Early and aggressive treatment for Crohn disease using biologics and immunomodulators.

ABSTRACT: Traditionally, medical providers have used the step-up approach to manage patients with Crohn disease, starting with 5-aminosalicylic acid derivatives, progressing to corticosteroids, and eventually to immunomodulators and biologics. However, a new top-down approach focuses on early and aggressive therapy with biologics and immunomodulators to reduce the rate of mucosal and intestinal damage. This article describes early and aggressive biologic and immunomodulator therapies and new therapeutic parameters compared with traditional step-up treatment for patients with Crohn disease.

[Novel immunomodulatory therapies in myasthenia gravis]. / Myasthénie grave : nouvelles thérapies immunosuppressives.

Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating weakness of skeletal muscles. Despite current treatments, a significant percentage of patients remain symptomatic. This review explores new immunosuppressive therapies and ongoing clinical trials in MG, including depletion of B lymphocytes with agents such as rituximab and inebilizumab, as well as the use of eculizumab, efgartigimod, satralizumab, tocilizumab, and CAR-T (Chimeric Antigen Receptor-T) cell therapy. These advancements aim to improve disease control and patients' quality of life.

La myasthénie grave (MG) est une maladie auto-immune caractérisée par une faiblesse fluctuante des muscles squelettiques. Malgré les traitements classiques, un pourcentage significatif de patients reste symptomatique. Cet article explore les nouvelles thérapies immunosuppressives et les essais cliniques en cours pour la MG, notamment la déplétion des lymphocytes B avec des agents tels que le rituximab et l'inébilizumab, ainsi que l'utilisation de l'éculizumab, de l'efgartigimod, du satralizumab, du tocilizumab et de la thérapie par cellules CAR-T (Chimeric Antigen Receptor-T). Ces avancées visent à améliorer le contrôle de la maladie et la qualité de vie des patients.

[Evaluation of the effectiveness of various regimens of the immunomodulatory drug Superlimf in the prevention of relapses of chronic abacterial prostatitis].

INTRODUCTION: Immune defense mechanisms, including a decrease in the functional activity of monocytes/macrophages, neutrophils, as well as a violation of the balance of pro- and anti-inflammatory cytokines, are important in the development of chronic abacterial prostatitis (CAP). The discovery of the cytokine system and the determination of their biological role in the development and functioning of the immune system and in the pathogenesis of a wide range of human diseases led to the development of a new direction in immunotherapy - cytokine therapy. The aim of the study was to evaluate the effectiveness of various regimens of the use of the immunomodulatory drug Superlimf in the prevention of recurrence of CAP. MATERIALS AND METHODS: The study included 90 patients with category IIIa CAP (NIH, 1995). All patients underwent basic complex therapy was performed, which included behavioral therapy, taking an 1-adrenoblocker, an antibacterial drug from the fluoroquinolone group for 28 days, as well as the drug Superlimph 10 ME 1 suppository rectally 2 times a day for 20 days. Dynamic follow-up was recommended for patients of group (CG) in the next 12 months. In the main group 1 (MG1), patients underwent basic complex therapy, after which a preventive courses of Superlimph 10 ME 1 suppository 1 time per day for 10 days every three months for 12 months was prescribed. In the main group 2 (MG2), patients also underwent basic complex therapy, after which a preventive courses of Superlimph 10 ME of 1 suppository was prescribed 2 times a day for 10 days every three months for 12 months. The effectiveness of the treatment was evaluated after 4 weeks (visit 2). Long-term treatment results were assessed after 3 months (visit 3), 6 months (visit 4), and 12 months (visit 5). RESULTS: The study groups were homogeneous, and the results of examinations obtained before treatment did not differ statistically significantly (p>0.05). At visit 2, 4 weeks after the start of therapy, a statistically significant positive dynamics of the studied indicators in the main groups and CG was recorded. Thus, the average score on the IPSS scale decreased by 56.4% from the initial value, on the Qol scale - by 57.7%, on the NIH-CPSI scale - 70.2%. The number of leukocytes in the prostate secretion decreased to the normal level to 7.9 in the field of vision, which is 86.2% less than the initial value. The average Qmax value also increased to a normal value of 15.2ml/s, which is 51.3% higher than the initial value (p<0.001). In this study, for the first time, a comparative analysis of two different regimens of preventive administration of the drug Superlimf was carried out. In MG1, the drug was prescribed to patients at a dose of 10 ME 1 time a day, in MG2 - 10 ME 2 times a day. The data obtained indicate a comparable effectiveness of both dosage regimens after 3 months of therapy. However, after 6 months and 12 months, the results in MG2 were statistically significantly better than in MG1. In addition, during 12 months of therapy, the number of relapses in MG2 was 2.3 times less. According to ultrasound examination, the volume of the prostate gland in CG, after a significant (p<0.001) decrease against the background of basic complex therapy, increased by 24.6% from visit 2 to visit 5, whereas in MG2 the average value of this indicator did not significantly change. And according to the Doppler study, by the end of the observation period at visit 5, hemodynamic parameters in CG were statistically significantly worse than in MG1 and MG2. CONCLUSION: Thus, the use of Superlymph in patients with CAP as a preventive therapy every 3 months results to a longer preservation of the therapeutic effect and improved hemodynamics in the prostate. In addition, preventive courses of Superlymph 10 units 2 times a day for 10 days led to an increase in the duration of the relapse-free period and a decrease in the number of recurrences within 12 months by 7 times, while preventive courses of Superlymph 10 units 1 time per day for 10 days decreased risk of recurrence by 3 times. According to our results, the most effective preventive scheme in patients with CAP is the use of Superlymph 10 units, 1 suppository 2 times a day for 10 days every 3 months.

Incidence and outcome of COVID-19 following vaccine and hybrid immunity in patients on immunosuppressive therapy: identification of protective post-immunisation anti-RBD antibody levels in a prospective cohort study.

OBJECTIVES: To assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication. METHODS: IMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2-5 weeks post-immunisation. RESULTS: Between 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels <6000 binding antibody units/mL were associated with an increased risk of COVID-19 following three (HR 1.37 (95% CI 1.08 to 1.74)) and four doses (HR 1.28 (95% CI 1.02 to 1.62)), and of COVID-19 re-infection (HR 4.47 (95% CI 1.87 to 10.67)). CONCLUSION: Vaccinated patients with IMID have a low risk of severe COVID-19. Hybrid immunity lowers the risk of infection. High post-immunisation anti-RBD levels protect against COVID-19. These results suggest that knowledge on COVID-19 history, and assessment of antibody levels post-immunisation can help individualise vaccination programme series in high-risk individuals. TRIAL REGISTRATION NUMBER: NCT04798625.

A novel T cell-redirecting anti-GPRC5D × CD3 bispecific antibody with potent antitumor activity in multiple myeloma preclinical models.

G-protein-coupled receptor class 5 member D (GPRC5D) is detected in malignant plasma cells in approximately 90% of patients diagnosed with multiple myeloma (MM). Here, we constructed BsAb5003, a novel humanized bispecific monoclonal antibody targeting CD3 and GPRC5D, and evaluated its therapeutic impact on MM. BsAb5003 induced specific cytotoxicity of GPRC5D-positive MM cells with concomitant T cell activation and cytokine release. The efficacy of BsAb5003 was associated with GPRC5D expression levels in MM cell lines. Flow cytometry analysis of bone marrow mononuclear cells (BMMNCs) from 49 MM patients revealed that GPRC5D was expressed in a wide population of MM patients, including heavily treated and high-risk patients. In ex vivo assays using BMMNCs, BsAb5003 induced potent efficacy against CD138 + MM cells in both newly diagnosed and relapsed/refractory patient samples in a GPRC5D expression-dependent manner. BsAb5003 significantly enhanced T cell activation and cytokine production in combination with immunomodulatory drugs (IMiDs) against MM cell lines. BsAb5003 also demonstrated significant inhibition of in vivo tumor growth by recruiting T cells. Taken together, these results suggest that T cell-redirecting bispecific antibody targeting GPRC5D as monotherapy and combination therapy with IMiDs could be a highly potent and effective treatment approach for a wide population of MM patients.

Equity, expense, and expertise in biologic commissioning: adding the patient to the equation.

INTRODUCTION: Immune-mediated inflammatory diseases (IMIDs) are increasingly managed effectively with biologic medicines. However, with relatively high unit costs, there remains a meaningful pressure to ensure streamlined, equitable, and inclusive prescription of biologics in the UK. Despite an increased awareness of the benefits of patient-centric shared decision making, patients remain on the periphery of biologic selection for the treatment of IMIDs. AREAS COVERED: We provide a patient perspective on core issues in the commissioning, prescription, and decision making around biologics for IMIDs in the UK, focusing on England. In particular, the crucial aspect of determining 'value' for different stakeholders, who necessarily have different priorities, is considered. EXPERT OPINION: There are disparities in commissioning, access to, and prescription of biologics for IMIDs in the UK. This creates an unequal treatment model and drives patient dissatisfaction with an 'experience lottery' for the management of disease. A more transparent approach to prescribing decisions, made in close consultation with patients, is essential for improving equity and experience with biologic treatment of IMIDs.

EFFECT OF SOME IMMUNOMODULATORY DRUGS ON EMBRYONIC DEVELOPMENT OF DANIO RERIO FISH.

At the current stage of healthcare development, the inclusion of immunomodulators in the complex pharmacotherapy of various immunoinflammatory and viral diseases is widely discussed, but due to the lack of sufficient research and a broad evidence base, not all drugs with similar properties are used in medicine. According to the information obtained from the instructions for the use of immunomodulators, it was obtained that the main contraindications to their use include the prescription of children, pregnant women, and women during breastfeeding. In this study, we evaluated the effects of immunomodulatory drugs: aminodihydrophthalazindione sodium and meglumine acridonacetate, on the early developmental stages of Danio rerio (Zebrafish) embryos.

scDrugPrio: a framework for the analysis of single-cell transcriptomics to address multiple problems in precision medicine in immune-mediated inflammatory diseases.

BACKGROUND: Ineffective drug treatment is a major problem for many patients with immune-mediated inflammatory diseases (IMIDs). Important reasons are the lack of systematic solutions for drug prioritisation and repurposing based on characterisation of the complex and heterogeneous cellular and molecular changes in IMIDs. METHODS: Here, we propose a computational framework, scDrugPrio, which constructs network models of inflammatory disease based on single-cell RNA sequencing (scRNA-seq) data. scDrugPrio constructs detailed network models of inflammatory diseases that integrate information on cell type-specific expression changes, altered cellular crosstalk and pharmacological properties for the selection and ranking of thousands of drugs. RESULTS: scDrugPrio was developed using a mouse model of antigen-induced arthritis and validated by improved precision/recall for approved drugs, as well as extensive in vitro, in vivo, and in silico studies of drugs that were predicted, but not approved, for the studied diseases. Next, scDrugPrio was applied to multiple sclerosis, Crohn's disease, and psoriatic arthritis, further supporting scDrugPrio through prioritisation of relevant and approved drugs. However, in contrast to the mouse model of arthritis, great interindividual cellular and gene expression differences were found in patients with the same diagnosis. Such differences could explain why some patients did or did not respond to treatment. This explanation was supported by the application of scDrugPrio to scRNA-seq data from eleven individual Crohn's disease patients. The analysis showed great variations in drug predictions between patients, for example, assigning a high rank to anti-TNF treatment in a responder and a low rank in a nonresponder to that treatment. CONCLUSIONS: We propose a computational framework, scDrugPrio, for drug prioritisation based on scRNA-seq of IMID disease. Application to individual patients indicates scDrugPrio's potential for personalised network-based drug screening on cellulome-, genome-, and drugome-wide scales. For this purpose, we made scDrugPrio into an easy-to-use R package ( https://github.com/SDTC-CPMed/scDrugPrio ).

Unveiling Immunomodulatory Effects of Euglena gracilis in Immunosuppressed Mice: Transcriptome and Pathway Analysis.

The immunomodulatory effects of Euglena gracilis (Euglena) and its bioactive component, ß-1,3-glucan (paramylon), have been clarified through various studies. However, the detailed mechanisms of the immune regulation remain to be elucidated. This study was designed not only to investigate the immunomodulatory effects but also to determine the genetic mechanisms of Euglena and ß-glucan in cyclophosphamide (CCP)-induced immunosuppressed mice. The animals were orally administered saline, Euglena (800 mg/kg B.W.) or ß-glucan (400 mg/kg B.W.) for 19 days, and CCP (80 mg/kg B.W.) was subsequently administered to induce immunosuppression in the mice. The mice exhibited significant decreases in body weight, organ weight, and the spleen index. However, there were significant improvements in the spleen weight and the spleen index in CCP-induced mice after the oral administration of Euglena and ß-glucan. Transcriptome analysis of the splenocytes revealed immune-related differentially expressed genes (DEGs) regulated in the Euglena- and ß-glucantreated groups. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that pathways related with interleukin (IL)-17 and cAMP play significant roles in regulating T cells, B cells, and inflammatory cytokines. Additionally, Ptgs2, a major inflammatory factor, was exclusively expressed in the Euglena-treated group, suggesting that Euglena's beneficial components, such as carotenoids, could regulate these genes by influencing immune lymphocytes and inflammatory cytokines in CCP-induced mice. This study validated the immunomodulatory effects of Euglena and highlighted its underlying mechanisms, suggesting a positive contribution to the determination of phenotypes associated with immune-related diseases and the research and development of immunotherapies.

The effect of immunomodulatory drugs on bone metabolism of patients with multiple myeloma.

INTRODUCTION: Immunomodulatory drugs (IMiDs) are widely used in the management of newly diagnosed and relapsed/refractory multiple myeloma patients. These agents show their potential effect on myeloma bone disease (MBD), including inhibition of osteoclasts activity and effects on osteoblasts differentiation. It is unclear whether these effects are direct, which may have an impact on bone formation markers when combined with proteasome inhibitors. AREAS COVERED: This review summarizes the available evidence on the role of IMiDs in microenvironment regulation and their potential effects on bone metabolism. The literature search methodology consisted of searching PubMed for basic and clinical trials using medical subject terms. Included articles were screened and evaluated by the coauthors of this review. EXPERT OPINION: As a therapeutic option, IMiDs directly affect preosteoblast/osteoclast differentiation. The combination of proteasome inhibitors may counteract the short-term up-regulation of osteogenic activity markers, and therefore intravenous zoledronic acid is recommended, however, obtaining a more significant myeloma response will have a long-term positive impact on myeloma bone disease.

Outcome Reporting Bias in Clinical Trials Researching Disease-Modifying Therapy in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Outcome reporting bias occurs when publication of trial results is dependent on clinical significance, thereby threatening the validity of trial results. Research on immunomodulatory drugs in multiple sclerosis has thrived in recent years. We aim to comprehensively examine to what extent outcome reporting bias is present in these trials and the possible underlying factors. METHODS: We identified clinical trials evaluating the efficacy and safety of immunomodulatory drugs in patients with multiple sclerosis (MS) registered in ClinicalTrials.gov after September 2007 and completed before the end of 2018. Information about study design, type of funding, and primary and secondary outcome measures was extracted from the registry. Timing of registration in relation to study initiation and subsequent amendments to the planned outcomes were reviewed. Publications related to these trials were identified in several bibliographic databases using the trial registration number. Registered primary and secondary outcomes were recorded for each trial and compared with outcomes in the publication describing the main outcomes of the trial. RESULTS: A search of ClinicalTrials.gov identified 535 eligible registered clinical trials; of these, 101 had a matching publication. Discrepancies between registered and published primary and secondary outcomes were found in 95% of the trials, including discrepancies between the registered and published primary outcomes in 26 publications. Forty-four percent of the published secondary outcomes were not included in the registry. A similar proportion of registered and nonregistered reported primary efficacy outcomes were positive (favoring the intervention). Nonindustry-funded and open-label trials in MS were more prone to selective primary outcome reporting, although these findings did not reach statistical significance. Only two-thirds of the trials were registered in ClinicalTrials.gov before the trial start date, and 62% of trials made amendments in registered outcomes during or after the trial period. DISCUSSION: Selective outcome reporting is prevalent in trials of disease-modifying drugs in people with MS. We propose methods to diminish the occurrence of this bias in future research.

Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile.

BACKGROUND: Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging. METHODS: An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization. RESULTS: Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile. CONCLUSIONS: Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer.

Focused ultrasound (FUS) combined with intravascularly circulating microbubbles can transiently increase the permeability of the blood-brain barrier (BBB) to enable targeted therapeutic delivery to the brain, the clinical testing of which is currently underway in both adult and pediatric patients. Aside from traditional cancer drugs, this technique is being extended to promote the delivery of immunomodulating therapeutics to the brain, including antibodies, immune cells, and cytokines. In this manner, FUS approaches are being explored as a tool to improve and amplify the effectiveness of immunotherapy for both primary and metastatic brain cancer, a particularly challenging solid tumor to treat. Here, we present an overview of the latest groundbreaking research in FUS-assisted delivery of immunomodulating agents to the brain in pre-clinical models of brain cancer, and place it within the context of the current immunotherapy approaches. We follow this up with a discussion on new developments and emerging strategies for this rapidly evolving approach.

Use of coronarycomputed tomography for cardiovascular risk assessment in immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are recognised risk factors for accelerated atherosclerotic cardiovascular disease (CVD), particularly in younger individuals and women who lack traditional CVD risk factors. Reflective of the critical role that inflammation plays in the formation, progression and rupture of atherosclerotic plaques, research into immune mechanisms of CVD has led to the identification of a range of therapeutic targets that are the subject of ongoing clinical trials. Several key inflammatory pathways implicated in the pathogenesis of atherosclerosis are targeted in people with IMIDs. However, cardiovascular risk continues to be systematically underestimated by conventional risk assessment tools in the IMID population, resulting in considerable excess CVD burden and mortality. Hence, there is a pressing need to improve methods for CVD risk-stratification among patients with IMIDs, to better guide the use of statins and other prognostic interventions. CT coronary angiography (CTCA) is the current first-line investigation for diagnosing and assessing the severity of coronary atherosclerosis in many individuals with suspected angina. Whether CTCA is also useful in the general population for reclassifying asymptomatic individuals and improving long-term prognosis remains unknown. However, in the context of IMIDs, it is conceivable that the information provided by CTCA, including state-of-the-art assessments of coronary plaque, could be an important clinical adjunct in this high-risk patient population. This narrative review discusses the current literature about the use of coronary CT for CVD risk-stratification in three of the most common IMIDs including rheumatoid arthritis, psoriasis and systemic lupus erythematosus.

Prevalence of Pretreatment Testing Recommended for Patients With Chronic Inflammatory Skin Diseases.

Importance: Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear. Objective: To determine the prevalence of pretreatment testing that is recommended for patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis). Design, Setting, and Participants: This descriptive analysis of US commercial insurance claims databases from December 31, 2002, to December 31, 2020, included adult patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis) who started an immunomodulatory agent, including methotrexate, tumor necrosis factor α inhibitors, interleukin (IL)-17Ai, ustekinumab, IL-23i, dupilumab, or apremilast. Main Outcomes and Measures: The proportion of patients who underwent the screening tests as suggested by professional societies-including for tuberculosis, hepatitis, and liver function; complete blood cell counts; and lipid panels-were determined within 6 months before and during 2 years after treatment start. Results: A total of 122 308 patients with CISDs (median [IQR] age, 49 [38-58] years; 63 663 [52.1%] male) starting systemic immunomodulatory treatment in the US were included. Treatment for patients with CISDs comprised methotrexate (28 684), tumor necrosis factor α inhibitors (40 965), ustekinumab (12 841), IL-23i (6116), IL-17Ai (9799), dupilumab (7787), or apremilast (16 116). Complete blood cell count was the most common test, performed in 41% (3161/7787) to 69% (19 659/28 684) of individuals before initiation across treatments. Between 11% (889/7787) and 59% (3613/6116) of patients had tuberculosis screening within 6 months before treatment, and 3% (149/4577) to 26% (1559/6097) had updated tests 1 year later. Between 13% (1006/7787) and 41% (16 728/40 965) had hepatitis panels before treatment. Low pretreatment testing levels before apremilast (15% [2331/16 116] to 45% [7253/16 116]) persisted a year into treatment (9% [816/8496] to 36% [2999/8496]) and were similar to dupilumab (11% [850/7787] to 41% [3161/7787] vs 3% [149/4577] to 25% [1160/4577]). Conclusions and Relevance: In this descriptive analysis of patients with CISDs starting systemic immunomodulatory treatment in the US, less than 60% received the recommended pretreatment testing. Additional research is required to understand whether variations in testing affect patient outcomes.

Choosing immunomodulating therapies for the treatment of COVID-19: recommendations based on placebo-controlled trial evidence.

BACKGROUND: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy. OBJECTIVES: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19. SOURCES: We reviewed COVID-19 treatment guidelines (World Health Organization [WHO], Infectious Diseases Society of America [IDSA] and The National Institutes of Health [NIH]) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated. CONTENT: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), IL-6 antagonists [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), JAK inhibitors [Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022;6:CD015209] (cited 34), and complement C5a inhibitors [Tsai CL, Lai CC, Chen CY, Lee HS. The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: A systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2023;21:77-86] (cited 1). Using the same randomized clinical trials, we evaluated the four meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (Risk Ratio [RR] 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]), and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65 [95% CI, 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]). IMPLICATIONS: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low- or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.

Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis.

Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and ß-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others.