Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 24 appraisals
Rheumatic diseases clinics of North America
Machine Learning-Enhanced Autoantibody Discovery and Diagnostics in Systemic Autoimmune Rheumatic Diseases
The growing implementation of machine learning (ML) has extended into autoantibody research for the study of systemic autoimmune rheumatic diseases (SARDs). ML methods offer a promising approach for efficiently handling and identifying important signals within the big data generated by modern autoantibody technologies. The novel biomarkers identified through advanced ML techniques show promise in outperforming current clinical tools, bringing us closer to the goal of precision medicine. In this article, we will provide an overview of ML approaches and how they have been applied in autoantibody research to improve the diagnosis and characterization of SARDs.
2 Aug 2026
Read appraisal →RMD open
Anakinra for intravenous immunoglobulin-resistant Kawasaki disease: a systematic literature review
BACKGROUND: Approximately 10%-20% of patients with Kawasaki disease (KD) are resistant to intravenous immunoglobulins (IVIG) and are at increased risk of developing coronary artery aneurysms (CAA). A potential therapeutic role of anakinra (ANK) in refractory KD has been suggested. The aim of this work is to systematically review and critically appraise the available clinical evidence on the use of ANK in the treatment of IVIG-resistant KD, focusing on treatment indications, timing, dosage, efficacy on fever, inflammation, CAA and safety. METHODS: A systematic literature search was conducted across PubMed, Embase, Web of Science, Cochrane Library, Emcare, Academic Search Premier and Google Scholar from inception to 9 October 2025, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included all study designs reporting outcomes of patients with KD treated with ANK. RESULTS: Thirty-two publications (31 identified through database search and one by cross-referencing) describing 81 patients were included. Most reports were single cases or small series, with two early-phase clinical trials. Treatment with ANK was associated with resolution of fever and systemic inflammation in 94.9% of patients. Complete CAA resolution was reported in 32% and stabilisation/dimensional reduction in 56.3%. No serious safety concerns were identified. However, these findings derive from heterogeneous and low-quality evidence and should be interpreted with caution. CONCLUSIONS: In IVIG-resistant KD, ANK was effective in controlling systemic inflammation, although more data are needed to assess its efficacy on coronary outcomes. While these findings are encouraging in supporting consideration of ANK for refractory KD, larger randomised clinical studies are warranted to define optimal ANK timing of introduction and dosing, and to evaluate its long-term efficacy on cardiac outcomes. PROSPERO REGISTRATION NUMBER: CRD420252129435.
31 July 2026
Read appraisal →Genome biology
IDEAL-Age: an interpretable deep learning framework for single-cell resolution profiling of immunological aging
Immunosenescence increases susceptibility to infection and reduces vaccine responsiveness, yet bulk transcriptomic clocks obscure the cellular heterogeneity underlying this process. Here, we present IDEAL-Age, an interpretable deep learning framework that operates directly on single-cell PBMC transcriptomes. Benchmarking against 35 methods across independent cohorts demonstrates superior predictive performance. The framework's interpretability uncovers linear and non-linear gene contribution trajectories that reveal phase-specific physiological transitions, and identifies youth-associated or aging-associated cellular roles. Application to systemic lupus erythematosus reveals accelerated immunological aging driven by interferon-associated monocyte shifts. IDEAL-Age establishes a high-resolution computational framework for deciphering systemic immune aging.
27 July 2026
Read appraisal →Infectious diseases of poverty
Broadly neutralizing antibodies for HIV therapy in clinical trials: a systematic review
BACKGROUND: Lifelong daily antiretroviral therapy (ART) effectively suppresses human immunodeficiency virus type 1 (HIV-1) replication but does not eradicate the virus, underscoring the urgent need for long-acting antivirals and functional cure strategies. Broadly neutralizing antibodies (bNAbs) have emerged as a promising approach for achieving durable HIV-1 remission. In this systematic review, we summarize recent advances in the development of bNAbs for HIV-1 treatment. METHODS: We searched PubMed, Embase, and Web of Science for clinical trials published up to March 22, 2026. We included data evaluating intravenously administered bNAbs, with or without concomitant conventional ART, and comparing them with placebo, ART or no intervention. These data were used to evaluate the pharmacokinetics, antiviral efficacy, resistance profiles, immunologic effects, and safety of intravenously administered bNAbs. RESULTS: LS-modified bNAbs extended half-life by 2- to 5-fold relative to their parental counterparts (e.g., VRC01LS: 71 vs 15 days), although viremia reduced half-life by 20-40%. In viremic participants harboring bNAb-sensitive virus, monotherapy achieved viral load (VL) reductions of 0.93-1.8 log₁₀ copies/ml, with rebound occurring within approximately 4-8 weeks, whereas combinations regimens achieved declines of up to 2.04 log₁₀ copies/ml and delayed rebound to 15-33 weeks. No consistent reduction in total reservoir size was observed, although early intervention and baseline viral sensitivity appeared to limit reservoir expansion. Resistance emerged through epitope-proximal mutations, with cross-resistance observed mainly among antibodies targeting shared epitope classes. Overall, bNAbs were well tolerated, with rare discontinuations (0.4%) and low immunogenicity. CONCLUSIONS: LS-engineered bNAbs exhibit a longer half-life than their parental antibodies. Combination regimens achieve greater VL reductions and a longer delayed rebound compared with monotherapy, indicating that LS-modified multi-epitope bNAb cocktails are promising for long-acting HIV-1 remission. To become clinically competitive, larger resistance-guided trials are needed to extend dosing intervals, improve resistance mitigation, and define optimal integration with other long-acting therapies.
4 July 2026
Read appraisal →Journal of the Egyptian National Cancer Institute
Artificial intelligence in cancer immunotherapy: current trends in predicting response and personalizing treatment
Artificial intelligence (AI) can transform cancer immunotherapy by enabling more accurate prediction of treatment responses, the discovery of specific biomarkers, and the development of personalised treatment plans. Traditional single-marker biomarkers (PD-L1, TMB, MSI) lack consistency across tumour types and cannot be used to assess tumour heterogeneity or the dynamic tumour microenvironment (TME). This review synthesises developments in multimodal AI models that combine genomics, transcriptomics, radiomics, digital pathology (pathomics), circulating biomarkers, and clinical evidence to create composite predictive signatures with significantly better discriminatory value. AUCs over 0.8 have been seen in a few retrospective studies with deep learning and ensemble models on whole-slide images, CT/MRI/PET radiomics, spatial and single-cell omics, and multi-omics fusion models, but prospective and multicentre validation is scarce, and external validation often shows deterioration in performance. AI is also used to enhance the translational pipelines of adoptive cell therapies (e.g., CAR-T) by improving patient selection, manufacturing (e.g., digital twins), and early toxicity prediction (e.g., CRS, ICANS). Nevertheless, clinical implementation remains hindered by data heterogeneity, bias, poor longitudinal validation, limited reproducibility, and a lack of transparency in most models, even though prospective, multicenter validation and explainable AI are crucial for clinician trust and regulatory acceptance. New systems such as federated learning, foundation models, spatial omics, digital twins, and wearable monitoring represent paths to generalizable, privacy-preserving, and actionable systems in clinical practice. To achieve the potential of AI, the generation of data will need to be standardized, reporting must be transparent, interdisciplinary, and regulatory frameworks must be strengthened focusing on the practical use of AI and patient safety. By taking these steps, AI could be shifted to prospective clinical decision support, which uses AI to meaningfully enhance personalization and outcomes in cancer immunotherapy based on a retrospective research tool.
30 May 2026
Read appraisal →mAbs
Prediction of antibody non-specificity using protein language models and biophysical parameters
The development of therapeutic antibodies requires optimizing target binding affinity and pharmacodynamics, while ensuring high developability potential, including minimizing non-specific binding. In this study, we address this problem by predicting antibody non-specificity by two complementary approaches: (1) antibody sequence embeddings by protein language models (PLMs) and (2) a comprehensive set of sequence-based biophysical descriptors. We benchmark the PLM embeddings against interpretable, sequence-derived biophysical descriptors and use fragment-specific models (variable heavy (VH) and variable light (VL) chains, concatenated regions, and individual complementary-determining regions (CDRs) to identify region-level determinants of non-specificity in functional antibodies that bind defined targets. These models were trained on previously published human and mouse antibody data and tested on three public datasets. We show that non-specificity is best predicted from the VH domain and heavy-chain CDRs. These region-level analyses show that heavy-chain features, especially H-CDR3, dominate the predictive signal. The top performing PLM, a VH domain-based Evolutionary Scale Modeling 1 v LogisticReg model, resulted in 10-fold cross-validation accuracy of up to 71%. While predictive accuracy is comparable to classical machine-learning baselines, PLM-based embeddings provide sequence-context representations that yield consistent region-level attribution and provide complementarity to the classical models by enhancing the reliability of predicted non‑specificity scores when used in combination. Our biophysical descriptor-based analysis identified the isoelectric point as a key driver of non-specificity, consistent with previous reports. Our findings highlight the importance of biophysical properties in predicting antibody non-specificity and highlight the potential of PLMs for the development of antibody-based therapeutics. These conclusions are robust to alternative class definitions and are not driven by VH-VL mutational bias. We illustrate the generalizability and practical use of the PLM approach by extending it to therapeutic antibodies and nanobodies, providing a tool for early-stage developability assessment, and we make the models publicly available.
29 May 2026
Read appraisal →Rheumatology international
Targeting type I interferon in lupus panniculitis: a case-based systematic literature review
Lupus panniculitis (LEP) is a rare form of cutaneous lupus (CLE) characterised by progressive, often disfiguring course and poor response to treatment. Type I interferon inhibition through anifrolumab (ANF) is effective in CLE but limited data are available for its use in LEP. To address this issue, we screened patients with CLE and/or systemic lupus erythematosus (SLE) for biopsy-proven diagnoses of LEP and treatment with ANF. Besides demographics, general clinical features, concomitant treatments before and after ANF and safety signals, we measured disease activity and damage with the SLE disease activity index 2000 (SLEDAI-2 K), the CLE Disease Area and Severity Index activity (CLASI-A) and damage scores and the SLE International collaborating clinics/American College of Rheumatology damage index. The same data were retrieved, when available, from existing cases extracted from systematic literature review. Sixteen cases were identified, including 3/421 newly described patients, with two receiving ANF as first-line immunosuppressant and one as an early treatment devoid of oral corticosteroids. All patients had a good response to treatment and most of them could taper or discontinue corticosteroids. CLASI-A scores were markedly reduced after ANF treatment [11.5 (7-29)] to 0 (0-2); p = 0.005]. The time to response was within five months in most cases. No significant adverse events were reported. Taken together, our data suggest that ANF might be effective in LEP and used as a first-line treatment to prevent LEP-related damage accrual.
21 May 2026
Read appraisal →Scientific reports
Cytokines and immunologic checkpoint molecules in predicting success of allergen immunotherapy.
There are large variations in how individual patients respond to allergen immunotherapy (AIT) against grass and/or birch allergy. There are currently no reliable biomarkers to predict which patients are likely to benefit from the treatment. The purpose of this study was to examine the potential of cytokine and soluble immunologic checkpoint molecule (ICM) levels as biomarkers for AIT success. Blood samples collected before starting AIT were analyzed for concentration of 92 different cytokines and 14 different ICMs. Traditional univariable statistical analysis was performed to evaluate differences between responders and non-responders. Furthermore, both unsupervised and supervised machine learning algorithms were used for multivariable analysis of differences between the responders and non-responders and to try to identify clusters within the subjects which could potentially be linked to endotypes of allergic rhinitis. Neither univariable nor multivariable analysis showed any significant correlations between AIT outcome and pre-treatment levels of cytokines or soluble ICM. In the cluster analysis, 4 clustering algorithms consistently grouped 48 of the 60 subjects into 3 distinct clusters. However, these clusters did not correlate with clinical characteristics, indicating that the clusters are unlikely to represent actual biological endotypes. The findings of this study did not provide evidence supporting the use of pre-treatment levels of cytokines and ICM as biomarkers for AIT outcome.
20 May 2026
Read appraisal →Drug discoveries & therapeutics
Efficacy and safety of filgotinib versus tocilizumab in active rheumatoid arthritis: A randomized, open-label, multicenter study with clinical and musculoskeletal ultrasound evaluation (TRANSFORM study)
Janus kinase (JAK) and interleukin-6 (IL-6) inhibitors are therapeutic options for patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); however, no randomized controlled trial has compared their efficacy and safety. Since both act through the JAK-signal transducer and activator of transcription pathway, a comparative evaluation is warranted. We conducted a prospective, randomized, open-label trial at 55 centers in Japan, randomizing patients with active RA despite csDMARD therapy in a 1:1 ratio to receive 200 mg/day filgotinib or subcutaneous tocilizumab as monotherapy; the primary endpoint was American College of Rheumatology (ACR) 50 at week 12, and secondary endpoints included clinical disease activity indices, musculoskeletal ultrasonography scores, patient-reported outcomes, and serum biomarkers through 52 weeks. Twenty-six patients were enrolled (13 per group) before study termination due to insufficient recruitment, and descriptive analyses were performed. At week 12, ACR50 was achieved in 38.5% (5/13) patients in the filgotinib group and 46.2% (6/13) in the tocilizumab group (risk difference: -7.69%; 95% confidence interval: -42.26 to 28.8). Both groups showed early and sustained improvements in disease activity from week 2. The improvement in patient global assessment scores was greater with filgotinib at week 2 but the difference diminished thereafter, and serum IL-6 level decreased with filgotinib but increased with tocilizumab. Four serious adverse events occurred with filgotinib, including infections and cardiac events. Because this study was underpowered and the analysis was descriptive, larger studies are needed to confirm these findings and define optimal use. (The study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) as jRCTs071200107 and in ClinicalTrials.gov as NCT05090410.).
18 May 2026
Read appraisal →Blood
Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia
To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.
16 May 2026
Read appraisal →JMIR medical informatics
Adverse Pregnancy Outcomes in Women With Immune Abnormalities: Machine Learning Model Development and Validation Using First-Trimester Sonographic Features
BACKGROUND: The maintenance and progression of pregnancy rely on immune homeostasis at the maternal-fetal interface. However, pregnancy complicated by autoimmune abnormalities can disrupt this balance and significantly increase the risk of adverse pregnancy outcomes (APOs). OBJECTIVE: This study aimed to (1) develop an interpretable predictive tool for APOs in patients with immune abnormalities and (2) interpret the models using Shapley additive explanations (SHAP) values. METHODS: This study retrospectively analyzed clinical data from 288 patients with autoimmune abnormalities at Yichang Central People's Hospital between 2019 and 2024. Feature selection was performed using both the Boruta algorithm and Least Absolute Shrinkage and Selection Operator regression to identify optimal predictive factors associated with APOs. Nine machine learning models were developed and subsequently underwent a comprehensive comparative evaluation of their predictive performance, leading to the identification of the optimal predictive model. SHAP values were generated to provide interpretable insights into model predictions. RESULTS: A total of 288 patients were included in the study, 124 (43.06%) of whom had APOs. The extreme gradient boosting algorithm was shown to be the optimal model after a comparison of 9 different models utilizing various metrics. The SHAP analysis showed that crown-rump length at 6+0 to 8+6 weeks, the number of other drugs, the number of complications during pregnancy, gestational sac volume at 6+0 to 8+6 weeks, and yolk sac diameter change at 6+0 to 8+6 weeks were the key predictive factors affecting APOs. CONCLUSIONS: The study developed an interpretable predictive tool for APOs in patients with immune abnormalities, which may assist clinicians in making early intervention decisions.
14 May 2026
Read appraisal →Lancet (London, England)
Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to-severe systemic lupus erythematosus: findings from Cohort B of a multicentre, international, double-blind, placebo-controlled dose-finding phase 2 trial
BACKGROUND: Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). METHODS: Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. FINDINGS: Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. INTERPRETATION: In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. FUNDING: Merck Healthcare (Darmstadt, Germany).
13 May 2026
Read appraisal →Antiviral therapy
Factors associated with immunological non-response in HIV patients receiving antiretroviral therapy in Southeast Asia: A systematic review
ObjectiveThis systematic review summarizes factors associated with immunological non-response (INR) among people with HIV on antiretroviral therapy (ART) in Southeast Asia.MethodsWe conducted a systematic search of PubMed, ScienceDirect, DOAJ, and Lens.org for studies published between 2010 and 2025. Observational studies examining immunological outcomes following ART initiation and related factors were included. Study quality was assessed using the Newcastle-Ottawa Scale, and results were synthesized using a harvest plot.ResultTen eligible studies were included in the synthesis, comprising a total of 6,988 participants with substantial heterogeneity observed across studies. Factors associated with INR included age, sex, baseline CD4 cell count, HIV RNA levels, and co-infections. Among these factors, baseline CD4 cell count at the initiation of ART emerged as the most consistently associated determinant; lower baseline CD4 levels were linked to a higher risk of INR even with virological suppression.ConclusionThis review highlights baseline immunological status at ART initiation as a key predictor of immunological non-response in Southeast Asia. These findings underscore the critical importance of early HIV diagnosis and timely initiation of ART to prevent advanced immune damage and optimize immunological recovery.
12 May 2026
Read appraisal →Journal for immunotherapy of cancer
Safety and immunogenicity of a tri-antigen vaccine targeting IGFBP-2, HER2, and IGF-IR in participants with non-metastatic breast cancer
BACKGROUND: Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer. Current treatment consists of surgery, radiation, and often systemic therapy exposing patients to unnecessary health risks. Vaccines targeting DCIS may be a way to intercept preinvasive lesions and prevent the development of invasive breast cancer. METHODS: We developed a Th1 selective multiantigen, polyepitope plasmid-DNA vaccine encoding segments of IGFBP-2, HER2, and IGF-IR, all antigens expressed in hormone receptor positive and negative DCIS. We then performed a Phase I study in participants with non-metastatic breast cancer with no evidence of disease. The primary objective was to assess the safety of 3 monthly intradermal doses (150, 300, or 600 µg) of the tri-antigen vaccine with granulocyte macrophage colony-stimulating factor as an adjuvant. 32 participants were enrolled, 10 per dose level. Toxicity evaluations occurred monthly with vaccination and at 1 and 6 months after the last vaccine. Blood was collected at baseline and at 1 and 6 months after the last immunization to assess cellular immune responses. Participants were followed annually for 5 years for long-term toxicity. RESULTS: There was no significant difference in adverse events (AEs) across dose levels and all related AEs were grades 1 or 2. All doses were immunogenic; responders included 70% of participants at the 150 µg dose level, 67% at the 300 µg dose, and 40% at the 600 µg dose level. All participants at the 300 µg dose retained significant Th1-antigen-specific immune response at 6 months after end of immunizations. T-cells derived from vaccine immunologic responders exhibited gene expression profiles that indicated an increased metabolic fitness as compared with immunologic non-responders. CONCLUSIONS: The tri-antigen vaccine appears safe and immunogenic. The intermediate dose (300 µg) was chosen as the Phase II dose due to the long-term persistence of immunity after vaccination. The vaccine will be studied in Phase II trials for the treatment of DCIS. TRIAL REGISTRATION NUMBER: NCT02780401.
11 May 2026
Read appraisal →The Journal of dermatological treatment
A safety checklist before initiating second-generation immunomodulating drugs for inflammatory dermatoses: a systematic review
BACKGROUND/AIM: Second-generation immunomodulating drugs for inflammatory dermatoses have expanded over the past decades. Contraindications and special warnings must be considered before starting any treatment, but identifying all relevant safety information can be time-consuming. The objective is to provide an overview of contraindications, special warnings, and boxed warnings with the aim to establish a safety checklist, covering second-generation immunomodulatory therapies. METHODS: We identified contraindications, special warnings and boxed warnings provided by the European Medicines Agency and the US Food and Drug Administration, for second-generation immunomodulating drugs approved for inflammatory dermatoses. Both topical and systemic therapies were included. RESULTS: Most drug classes had warnings related to infections. Herpes zoster was listed for anti-CD20, IL-12/23i, INFi, JAKi and TYK2i, where hepatitis reactivation was reported for anti-CD20, TNFi, IL-17i, anti-BAFF, JAKi and TYK2i. Malignancy risk including skin cancer was mentioned for most classes, except IL-23i, IL-17i, IL-13i, IL-4/13i, IL-31i, IL-36i and PDE4i. Other serious warnings included neurological, cardiovascular, thrombotic, hepatic, renal, gastrointestinal, and psychiatric adverse events. CONCLUSION: This work provides a simple stepwise approach to managing contraindications and special warnings. Our safety checklist gives clinicians a rapid overview of contraindications, special warnings, and boxed warnings for the available drug classes approved for inflammatory dermatoses.
10 May 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial
BACKGROUND: Autoantibody-mediated complement activation drives pathology in acetylcholine receptor (AChR) antibody-positive generalised myasthenia gravis. Newer targeted therapies lower overall antibody concentrations or inhibit complement activity. We aimed to evaluate an siRNA (cemdisiran) targeting complement component 5 (C5) as monotherapy and in combination with a C5 antibody (pozelimab) in generalised myasthenia gravis. METHODS: NIMBLE is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 86 centres in 13 countries. We enrolled patients aged 18 years or older with a diagnosis of generalised myasthenia gravis, positive serology for anti-AChR or anti-LRP4 antibodies, and a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or greater. Patients were randomly allocated to receive cemdisiran monotherapy (600 mg every 12 weeks; cemdisiran group), pozelimab monotherapy (200 mg every 4 weeks; pozelimab group), combined cemdisiran (200 mg every 4 weeks) and pozelimab (200 mg every 4 weeks; combination group), or placebo, all administered subcutaneously, during a 24-week double-blind treatment period. The primary endpoint was change from baseline in MG-ADL scores at week 24, assessed in the modified intention-to-treat (mITT) primary analysis set (the first 245 randomly allocated patients who received any dose of study treatment and had at least one post-baseline assessment). A prespecified hierarchal statistical testing strategy was used; multiplicity was controlled for comparisons of cemdisiran versus placebo and combination versus placebo (pozelimab was not statistically tested against placebo and was used only to assess the contribution of components to the combination treatment). Safety was mainly assessed by recording of treatment-emergent adverse events in all patients who received any dose of study treatment. This study is registered with ClinicalTrials.gov (NCT05070858); the current status is active, not recruiting. FINDINGS: Between Jan 20, 2022 and July 18, 2025, 390 participants were screened and, as of the data cut-off presented in this report (July 8, 2025), 284 were randomly allocated to the cemdisiran group (79 [28%] patients), pozelimab group (50 [18%]), combination group (80 [28%]), and placebo group (75 [26%]). Of 277 patients who received any study treatment, 263 (95%) completed the double-blind treatment period. In the mITT primary analysis set, at week 24, the least-squares mean change from baseline in MG-ADL total score was -4·5 (SE 0·4) in the cemdisiran group (n=64), -4·0 (0·4) in the combination group (n=67), and -2·2 (0·5) in the placebo group (n=59). Placebo-adjusted least-squares mean differences in MG-ADL score at week 24 were -2·3 (SE 0·7; 95% CI -3·6 to -1·0; p=0·0005) in the cemdisiran group and -1·7 (0·7; -3·0 to -0·4; p=0·0086) in the combination group. The proportion of participants with at least one adverse event during the double-blind treatment period was 54 (69%) of 78 in the cemdisiran group, 65 (81%) of 80 in the combination group, 40 (82%) of 49 in the pozelimab group, and 54 (77%) of 70 in the placebo group. The most common adverse event in the cemdisiran group was upper respiratory tract infection (nine [12%] of 78 patients), which occurred at a similar incidence in the placebo group (eight [11%] of 70). No serious or meningococcal infections occurred in the cemdisiran group. Adverse events leading to treatment discontinuation occurred in two participants (3%) in the placebo group and one participant (2%) in the pozelimab group. No deaths occurred during the double-blind treatment period. Two deaths occurred after the double-blind treatment period, one of which was assessed as treatment-related by the investigator but not treatment-related by the sponsor. INTERPRETATION: Cemdisiran monotherapy and combination therapy were effective in the treatment of generalised myasthenia gravis, and were generally well tolerated. Subcutaneous dosing of cemdisiran, administered every 3 months, could provide a convenient treatment approach for generalised myasthenia gravis. FUNDING: Regeneron Pharmaceuticals.
10 May 2026
Read appraisal →Lancet (London, England)
Safety and efficacy of the monoclonal antibody L9LS for malaria prevention in children exposed to perennial malaria transmission in Kenya: a randomised, double-blind, placebo-controlled, phase 2 trial
BACKGROUND: Malaria remains a major cause of mortality globally, especially among young children in sub-Saharan Africa. The long-acting monoclonal antibody L9LS has shown high efficacy in preventing malaria in children aged 6-10 years exposed to seasonal transmission but remains untested in perennial transmission settings and younger children. We assessed the safety, tolerability, and efficacy of L9LS in infants and children in a high perennial malaria transmission setting. METHODS: This double-blind, two-part, randomised, placebo-controlled, phase 2 trial was done in Siaya county in western Kenya. In parts 1a and 1b, we tested the safety and tolerability of L9LS using an age de-escalation and dose escalation approach and randomly assigned (3:1) cohorts of healthy children (three cohorts aged 5-10 years, three cohorts aged 5-59 months, and two cohorts aged 5-71 months) to L9LS at doses of 5, 10, 20, 30, or 40 mg/kg subcutaneously or to placebo (normal saline). In part 2, healthy children aged 5-59 months were randomly assigned (1:1:1) by use of centralised computer-generated lists to receive two doses of L9LS at 10-20 mg/kg at baseline and month 6, one dose of L9LS at baseline and placebo at month 6, or placebo at both timepoints. Children were followed up for 12 months with monthly clinic visits and blood smear collections. Primary safety outcomes were incidence and severity of local and systemic solicited adverse events within 7 days of dosing and serious adverse events throughout follow-up. The primary efficacy endpoint was Plasmodium falciparum infection detected by blood smear over 12 months. Primary analyses were done in the modified intention-to-treat population, consisting of all randomly assigned participants who received the study intervention. This trial is registered with ClinicalTrials.gov (NCT05400655) and is complete. FINDINGS: In parts 1a and 1b, 96 children were enrolled and randomly assigned between Oct 1, 2022, and Jan 16, 2024; 72 participants were assigned to L9LS and 24 were assigned to placebo. In part 2, 324 children aged 5-59 months were enrolled and randomly assigned between Jan 26 and June 2, 2023; 108 children were assigned to one-dose L9LS, 106 to two-dose L9LS, and 110 to placebo. Across all study parts, grade 3 or worse treatment-related adverse events occurred after four (1%) of 384 L9LS injections and two (1%) of 338 placebo injections; these events all resolved by study end. The proportion of solicited and unsolicited adverse events was similar across all L9LS dose groups. There were no serious adverse events related to the trial. In part 2, 70 (66%) of 106 children in the two-dose L9LS group had at least one P falciparum infection during the 12-month follow-up versus 91 (83%) of 110 children in the placebo group (protective efficacy 42·7%, 95% CI 22·5-57·7; p=0·0003). INTERPRETATION: L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6-12 months. A higher dose of L9LS might be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P falciparum transmission. FUNDING: Gates Foundation.
2 May 2026
Read appraisal →Journal for immunotherapy of cancer
Phase 2 trial of pTVG-HP ± pTVG-AR DNA vaccines and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)
BACKGROUND: We previously reported a trial using pembrolizumab with a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Favorable clinical outcomes were associated with T-cell activation, suggesting immune response to vaccination was critical. In the current trial, we evaluated whether immunization with two vaccines, to broaden the T-cell response to other cancer-associated antigens, would elicit greater anti-tumor efficacy. MATERIALS AND METHODS: 60 patients with mCRPC were treated with vaccine on days 1 and 8 of a 3 week cycle, with pembrolizumab given on day 1 of each cycle. Patients in Arm A (n=30) received pTVG-HP as the vaccine, and patients in Arm B (n=30) received pTVG-AR (encoding the ligand-binding domain of the androgen receptor) alternating with pTVG-HP every two cycles. After eight cycles (6 months), patients continued to receive pembrolizumab alone, with the option to receive further booster immunizations at prostate-specific antigen (PSA) progression. The primary objective was 6-month progression-free survival (PFS). Secondary objectives included safety, objective response rate, PSA response rate, overall survival (OS), and immunological evaluations. RESULTS: Overall median time to progression was 24 weeks (24 weeks Arm A, 24 weeks Arm B, p=0.80). The month 6 PFS rate was 51% in Arm A and 45% in Arm B. Median OS was 2.8 years (2.5 years Arm A, 3.7 years Arm B, p=0.16). 20% of patients in each arm experienced a PSA decline of >50%. 20 patients (n=8 Arm A, n=12 Arm B) had measurable disease, and 6/20 (30%) experienced a partial response. Eight patients received booster immunizations after 6 months, 3 of whom subsequently experienced a PSA decline. Three patients in Arm B experienced creatine kinase elevation with or without increased transaminases, which were not observed in Arm A. T cell immune responses to both antigens were detected in patients treated in Arm B. CONCLUSIONS: Treatment with DNA vaccines and pembrolizumab demonstrated anti-tumor activity in terms of PSA declines and objective responses. The addition of pTVG-AR did not significantly increase measures of clinical efficacy; however, it was associated with a slight increase in toxicity to tissues that also express AR. TRIAL REGISTRATION NUMBER: NCT04090528.
27 Apr 2026
Read appraisal →Medicine
Safety assessment of intravenous immunoglobulins in pediatric population: A systematic review of adverse events
BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic intervention utilized in various disorders due to its antimicrobial, antiinflammatory, and immunomodulatory properties. The market offers a range of IVIG products, leading to variations in efficacy and safety profiles. This study aimed to systematically evaluate the safety profile of IVIG administration in pediatric patients. METHODS: A systematic search was conducted on PubMed, Embase, and Cochrane databases using predetermined MeSH terms, covering the period from January 1, 2000, to October 15, 2022. Two independent reviewers performed relevance screening. Inclusion criteria encompassed English-language studies involving patients below 18 years of age who received IVIG treatment. Included studies were limited to peer-reviewed full-text publications with a minimum of 5 patients. A total of 8 studies met the inclusion criteria, encompassing 1088 pediatric patients. RESULTS: Eight studies met the inclusion criteria (total 1088 pediatric patients). Five studies reported patient-level adverse event data suitable for pooling (688 patients). Among these 688 patients, 267 (38.8%) experienced adverse events (AEs). Among reported AEs, the most frequent were headache 68/267 (25.5%) and fever 47/267 (17.6%). Less common AEs included nausea 12/267 (4.5%) and fatigue 12/267 (4.5%). Four studies recorded a total of 2960 IVIG infusions, with 12.6% of infusions accompanied by AEs. The predominant AEs during infusions were headache (54.3%) and fever (29.4%). Cough (0.8%) and nausea (1.6%) were the least commonly observed AEs. Other AEs such as rash, vomiting, and abdominal pain were also reported. Of the 23 full-text articles reviewed, 8 were included. The remaining 15 were excluded due to the following reasons: 6 for duplicate data, 4 for inappropriate study design, 3 for not meeting the minimum number of patients, and 2 for incomplete adverse event reporting. These reasons are now detailed in the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. CONCLUSION: IVIG therapy demonstrates good tolerability in pediatric patients, with an overall favorable safety profile, aside from mild AEs associated with its administration. Serious AEs were infrequent and mainly observed in high-risk patients. Headache was the most prevalent AE, which seldom required hospitalization and could be effectively managed with acetaminophen. Other AEs were generally mild systemic reactions. Notably, AEs appear to be more frequent during the initial exposure to IVIG.
19 Apr 2026
Read appraisal →Inflammation research : official journal of the European Histamine Research Society ... [et al.]
The calcium-sensing receptor in sepsis and septic shock, mechanistic pathways and translational perspectives: a systematic review.
BACKGROUND: Sepsis and septic shock are major causes of mortality in critically ill patients. They are linked to widespread metabolic and immune dysregulation, including alterations in calcium and phosphate homeostasis. The calcium-sensing receptor (CaSR) not only plays a role in mineral balance, but also modulates key immune pathways and may contribute to the pathogenesis of sepsis. METHODS: A systematic literature review was conducted according to PRISMA 2020 guidelines. Four databases (PubMed, EMBASE, Cochrane Library, and Google Scholar) were searched for studies published since 1990. To be eligible for inclusion, articles had to be original research, reviews, or clinical trials involving adult models (mammalian or human). Full-text availability was required. Risk of bias was assessed for all studies included. RESULTS: Sixty-six articles met the inclusion criteria: 49 original studies and 17 reviews. No randomized controlled trials or meta-analyses were identified. Most studies relied on in vitro or in vivo models. CaSR was consistently reported to be upregulated or activated following exposure to bacterial and inflammatory stimuli in immune cells, including monocytes and lymphocytes. CaSR activation promotes proinflammatory cytokine release, notably IL-1β via the NOD like receptor family 3 (NLRP3) inflammasome although results in intestinal epithelial models remain inconsistent. In non-septic models, CaSR activation was associated with tissue and organ injury, including renal and cardiac damage, as well as vasoplegia related to endothelial dysfunction. Preclinical models of pneumonia and endotoxemia suggest that CaSR antagonists may effectively mitigate inflammation and organ injury. CONCLUSION: This systematic review identifies the CaSR as an amplifier of the host inflammatory response across both septic and non-septic preclinical models The lack of robust clinical data underscores the need for translational studies assessing CaSR expression or activity in patients with sepsis or septic shock, alongside in vivo validation of CaSR inhibition as a therapeutic strategy.
19 Apr 2026
Read appraisal →The New England journal of medicine
Ianalumab plus Eltrombopag in Immune Thrombocytopenia
BACKGROUND: Current second-line treatments for immune thrombocytopenia (ITP) require long-term administration. Ianalumab, a monoclonal antibody targeting B cells, is being assessed as a short-course second-line therapy in ITP. METHODS: In this phase 3, randomized, double-blind trial, we assigned, in a 1:1:1 ratio, adults with primary ITP and an insufficient response or a relapse after first-line glucocorticoid therapy to receive ianalumab at a dose of 9 mg or 3 mg per kilogram of body weight or placebo once monthly for 4 months. Eltrombopag, an oral thrombopoietin-receptor agonist, was administered once daily in each group according to local prescribing information; the dose was tapered until discontinuation by the end of week 24 in eligible patients. The primary end point was freedom from treatment failure, as determined in a time-to-event analysis, with treatment failure defined by a platelet count of less than 30×109 per liter more than 8 weeks after randomization, initiation of rescue therapy more than 8 weeks after randomization, initiation of new ITP therapy, inability to taper or discontinue eltrombopag because of an inadequate platelet count, or death from any cause, whichever occurred first. The key secondary end point was a stable response at 6 months, defined by a platelet count of at least 50×109 per liter in at least 75% of the measurements between weeks 19 and 25 without use of rescue therapy or new ITP therapy. Safety was assessed. RESULTS: A total of 152 patients underwent randomization: 50 to the 9-mg ianalumab group, 51 to the 3-mg ianalumab group, and 51 to the placebo group. The estimated probability of being free from treatment failure at 12 months was 54% (95% confidence interval [CI], 39 to 67) in the 9-mg group, 51% (95% CI, 36 to 64) in the 3-mg group, and 30% (95% CI, 18 to 43) in the placebo group. The time to treatment failure was significantly longer with ianalumab plus eltrombopag than with placebo plus eltrombopag; the estimated hazard ratio for treatment failure (ianalumab vs. placebo) was 0.55 (P = 0.04) in the 9-mg group and 0.58 (P = 0.045) in the 3-mg group. The percentage of patients with a stable response at 6 months was significantly higher in the 9-mg group than in the placebo group (62% vs. 39%; P = 0.045). The overall frequency of adverse events during the treatment period was generally similar in the three groups. The frequency of serious adverse events was 16% in the 9-mg group, 6% in the 3-mg group, and 4% in the placebo group. CONCLUSIONS: Ianalumab plus eltrombopag led to a longer time to treatment failure than placebo plus eltrombopag. (Funded by Novartis; VAYHIT2 ClinicalTrials.gov number, NCT05653219.).
16 Apr 2026
Read appraisal →Journal of investigational allergology & clinical immunology
Dupilumab in Eosinophilic Gastrointestinal Disorders With Extraesophageal Involvement: A Pediatric Case Series and Systematic Review
Dupilumab has proven effective in the treatment of eosinophilic esophagitis (EoE) in randomized controlled trials. Its efficacy in other, less common and generally more severe eosinophilic gastrointestinal disorders (EGIDs) is scientifically plausible, although it has not been studied to date. Our objective was to describe published and our experience on the empirical use of dupilumab in patients affected by EGIDs with extraesophageal involvement. We retrospectively analyzed the medical charts of children diagnosed with extraesophageal EGIDs treated with dupilumab at our tertiary medical center. The Medline, Embase, and Cochrane databases were searched up to January 2025 for articles describing the use of dupilumab in patients with diagnosed or suspected extraesophageal EGID. Our cohort included 8 patients with a clinical and histological diagnosis of EGID and extraesophageal involvement. All of them had recurrent gastrointestinal symptoms refractory to standard treatments. Three patients had growth retardation. In all patients, symptoms and macroscopic and histological abnormalities, including eosinophilic infiltration, quickly improved after initiation of dupilumab. The systematic review identified 11 case reports (n=29 patients) of pediatric and adult patients with extraesophageal EGIDs treated with dupilumab. All 11 reports described significant clinical and histological improvement following therapy. Clinical experience suggests that dupilumab is effective in treating pediatric EGIDs with extraesophageal features. Given the rarity and high morbidity of these disorders, dupilumab could be considered a reasonable option while waiting for high-quality evidence from ongoing randomized controlled trials.
16 Apr 2026
Read appraisal →Vaccine
The safety and efficacy of in situ vaccine FOLactis for advanced hepatic malignancies.
BACKGROUND: Recent years have witnessed the emergence of a novel research direction in the field of tumor vaccines. An in situ vaccine known as FOLactis, comprised of genetically engineered Lactococcus lactis expressing a fusion protein of Fms-like tyrosine kinase 3 ligand (Flt3L) and co-stimulator OX40 ligand (OX40L), was developed by the Oncology Centre of Nanjing Drum Tower Hospital. The present study was designed to evaluate the efficacy and safety of combination therapy based on intratumoral injection of the in situ vaccine FOLactis and intravenous PD-1 monoclonal antibody in combination with immunoradiotherapy or low-dose chemotherapy in the treatment of advanced hepatic malignancies. METHODS: In this exploratory clinical study, patients with advanced hepatic malignancies were enrolled and randomly assigned to Group A and Group B, corresponding to different treatment regimens. The treatment regimen in Group A consisted of the in situ vaccine FOLactis combined with a PD-1 monoclonal antibody and immunoradiotherapy (5Gy/fraction×3fractions). In contrast, the regimen in Group B included the in situ vaccine FOLactis, a PD-1 monoclonal antibody, and low-dose chemotherapy (cisplatin plus vincristine). All treatments were given in 21-day cycles. The primary observation indicator of the study was the objective response rate (ORR) as defined by RECIST v1.1. Secondary observation indicators included the disease control rate (DCR) and the incidence of adverse events. RESULTS: A total of 18 eligible patients were included in the study. In Group A, the ORR and DCR for targeted lesions were 33.3%(95%CI:12.1-64.6%) and 77.8%(95%CI:45.3-96.1%), while the ORR and DCR for non-targeted lesions were 22.2%(95%CI:3.9-54.7%) and 66.7%(95%CI:35.4-87.9%), respectively. Targeted and non-targeted lesions in Group B did not reduce significantly, and their respective DCRs were 66.7%(95%CI:35.4-87.9%) and 22.2%(95%CI:3.9-54.7%). Patients in Group A experienced no significant adverse events. Patients in Group B experienced grade 1-2 hyperthermia as a side effect. CONCLUSIONS: The combination therapy based on the in situ vaccine FOLactis and intravenous PD-1 monoclonal antibody showed a certain degree of anti-tumor effect, and was safe and well tolerated in patients with advanced hepatic malignancies. TRIAL REGISTRATION: The Ethics Committee of Nanjing Drum Tower Hospital approved this study (approval number 2022-101-01). The associated trial is registered at ChiCTR.gov.cn (ChiCTR2200060660).
12 Apr 2026
Read appraisal →The New England journal of medicine
A Phase 2 Randomized Trial of Mezagitamab in Primary Immune Thrombocytopenia
BACKGROUND: Immune thrombocytopenia (ITP) is a disorder of increased platelet destruction and reduced platelet production and is associated with an increased bleeding risk and a compromised quality of life. Available therapies are ineffective in at least 20% of cases. Mezagitamab is an anti-CD38 antibody that targets plasma cells, plasmablasts, and natural killer cells. METHODS: We conducted this multicenter, double-blind, randomized, placebo-controlled trial to assess the safety and efficacy of mezagitamab at a dose of 100 mg, 300 mg, or 600 mg, as compared with placebo, administered subcutaneously once weekly for 8 weeks in adults with persistent or chronic ITP (mean platelet count on ≥2 measurements, <30,000 per microliter). The primary end point was adverse events. A key secondary efficacy end point was a platelet response (defined by a platelet count of ≥50,000 per microliter and ≥20,000 per microliter above the baseline value) on at least two visits at any time through week 16. RESULTS: In the combined mezagitamab groups (28 participants), the mean age was 50 years (range, 24 to 88) and the mean number of previous ITP therapies was 4 (range, 1 to 9); in the combined placebo groups (13 participants), the mean age was 39 years (range, 20 to 65) and the mean number of previous ITP therapies was 4 (range, 1 to 13). The mean baseline platelet count was 19,100 and 17,300 per microliter, respectively. Adverse events were reported in 19 of 28 participants (68%) in the combined mezagitamab groups and in 9 of 13 participants (69%) in the combined placebo groups; adverse events of grade 3 or higher in 5 of 28 participants (18%) and in 3 of 13 participants (23%), respectively; and serious adverse events in 4 of 28 participants (14%) and in 1 of 13 participants (8%). Through week 16, a platelet response was observed in 10 of 11 participants (91%) in the mezagitamab 600-mg group and in 3 of 13 participants (23%) in the combined placebo groups. CONCLUSIONS: Treatment with mezagitamab led to increased platelet counts, with a safety profile that appeared to be similar to that of placebo among participants with persistent or chronic ITP. (Funded by Takeda Development Center Americas; ClinicalTrials.gov number, NCT04278924.).
9 Apr 2026
Read appraisal →