, 95%CI: 1.13-8.61), while those with autoimmune disease had reduced odds of acute kidney injury (aOR=0.30, 95%CI: 0.10-0.87). There were no significant differences in the length of hospital stay, the total healthcare expenditures, mortality and the other complications (cardiac arrest, acute kidney injury, respiratory failure, disseminated intravascular coagulation, and acute liver failure) among HLH secondary to cancer versus other risk factors. Discussion: Our study findings demonstrate that infection is the most common trigger for secondary HLH in the U.S., followed by malignancy. This is consistent with existing literature. Individuals who develop HLH associated with the infection have a 3-fold higher odds of acute respiratory failure compared to those with HLH resulting from other cancer. This warrants increased vigilance, and the potential need for a lower threshold for mechanical ventilation to mitigate adverse outcomes in patients with HLH secondary to infection.

Insights from a Veterans Health Administration Database Analysis: Immune-Related Adverse Effects of Immunotherapy in Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Despite the high success rates in treating Classical Hodgkin lymphoma (cHL), a specific group of patients still experience relapsed or refractory (R/R) disease, affecting approximately 10-20% of cases. The use of immunotherapy with checkpoint inhibitors (CPIs) has emerged as a promising approach, demonstrating impressive efficacy in R/R cHL patients [2,3]. However, there is a lack of real-world evidence regarding the immune-related adverse effects (irAEs) associated with immunotherapy in this relatively rare patient population. To address this gap, this study leverages the Veterans Health Administration (VHA) database to investigate irAEs, providing valuable insights to optimize treatment decisions. Methods: A retrospective analysis was conducted on Hodgkin lymphoma patients who received immunotherapy from the VHA Corporate Data Warehouse from 2014-2022. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and US territories. Data was collected to determine the baseline characteristics, disease factors, detailed AE occurrence as well as outcomes in this cohort. Results: The analysis included 68 cHL patients who received immunotherapy. The cohort had a mean age of 62.2 years (SD=15.9) and a median age of 66 years (IQR 54-72). The majority of the patients were male (97%) and White (80%) and only 6% of patients had a history of autoimmune disease. The distribution of patients across stages was as follows: Stage 1 (5%), Stage 2 (15%), Stage 3 (40%), and Stage 4 (40%). Additionally, 20% of patients underwent autologous stem cell transplantation (ASCT), with 10% receiving immunotherapy before transplantation and the remaining 10% receiving it post-transplant. In our cohort, 31% had documented adverse effects related to immunotherapy. The most common adverse events observed were hematological/cytopenias (8%), dermatologic/rash (6%), endocrine-related (6%), pneumonitis (5%), hepatitis (2%), myocarditis (2%), and other adverse events (8%). Discontinuation of therapy due to irAEs occurred in 12% of patients. These findings align with prior literature, which has consistently reported thyroid gland dysfunction (such as hypothyroidism and thyroiditis) and rash as the most frequently observed immune-related adverse events [2]. The most common management of irAEs were holding therapy followed by use of corticosteroids. Kaplan-Meier survival analysis revealed a median overall survival of 55.4 months (IQR=37.2-59.2), with a median follow-up time of 36.4 months (IQR=21.6 -58.6). Conclusion: This study, utilizing the VA database, provides a distinctive and valuable perspective on irAEs associated with immunotherapy in cHL patients. By leveraging a comprehensive database on a large scale, this study significantly enhances our comprehension of immunotherapy in the context of cHL, thereby offering crucial guidance for treatment decisions concerning relapsed/refractory Hodgkin lymphoma patients. The findings of this study strongly indicate the sustained benefits of immune checkpoint inhibitors (ICI) in this population, emphasizing the importance of close patient monitoring to detect and manage immune-related adverse events at an early stage, thereby preventing life-threatening complications.

THU392 Type B Insulin Resistance: A Rare Cause Of Hypoglycemia

Abstract Disclosure: S.Z. Bhat: None. A. Sidhaye: None. A.H. Hamrahian: None. Introduction: Non-diabetic hypoglycemia in patients with diabetes mellitus is rare. Type B insulin resistance syndrome (TBIRS), caused by insulin receptor antibodies, presents with severe insulin resistance, but can uncommonly result in a hypoglycemic picture. Clinical Case: A 59-year-old woman with a history of SLE, T2DM, and primary hyperparathyroidism was admitted for acute confusion and found to have a POC glucose of 30 mg/dl. Her symptoms improved after IV glucose administration. She was on a stable basal-bolus insulin regimen of 0.8 U/kg/day and had unintentional 100-pound weight loss over 1 year. Significant exam findings included BMI of 29 kg/m2, gingival hyperplasia, and acanthosis nigricans. Aside from insulin, she took no medications strongly associated with hypoglycemia. Labs including CBC, CMP, TFTs, and morning cortisol were normal. HbA1C and adiponectin levels were 7.7%, and 28 µg/ml (5-28), respectively. Given the suspicion of exogenous insulin-mediated hypoglycemia, only correctional insulin was used during hospitalization. She had a repeat hypoglycemic episode on the 2nd day with minimal insulin use. A 72-hour fasting test showed a whole blood glucose of 44 mg/dL with concurrent serum C-peptide of 1.72 ng/mL, serum insulin 55 mIU/L and pro-insulin 21.9 pmol/L 12 hours into fasting. MRCP showed an 11 mm cystic lesion in the pancreas and widespread lymphadenopathy. The CGM noted significant fasting and post-prandial hypoglycemia. Diagnosis of insulinoma was considered unlikely due to persistent post-prandial hyperglycemia. Oral hypoglycemic panel and insulin autoantibodies were negative. The patient’s history of SLE, high-normal adiponectin, history of hyperglycemia and the presence of acanthosis nigricans favored work-up for insulin resistance syndromes. Due to the non-availability of insulin receptor antibody testing in the US, blood work was sent to Dr. Lutz Schomburg’s lab at Institute for Experimental Endocrinology, Berlin, Germany. The patient’serum was positive for insulin receptor antibodies, tested via an immunoassay technique, with elevated binding index (BI) of 248, 251 and 247 on 3 different samples of the patient, and normal binding index in the control sample, leading to the diagnosis of type B insulin resistance syndrome (BI &amp;gt;3 is positive, &amp;gt;10 indicates high positivity). The patient was treated with diet modification and CGM use, with improvement in the frequency of hypoglycemic episodes. She declined immunomodulation therapy. Conclusion: Hypoglycemia is an uncommon presentation of TBIRS and should be considered in the differential of non-diabetic hypoglycemia, particularly in patients with a history of auto-immune disease. The mechanism for hypoglycemia is purported to be an insulin-mimetic effect of insulin receptor antibodies at low titers. Presentation: Thursday, June 15, 2023

Abnormal Promoter Methylation of Nucleotide-Binding Oligomerization Domain Containing 2 (NOD2) Gene in the Pathogenesis of Crohn’s Disease

Changes in the expression of nucleotide-binding oligomerization domain containing 2 (NOD2) play an important role in the pathogenesis of several autoimmune diseases, such as inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). It seems that epigenetic modifications, including DNA methylation, have an important role in the suppression of gene activity. In this study, the relationship between DNA methylation patterns of the promoter region of the NOD2 gene and the pathogenesis of CD was assessed. Colonic mucosal samples were obtained from 15 Iranian patients with CD and 15 matched healthy controls with no history of autoimmune diseases. After bisulfite conversion of genomic DNA, the DNA methylation status of three CpG sites in the promoter region of the NOD2 gene was determined by the real-time quantitative multiplex methylation-specific PCR assay. Using this approach, we identified a decreased level of methylation of the NOD2 promoter in the colonic mucosa of patients with CD (0.128±0.093 vs. 0.025±0.016, unmethylated DNA in CD vs. healthy controls, respectively, P&lt;0.000). According to our findings, promoter hypomethylation of the NOD2 gene in the colonic mucosa might contribute to the development and severity of CD.

From Daily to Rarity - A Case Report of Ulcerative Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is classified as a non-infectious neutrophilic dermatosis with poorly understood etiology. Pathergy, which is major trauma caused by a minor incident, has been associated as a preceding event for PG. The epidemiology of the disease reveals patients who present with PG have associated underlying conditions with the most common comorbidities reported as inflammatory bowel disease, rheumatoid arthritis, hematological and solid organ malignancies. Pyoderma gangrenosum is considered a diagnosis of exclusion. It is commonly a missed diagnosis leading to delays in treatment. A diagnostic guide which clinicians can use is the PARACELSUS score. The following case report will focus on a relatively healthy 50-year-old female with a past medical history of hypertension who is in complete remission from breast cancer. This case highlights the importance of keeping PG in the differential diagnosis in patients without a history of autoimmune disease.

Safety of Antithyroid Drugs in Avoiding Hyperglycemia or Hypoglycemia in Patients With Graves' Disease and Type 2 Diabetes Mellitus: A Literature Review.

Graves' disease (GD) may increase the difficulty of glucose control in patients with type 2 diabetes mellitus (T2DM). Therefore, selecting a drug with limited blood glucose side effects is an important issue in patients with T2DM and GD. Antithyroid drugs (ATDs)including propylthiouracil (PTU), methimazole, and carbimazoleare commonly prescribed for the treatment of GD. Here, we review and summarize the literature from the last 10 years and discuss the effects of current ATDs used for GD for blood glucose control in patients with T2DM. A search of the literature published between January 1, 2012 and December 1, 2022 was conducted using three major medical databases: Google Scholar, Ovid Medline, and Scopus. An initial search was conducted on PubMed using the MeSH terms "propylthiouracil," "methimazole," "carbimazole," and "hyperglycemia" or "hypoglycemia" in academic databases. All articles included "Graves' disease" and "type 2 diabetes mellitus" in the title. Based on the results of previous studies, the hyperglycemic andhypoglycemic side effects of ATDs can be explained by several possible mechanisms. The most widely accepted hypothesis is that sulfhydryl group drugs (e.g., methimazole and carbimazole) cleave the disulfide bond of insulin and enhance its immunogenicity, resulting in hypoglycemia. Moreover, some reports have indicated that methimazole is associated with hypoglycemia; therefore, if the patient has a history of autoimmune diseases, it is necessary to consider whether to change drugs or actively track the production of autoimmune antibodies. Innon-diabetic and diabetic patients with GD, the hyperglycemic and hypoglycemic side effects of PTU (on glycemic variation) were less than that of thiamazole. However, as relatively few reports have investigated the side effects of blood sugar changes, further research is necessary to confirm these effects. In addition to autoimmune diseases, drug side effects may need to be considered. These findings provide considerations for clinicians to select more appropriate ATDs for patients with GD and T2DM, and implement improved care guidelines.

Chondromatous metaplasia within native cardiac valves: clinicopathologic characterization with particular focus upon aortic valves.

Native cardiac valves in the setting of chronic injury may become thickened and disrupted by dystrophic calcification, which impede valve structure/function, and there may be evidence of chondromatous (i.e., cartilaginous, CM) metaplasia admixed with dystrophic calcification. In order to characterize the presence of CM in native cardiac valves - with particular focus upon aortic valves - a retrospective review of the histologic features of 46 native aortic valves (identified from 1094 sequentially reviewed native valves of all types) containing CM were focused upon, as well as correlation with other histopathologic features, and clinical and echocardiographic findings. The prevalence rate of CM was low, and greatest among aortic valves, less in mitral valves, and never identified in tricuspid or pulmonic valves. CM in aortic valves was less commonly identified in patients with a history of autoimmune disease. The rate of CM increased with degree of valve thickening and/or calcification. The proportion of aortic valves with CM increased with an increasing degree of stenosis and decreasing degree of regurgitation, and aortic valves with CM were more commonly associated with a smaller aortic valve area, and greater peak and mean gradients. The rate of osseous metaplasia, arterial vessels, capillary bed formation, and chronic inflammation were greater in aortic valves with CM compared to valves without. CM within aortic valves is an infrequent albeit identifiable histopathologic alteration associated with chronic valve disease alongside changes in valve thickening and calcification.

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia.

Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies. In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files. Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009). A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.

Uveitis as a Manifestation of Celiac Disease: A Population-Based Study

Introduction: The prevalence of celiac disease (CD) in the United States population has been estimated to be 0.71%, or 1 in 141, with the prevalence in first- and second-degree relatives of those affected being 4.55% and 2.59% respectively. Due to the multitude of ways in which this disease may initially present, it is important to screen for CD to avoid the potential consequences of inadequately managed disease. Many ophthalmic conditions have also been implicated as extraintestinal manifestations of CD, including uveitis. Despite several studies and case reports suggesting a positive correlation between CD and uveitis, there has yet to be a nationwide study in the United States quantifying this relationship. Therefore, the aim of this study is to conduct a large-scale multi-center population-based study to assess whether there is a statistically significant increased risk of uveitis in individuals with celiac disease. Methods: A validated multicenter and research platform database of more than 360 hospitals from 26 different healthcare systems across the United States consisting of data accumulated from 1999 to September 2022 was utilized to construct this study. We excluded patients with a history of autoimmune diseases, cataract surgery, or any type of eye infection. We included a subgroup of patients with a diagnosis of “uveitis” for further analysis. The risk of developing uveitis was calculated using a univariate logistic regression. A multivariate analysis was also done to account for confounding variables including African American ethnicity, male gender, sexually transmitted diseases, and celiac disease. Results: 70,632,440 patients were screened and a cohort of 46,895,750 individuals was selected for the final analysis after accounting for inclusion and exclusion criteria were met. The incidence of uveitis in patients with celiac disease in the past 3 years was 280 per 100,000 people. The prevalence of uveitis in the US population from 1999 to September 2022 was 150 per 100,000 people (0.15%). In order to adjust for confounding variables, a multivariate regression analysis was performed and showed an increased risk of being African-American (OR: 3.20%; 95% CI: 3.14-3.26) and male (OR: 1.13%; 95% CI: 1.12-1.16); and having a diagnosis of celiac disease (OR: 3.80%; 95% CI: 3.35-4.28) and sexually transmitted diseases (OR: 4.12%; 95% CI: 3.96-4.29) in patients with uveitis. Discussion: Recent population-based studies demonstrated that the prevalence of CD in the United States is much greater than previously thought, such that a trend of underdiagnoses is suspected to have occurred for several years. Many newly diagnosed uveitis cases, 48%, have been classified as idiopathic uveitis even after a complete workup was done. Several studies have been published in which a correlation between uveitis and CD is reported. The findings of this study further emphasize the importance of a thorough workup to evaluate for an underlying inflammatory process prior to diagnosing uveitis as idiopathic. Conclusion: In conclusion, we established that patients with celiac disease are at increased risk of developing uveitis after excluding and controlling for any confounding variables. In further studies, it could be interesting to investigate the impact of gluten-free diet in patients with celiac disease on the risk of developing uveitis.

Utilization of circulating tumor DNA (ctDNA) analysis to detect minimal residual disease post-surgery and disease progression in metastatic thymic tumors.

8598 Background: Thymic epithelial tumors (TETs) are rare and tend to have an indolent disease course. Follow-up consists of physical examinations and routine imaging (CT scans) with no currently available biomarkers to complement surveillance. This study aimed to assess the utility of ctDNA in MRD detection and disease monitoring in TETs. Methods: From Nov 2020 till Feb 2022, ctDNA analysis using a tumor-informed mPCR-NGS (Signatera) assay was performed on 29 patients (pts) with primary (pTETs) or metastatic TETs (mTETs). For pts with early-stage disease, the baseline ctDNA was measured 4-8 w post-surgery and repeated q3m. For mTETs, ctDNA was measured at the first visit, and then q3m with interval CT scan q3-4 m. ctDNA was quantified as mean tumor molecules (MTM)/mL of plasma. All pts had at least one measurement (up to 4). GraphPad was used for statistical analysis. Results: Of 29 pts overall, 9 pts were excluded at the time of analysis for various reasons; a) insufficient specimen (n=5), b) presence of concurrent active cancer (n=2), and c) final report delay (n=2). Of 20 evaluable pts, 7 pts had pTETs and 13 mTETs. The median age was 50 yrs (range, 17-72), and WHO histology distribution of AB=3, B1=5, B2=9, B3=12, TC=3. History of autoimmune disease and second malignancy (not active at the time of obtaining ctDNA) was reported in 33% (n=9) and 40% (n=8) of evaluable pts, respectively. Of 13 metastatic pts, 6 had stage IVA with pleural-only metastasis, 7 pts had Stage IVB with 2 extra-thoracic (liver, adrenal), and 5 with intrathoracic (lung, chest wall, and LNs) involvement. From 7 pTETs, 6 pts had R0 resection with undetectable post-operative ctDNA, while R1 resection with detectable ctDNA was reported (0.47 MTM/mL) in one pt. In mTETs, the mean level of ctDNA in pts with the stable disease was 0.18 MTM/mL (0.1-0.2), pleural-only progression 1.26 MTM/mL (0.1-1.9), and progressive disease (primary and/or pleural) 7.67 MTM/mL(5.04-9.5). Comparing the mean level of ctDNA in clinically stable metastatic pts with those who had progression, pts with pleural-only progression did not have a significantly higher level of ctDNA (p=0.51). In contrast, pts with primary and/or pleural progression had significantly higher levels of ctDNA (p=0.02). The level of ctDNA correlated with tumor size. An increase of 4-6mm in tumor size was associated with an approximate 0.2 MTM/mL increase in ctDNA or making the undetectable status detectable. Conclusions: The ctDNA level correlates well with the tumor volume in mTETs. In pTETs, ctDNA was negative following R0 resection but not in the R1, supporting its potential use as a surrogate biomarker for MRD. This is a pilot study, and the expansion of these data is ongoing to validate the utility of ctDNA testing in these settings. If validated, ctDNA may augment or minimize the routine use of CT scans for disease monitoring in resected and mTETs.

Results of SOC-2082 phase 2 study using metronomic gemcitabine, doxorubicin and docetaxel plus nivolumab as second/third-line therapy for advanced sarcoma.

11555 Background: Metronomic dosing of gemcitabine, doxorubicin and docetaxel causes less severe side effects than standard chemotherapy for advanced sarcoma. The addition of nivolumab to this regimen has potential to have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival (PFS); Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, ≥ 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles are continued every three weeks if the toxicity grade is ≤1. Results: This report on the modified intent-to-treat population (n=59). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. Best Overall Response = 8 PR, 44 SD, 7 PD. The disease control rate ( CR+PR+SD) was 88.1%. Median PFS was 5.1 (95% CI: 2.837-7.363) months; 6 month PFS rate 52.5%. Median OS, 15.3 (95% CI: 5.48-25.12) months, with 6-month OS 88%. Safety analysis: Grade 3/4 TRAEs include fatigue (n=18), nausea (n=13), neutropenia (n=10), thrombocytopenia (n=9), anemia (n=9), diarrhea (n=1). There were no unexpected adverse events. Conclusions: Taken together, the data suggests that nivolumab in combination with metronomic doses of gemcitabine, doxorubicin and docetaxel (1) may have synergistic activity, and (2) by indirect comparison, may be as effective as standard first line therapy for advanced sarcoma with manageable toxicity. Clinical trial information: NCT04535713 .

Cognitive and other neuropsychiatric symptoms in COVID-19: analysis of person-generated longitudinal health data from a community-based registry

ObjectiveTo describe cognitive symptoms in people not hospitalised at study enrolment for SARS-CoV-2 infection and associated demographics, medical history, other neuropsychiatric symptoms and SARS-CoV-2 vaccination.DesignLongitudinal observational study.SettingDirect-to-participant registry with community-based...