Efficacy of inflammation-based stratification for add-on celecoxib or minocycline in major depressive disorder: Protocol of the INSTA-MD double-blind placebo-controlled randomised clinical trial.

Introduction: Different lines of evidence confirm the involvement of the immune system in the pathophysiology of major depressive disorder. Up to 30% of depressed patients present with an immune-mediated subtype, characterized by peripheral inflammation (high-sensitive C-reactive protein (hsCRP) ≥ 3 mg/l) and an atypical symptom profile with fatigue, anhedonia, increased appetite, and hypersomnia. This immune-mediated subtype of MDD is associated with poorer response to first-line antidepressant treatment. Consequently, strategies for immune-targeted augmentation should be prioritised towards patients with this subtype. Meta-analyses have shown modest but heterogeneous treatment effects with immune-targeted augmentation in unstratified MDD cohorts, with celecoxib and minocycline as most promising first-line treatment options. However, no study has prospectively evaluated the effectiveness of a priori stratification by baseline inflammation levels for add-on celecoxib or minocycline in MDD. Methods: The INSTA-MD trial is a multicentre, 12-week, randomised, double-blind, placebo-controlled, parallel-group stratified clinical trial of adjunctive minocycline or celecoxib to treatment-as-usual for patients with MDD. Two hundred forty adult patients with Major Depressive Disorder who failed to remit with one or two trials of antidepressant treatment will be enrolled and allocated to high-hsCRP (hsCRP ≥3 mg/L) or low-hsCRP (hsCRP <3 mg/L) strata, where disproportional stratified sampling will ensure equally sized strata. Participants in each hsCRP stratum will be randomised to augment their ongoing antidepressant treatment with either adjunctive minocycline, celecoxib or placebo for a duration of 12 weeks, resulting in six treatment arms of each 40 participants. The primary objective is to evaluate the efficacy of immune-targeted augmentation with minocycline or celecoxib versus placebo, and the use of baseline hsCRP stratification to predict treatment response. Additionally, we will perform a head-to-head analysis between the two active compounds. The primary outcome measure is change in the Hamilton Depression Rating Scale (HDRS-17) total score. Secondary outcome measures will be response and remission rates, and change in inflammation-specific symptoms, adverse events and therapy acceptability (adherence). Further exploratory analyses will be performed with an array of peripheral inflammatory biomarkers, metabolic outcomes and physiological data. Expected impact: The aim of INSTA-MD is to advance the use of immune-targeted precision psychiatry, by supporting the implementation of targeted hsCRP screening and treatment of immune-mediated MDD as a cost-effective intervention in primary care settings. Based on previous studies, we expect immune-targeted augmentation with minocycline or celecoxib to yield a superior remission rate of 15-30% compared to treatment as usual for immune-mediated cases of MDD. By treating immune-related depression early in the treatment algorithm with repurposed first-line anti-inflammatory treatments, we can significantly improve the outcomes of these patients, and reduce the global societal and economic burden of depression. Ethics and dissemination: This protocol has been approved by the Medical Ethics Review Board (CTR - 04/08/2023). Registration details: Trial registration number NCT05644301 (Clinical trial.gov), EU-CT 2022-501692-35-00.

Helicobacter pylori and Its Treatment Impact on Immune-Mediated Ocular Diseases.

PURPOSE: Helicobacter pylori (HP), which colonizes exclusively in the gastrointestinal tract, has been reported to dysregulate the immune response and gives rise to several extra-gastrointestinal autoimmune disorders. However, the relationship between HP and immune-mediated ocular diseases remains ambiguous. This study aims to clarify the association between immune-mediated ocular diseases and HP infection, as well as the impact of HP treatment on the incidence of immune-mediated ocular diseases. METHODS: This is a retrospective population-based study using National Health Insurance Research Database in Taiwan. Patients with newly diagnosed peptic ulcer disease or HP infection between 2009 and 2015 were identified as HP group and compared to the non-HP group with one-to-one exact matching. Moreover, the incident risk of immune-mediated ocular diseases and its two subgroups (ocular surface and orbital inflammation group, intraocular inflammation group) were compared in HP patients with or without treatment. RESULTS: A total of 1,030,119 subjects in the non-HP group and 1,030,119 patients in the HP group were enrolled. The incidence rate of immune-mediated ocular diseases was significantly higher in the HP group (95% confidence interval (CI): 2.534-2.547). The incident rate ratio was significantly higher in HP with treatment than without treatment (HR: 1.654, 95% CI: 1.641-1.668). The Cox proportional hazards regression model demonstrated a significantly increased HR of immune-mediated ocular diseases in HP treated group (HR: 2.265, 95% CI: 2.024-2.534) and less increased HR in HP non-treated group (HR: 1.427, 95% CI: 1.273-1.598) when comparing to non-HP group. Subgroup analysis demonstrated a significantly higher incidence rate of ocular surface and orbital inflammation as well as intraocular inflammation in the HP group. CONCLUSION: This study illustrated a higher incidence of immune-mediated ocular diseases in HP infection, and a heightened risk following HP eradication.

Autoimmune Metaplastic Atrophic Gastritis (AMAG): Regional Demographics and Their Effect on Prevalence.

Autoimmune metaplastic atrophic gastritis (AMAG) is a chronic immune-mediated form of gastritis characterized by damage to oxyntic cells, ultimately resulting in both iron deficiency with or without anemia and pernicious anemia. The current dogma is that AMAG is a disease of White Northern European women of advanced age. We, therefore, sought to examine the prevalence of AMAG in biopsies obtained from populations enriched for self-identified Hispanics for cross-comparison against data from previously reported populations enriched for self-identified White, non-Hispanic patients. To that end, we prospectively collected 1708 sequential gastric biopsies performed at the University of Miami Hospitals/Jackson Health Systems clinics from 1692 patients over a 1-year period as well as pertinent clinical parameters. These Florida data were then compared against data previously collected from the Baltimore population, which has far lower numbers of Hispanic patients. Self-identified race and/or ethnicity were used. From these 1692 patients, we identified 79 patients (4.6%) with AMAG. These included 60 women (76%) and 19 men (24%), with a F:M ratio of 3.1:1. Patients had a median age of 60 years (range: 15-83). Self-identified race and/or ethnicity were: 60 (76.0%) Hispanic, 9 (11.4%) Black, 9 (11.4%) White, and 1 Asian (1.2%). The median age at initial presentation was: 51 years (range: 15-83) in Hispanics, 77.2 years (range: 46-74) in Blacks, 59 years (range: 49-79) in Whites, and 58 years in the only Asian patient. The overall demographics of AMAG largely mirrored the Florida population, with an over-representation of Hispanics (Florida inhabitants self-report as 70% Hispanic). The overall 4.6% prevalence of AMAG in the Florida population differed significantly from the 1.1% in Baltimore (p < .00001), a finding that presumably reflects the large Hispanic population. In fact, the prevalence of AMAG is far higher in Hispanic patients. Awareness of these data should increase recognition of AMAG in this population.

Immune-Mediated Inflammatory Diseases and Cancer - a dangerous liaison.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

Recent Updates on the Pathogenesis of Inflammatory Myopathies.

PURPOSE OF REVIEW: This review aims to provide a comprehensive and updated overview of autoimmune myopathies, with a special focus on the latest advancements in understanding the role of autoantibodies. We will begin by examining the risk factors and triggers associated with myositis. Next, we will delve into recent research on how autoantibodies contribute to disease pathogenesis. Finally, we will explore the latest innovations in treatment strategies and their implications for our understanding of myositis pathogenesis. RECENT FINDINGS: Recent research has revealed that myositis-specific autoantibodies can infiltrate muscle cells and disrupt the function of their target autoantigens, playing a crucial role in disease pathogenesis. Significant advances in treatment include CD19 CAR-T cell therapy, JAK-STAT inhibitors, and novel strategies targeting the type 1 interferon pathway in dermatomyositis. Additionally, the ineffectiveness of complement inhibitors in treating immune-mediated necrotizing myositis has challenged established views on disease mechanisms. Autoimmune myopathies are a collection of disorders significantly influenced by specific autoantibodies that drive disease pathogenesis. This review highlights the critical role of autoantibody research in deepening our understanding of these conditions and discusses recent therapeutic advancements targeting key pathogenic pathways.

Acute Cerebellitis Following COVID-19: Alarming Clinical Presentation Challenged by Normal Paraclinical Findings.

We report the case of an acute cerebellitis following COVID-19 in 32-year-old man who presented with a life-threatening critical cerebellar syndrome contrasting with normal paraclinical findings. Despite this fulminant critical presentation, the patient fully recovered in 37 days after early treatment with high-dose steroids and intravenous immunoglobulins. This case highlights the need for clinicians to be aware of acute cerebellitis following COVID-19, despite normal laboratory, imaging and electroencephalography findings and the importance to start appropriate treatment as soon as possible.

Prevalence and risk factors for complicated immuno-mediated uveitis: experience in a tertiary hospital.

OBJECTIVE: To describe the characteristics of patients with uveitis and ocular complications in a tertiary hospital. As well as to determine the risk factors for the development of an ocular complication. METHODS: Retrospective study of patients with uveitis evaluated in a Uveitis Unit of the Virgen de las Nieves Hospital from January 2018 to October 2022. A descriptive and analytical study was carried out using logistic regression to know the predictive factors of a poor ocular prognosis. RESULTS: A total of 127 patients were studied, of which 63% were women and 83.5% were Caucasian. The median age was 51 years IQR (15-88) years. Following the SUN classification, uveitis was predominantly bilateral (55.1%) and anterior (52%), had a recurrent evolution in 51,2% and only 12,6% were granulomatous. Of the total uveitis, 74,2% of the sample turned out to have an immune-mediated profile, although a final diagnosis was only reached in 46,1% of the patients. A total of 17,3% patients suffer from loss of vision. Visual complications in decreasing order were: posterior synechiae (15,6%), cystic macular edema (14.8%), cataracts (13,1%), glaucoma (8,2%), epiretinal membranes (4,9%) and neovascular membranes (1,7%) and retinal detachment (4%). In the bivariate analysis, ethnicity other than Caucasian was significant, p = 0,024, and a number of outbreaks greater than 2, p = 0,045. The rest of the variables analyzed were not significant. In the multivariate analysis, they were significant outbreaks OR: 1,2 CI (1,051-1,426) and ethnicity OR: 0,11 CI (0,014-0,938). CONCLUSIONS: The number of outbreaks and non-Caucasian race were related to a greater probability of presenting an ocular complication. An earlier and more specific diagnosis of the etiology, especially in these patients, would allow earlier treatment and improve their prognosis.

Esophageal lymphocytosis: exploring the knowns and unknowns of this pattern of esophageal injury.

INTRODUCTION: Lymphocyte-rich inflammation of the esophageal mucosa has gained increased awareness among pathologists and clinicians recently. Patients usually present with symptoms of esophageal dysfunction, including dysphagia and food bolus impaction. Endoscopy may show changes similar to eosinophilic esophagitis but may also be entirely normal ('microscopic esophagitis'). Three morphological subtypes or variant forms have been described which include lymphocytic, lichenoid and lymphocyte-predominant esophagitis. These need to be discriminated against other distinct causes of esophageal lymphocytosis, such as gastro-esophageal reflux disease and Candida infection. AREAS COVERED: This review provides an overview of diagnostic criteria and clinical associations of the disorder and presents an algorithmic approach to diagnosis. A comprehensive literature review was conducted using PubMed, Medline and Google Scholar databases to identify articles related to lymphocyte-rich esophageal inflammation, published up to March 2024. EXPERT OPINION: Lymphocyte-rich inflammation needs to be included in the differential diagnosis and clinical work-up of patients with esophageal dysfunction. There is currently considerable morphological overlap among published subtypes or variant forms. Follow-up studies of affected individuals are needed to formalize diagnostic parameters and identify the clinical course of disease in order to optimize treatment modalities.

[Translated article] Knowledge of biological therapy in patients with immune-mediated diseases. BIOINFO study.

OBJECTIVE: To determine the degree of knowledge about biological therapy and biosimilars in patients with immune-mediated inflammatory diseases treated in Outpatient Pharmaceutical Care Units. METHODS: Observational, prospective, and multicenter study during the period May 2020-March 2021. A survey (9 questions) was conducted before starting treatment in which the patients' level of knowledge about biological therapy and biosimilars was assessed. RESULTS: A total of 169 patients were included in the study. The average value for the different questions was 3.3±0.6 out of 5, while the average final result was 29.4 points out of 45. 64.5% of the patients had an acceptable level before starting the medication (>27 points). The multivariate analysis showed a statistically significant correlation (p<.05) with a better score at the beginning of treatment in those patients whose prescribing service was Rheumatology. CONCLUSIONS: In general, the level of knowledge prior to biological therapy in patients is acceptable, being higher in dosage and administration technique related-factors and what is related to the dosage and administration technique and where to find information related to the medication; the worst rated were those on biosimilars-related. The factor of being followed by rheumatology, was associated with better knowledge.