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BMC Medical Genomics Jun 2024Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have...
Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.
Topics: Cholangitis, Sclerosing; Humans; Genome-Wide Association Study; Models, Theoretical
PubMed: 38862968
DOI: 10.1186/s12920-024-01927-2 -
Circulation Research Jun 2024Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus... (Review)
Review
Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.
Topics: Myocarditis; Humans; Autoimmune Diseases; Animals; Autoantibodies; Autoimmunity; T-Lymphocytes; Autoantigens; Cardiac Myosins
PubMed: 38843292
DOI: 10.1161/CIRCRESAHA.124.323816 -
Nature Communications Jun 2024The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction...
The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.
Topics: Animals; Male; Mice; Abatacept; Allografts; Antilymphocyte Serum; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Interleukin-10; Interleukin-6; Lymphocyte Depletion; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Regulatory
PubMed: 38830846
DOI: 10.1038/s41467-024-48574-w -
Journal For Immunotherapy of Cancer May 2024Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed....
BACKGROUND
Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined.
METHODS
We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared.
RESULTS
Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4).
CONCLUSIONS
AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.
Topics: Humans; Artificial Intelligence; Immunotherapy; Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 38816231
DOI: 10.1136/jitc-2023-008599 -
Cureus Apr 2024Immunotherapies are powerful disease-modifying agents in treating autoimmune diseases like rheumatoid arthritis (RA). However, their unique mechanisms of action confer a...
Immunotherapies are powerful disease-modifying agents in treating autoimmune diseases like rheumatoid arthritis (RA). However, their unique mechanisms of action confer a broad spectrum of immune-related adverse events (irAEs), which tend to be rare but complex, with significant risk for morbidity and mortality. We report a case of transverse myelitis in a patient with RA whose joint disease had been well-controlled with long-term intravenous abatacept. Suspicion of an unusual irAE in this elderly patient, whose neurologic symptomatology was gradual and protracted, prompted the discontinuation of abatacept and the rapid initiation of corticosteroid therapy. These interventions yielded a favorable clinical outcome for the patient. We must draw clinicians' attention to this rare but potentially consequential adverse drug reaction.
PubMed: 38807813
DOI: 10.7759/cureus.59201 -
Cureus Apr 2024Type 1 diabetes mellitus is an autoimmune condition characterized by insulin deficiency resulting from loss of function of beta cells in the pancreas, leading to... (Review)
Review
Type 1 diabetes mellitus is an autoimmune condition characterized by insulin deficiency resulting from loss of function of beta cells in the pancreas, leading to hyperglycemia and associated long-term systemic complications and even death. Immunotherapy demonstrates beta cell function-preserving potential; however, its impact on C-peptide levels, a definitive biomarker of beta cell function, and endogenous insulin secretion remain unclear. A systematic review of various immunotherapeutic interventions is hence needed for a comprehensive assessment of their effectiveness as well as identifying research gaps and influencing future research and clinical decisions. An extensive literature search was done in PubMed, Scopus, and Cochrane Library databases using precise keywords and filters to identify relevant studies. Three independent reviewers assessed eligibility according to predetermined eligibility criteria, and data was extracted. The Cochrane risk of bias assessment tool (RoB 2.0) was used to evaluate the quality and validity of the included studies. A senior reviewer resolved discrepancies and differences of opinion between independent reviewers. A total of 11 studies were included, with 1464 study participants. Both Phase II and III trials were included. Within the included studies, four studies assessed the anti-CD3 monoclonal antibody otelixizumab as an intervention. Another anti-CD3 monoclonal antibody, teplizumab, was assessed as an intervention in four studies, whereas two studies assessed the anti-CD20 antibody rituximab and one study assessed abatacept as its interventional drug. Otelixizumab demonstrated benefits at higher doses but was associated with adverse effects like Ebstein-Barr virus reactivation and cytomegalovirus infection, while at lower doses it failed to show a significant difference in C-peptide levels or glycosylated hemoglobin (HbA1c). Teplizumab, on the other hand, showed promise in reducing C-peptide loss and exogenous insulin requirements and was associated with adverse events such as rash, lymphopenia, urinary tract infection, and cytokine release syndrome. However, these reactions were only associated with therapy initiation, and they subsided on their own. Rituximab improved C-peptide responses, and abatacept therapy demonstrated reduced loss of C-peptide, improved C-peptide levels, and lowered HbA1c. Teplizumab, rituximab, otelixizumab, and abatacept show potential for preserving beta cell function by reducing C-peptide loss in patients with type I diabetes mellitus. However, careful monitoring of adverse reactions, particularly viral infections and cytokine release syndrome, is necessary for the safe implementation of these therapies.
PubMed: 38800168
DOI: 10.7759/cureus.58981 -
The Korean Journal of Internal Medicine May 2024The aim of this study was to compare the short- and long-term retention rates of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in...
BACKGROUND/AIMS
The aim of this study was to compare the short- and long-term retention rates of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in Korean patients with seropositive rheumatoid arthritis.
METHODS
This study was conducted with 1,538 treatment courses of 1,063 patients, including adalimumab (n = 332), etanercept (n = 369), infliximab (n = 146), abatacept (n = 152), tocilizumab (n = 299), tofacitinib (n = 136), and baricitinib (n = 104), in patients with seropositive rheumatoid arthritis who started b/tsDMARD treatment between 2008 and 2020 at Seoul St. Mary's Hospital. Discontinuation 1 and 3 years after the first prescription of each drug was investigated. Kaplan- Meier estimates of time to discontinuation were calculated to compare the difference in drug retention rate for each drug. Patient-level predictors of drug discontinuation were evaluated using a Cox proportional hazards model.
RESULTS
The overall 1-year drug retention rate was from 60.1% for adalimumab to 90.0% for tofacitinib in the b/tsDMARD-naïve group, and from 55.2% for infliximab to 84.8% for tofacitinib in the b/tsDMARD-experienced group. The 3-year drug retention rate was from 36.9% for infliximab to 86.5% for tofacitinib in the b/tsDMARD-naïve group, and from 31.0% for infliximab to 65.4% for tocilizumab in the b/tsDMARD-experienced group. Drug discontinuation appeared to be affected by specific types of b/tsDMARDs.
CONCLUSIONS
Tocilizumab and tofacitinib are less commonly discontinued compared to tumor necrosis factor-α inhibitors at 1 and 3 years. Specifically, tofacitinib in the b/tsDMARD-naïve group and tocilizumab in the b/tsDMARD-experienced group showed the highest 3-year retention rates.
PubMed: 38798047
DOI: 10.3904/kjim.2023.297 -
Cureus Apr 2024The administration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines has played a pivotal role in managing the COVID-19 pandemic....
INTRODUCTION
The administration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines has played a pivotal role in managing the COVID-19 pandemic. Nonetheless, there have been instances of atypical immune reactions to the vaccine, notably among patients with autoimmune inflammatory rheumatic diseases such as rheumatoid arthritis (RA).
AIM
This study was designed to analyze the cytokine profiles of RA patients who suffered from severe or fatal disease flares after receiving the SARS-CoV-2 mRNA vaccine, to unravel the immunological bases for such responses.
METHODS
We conducted a retrospective observational study involving three RA patients. These individuals had their disease under control prior to experiencing severe disease flares post-mRNA vaccination. A detailed serum cytokine analysis was carried out and compared with that of a healthy control group.
RESULTS
Post-vaccination, each patient displayed a marked cytokine storm, with notably increased levels of IL-1β (342, 109, and 27.5 pg/mL, respectively), IL-6 (67.8, 82.7, and 201 pg/mL, respectively), IL-17A (172, 51.6, and 30.3 pg/mL, respectively), and TNF-α (279, 97.5, and 59.4 pg/mL, respectively). Two patients responded well to treatment with biological and synthetic DMARDs, including baricitinib and abatacept. Unfortunately, one patient passed away even after receiving tocilizumab.
CONCLUSION
The findings from the comprehensive cytokine assays indicate severe cytokine abnormalities, pointing to cytokine storm syndrome. This suggests that SARS-CoV-2 mRNA vaccination may trigger a disruption in immune homeostasis, potentially leading to the acute worsening of pulmonary complications in RA patients, even those with previously low disease activity. It's necessary to weigh the risks of severe outcomes from COVID-19 against the potential for flares or other adverse reactions following vaccination. Such risk assessments should take into account the individual patient's health status, existing conditions, and other risk factors. Close follow-up after vaccination is crucial, especially for patients with RA.
PubMed: 38779245
DOI: 10.7759/cureus.58740 -
Pilot and Feasibility Studies May 2024Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS),...
Assessing the effects of distinct biologic therapies on rheumatoid arthritis pain by nociceptive, neuropathic and nociplastic pain components: a randomised feasibility study.
BACKGROUND
Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS), including biologic therapies, many people with RA continue to experience significant pain. We aimed to determine whether performing a comprehensive pain evaluation is feasible in people with active RA receiving conventional DMARDs and biologic therapies.
METHODS
The BIORA-PAIN feasibility study was an open-label, randomised trial, which recruited participants suitable for treatment with biologic therapy. The primary feasibility outcomes were recruitment, randomisation and retention of eligible participants. All participants underwent pain assessment for nociceptive, neuropathic and nociplastic pain during the 12-month study period, with quarterly assessments for VAS (Visual Analogue Scale) pain, painDETECT and QST (quantitative sensory testing). This trial was registered in clinicaltrials.gov NCT04255134.
RESULTS
During the study period, 93 participants were screened of whom 25 were eligible: 13 were randomised to adalimumab and 12 to abatacept. Participant recruitment was lower than expected due to the COVID-19 pandemic. Pain assessments were practical in the clinical trial setting. An improvement was observed for VAS pain from baseline over 12 months, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.1) in the adalimumab group. There was a reduction in painDETECT and improvement in QST measures in both treatment groups during the study. Participant feedback included that some of the questionnaire-based pain assessments were lengthy and overlapped in their content. Adverse events were similar in both groups. There was one death due to COVID-19.
CONCLUSIONS
This first-ever feasibility study of a randomised controlled trial assessing distinct modalities of pain in RA met its progression criteria. This study demonstrates that it is feasible to recruit and assess participants with active RA for specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Our data suggests that it is possible to stratify people for RA based on pain features. The differences in pain outcomes between abatacept and adalimumab treated groups warrant further investigation.
TRIAL REGISTRATION
NCT04255134, Registered on Feb 5, 2020.
PubMed: 38755699
DOI: 10.1186/s40814-024-01505-4 -
Transplant International : Official... 2024
Topics: Humans; Abatacept; Pancreas Transplantation; Immunosuppressive Agents; Male; Female; Adult; Middle Aged; Graft Rejection; Cohort Studies; Graft Survival; Retrospective Studies
PubMed: 38689693
DOI: 10.3389/ti.2024.12778