IgM-enriched immunoglobulin human 5g/100ml solution for infusion vials

ObjectiveTo provide an updated systematic review and meta-analysis of the estimated pooled of anti-Annexin A5 antibodies (AnxA5-Abs) and Annexin A5 resistance (A5R) across antiphospholipid syndrome (APS) phenotypes.MethodsPubMed, EMBASE, and the Cochrane Library were searched from inception to June 2018 and updated in August 2025. Eligible studies included adults tested for AnxA5-Abs (IgG/IgM) and/or A5R who fulfilled revised Sapporo/Sydney APS clinical criteria. Pooled prevalences were estimated using Freeman-Tukey random-effects models and stratified by phenotype, serologic status, and autoimmune disease. Univariable and multivariable meta-regression evaluated predictors of IgG AnxA5-Abs and A5R. The protocol was registered in PROSPERO (CRD42018099462).ResultsFifty-eight studies were included, comprising 6960 patients and 2417 controls. In obstetric APS cohorts, pooled IgG AnxA5-Abs prevalence was 21.2% (95% CI 7.4-39.2) versus 4.0% (1.7-7.1) in controls; thrombotic APS showed 10.3% (5.7-15.8). IgM AnxA5-Abs were less frequent and showed weaker associations. IgG AnxA5-Abs prevalence was higher in seropositive APS (27.1%) and seronegative APS (20.4%) than in mixed/unstratified APS (11.7%). Among systemic lupus erythematosus (SLE) patients with APS-related clinical manifestations, IgG AnxA5-Abs prevalence was 31.7% versus 16.3% in SLE controls without clinical APS manifestations. A5R prevalence was higher in obstetric (29.9%) and thrombotic APS (28.8%) than in controls (17.5%). Obstetric APS independently predicted higher IgG AnxA5-Abs prevalence.ConclusionIgG AnxA5-Abs and A5R are enriched in Sapporo-defined obstetric APS, with weaker and less consistent associations in thrombosis-only APS. These findings support the biological plausibility of AnxA5 disruption in obstetric APS and identify AnxA5-related biomarkers as promising candidates for future validation. However, prospective external validation using standardized assays, pre-specified thresholds, and demonstration of incremental prognostic value are essential prerequisites before clinical risk stratification use.

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ObjectivesTo evaluate randomized adult evidence on adjunctive immunoglobulin M (IgM)-enriched immunoglobulin for sepsis and septic shock, with emphasis on short-term mortality, endpoint heterogeneity, statistical robustness, and harms reporting.Data sourcesMEDLINE, PubMed, Embase, CENTRAL, and Web of Science were searched from inception to September 2025. Reference lists of eligible articles and relevant reviews were screened, forward citation searching was performed, and study registers were checked for additional records.Study selectionRandomized controlled trials enrolling adults with sepsis, severe sepsis, or septic shock were eligible when they evaluated an IgM-enriched immunoglobulin preparation in addition to standard care and reported extractable mortality or clinically relevant outcomes. The protocol-concordant core synthesis included English-language adult Pentaglobin trials with extractable short-term mortality data. Two post hoc extensions were labeled explicitly: a language-inclusive Pentaglobin sensitivity analysis and an exploratory formulation-class analysis incorporating the phase II Concentrated IgM for Application (CIGMA) trimodulin trial.Data extractionTwo reviewers independently screened records, assessed full texts, extracted study characteristics, endpoint timing, mortality events, and reported adverse events, and resolved disagreements by discussion or third-reviewer adjudication. Risk of bias was assessed with Cochrane Risk of Bias 2 tool for randomized trials, and certainty was judged with the Grading of Recommendations Assessment, Development, and Evaluation principles.Data synthesisSix English-language randomized Pentaglobin trials with extractable short-term mortality data (411 participants) contributed to the protocol-concordant core synthesis. The primary pooled estimate was directionally favorable but statistically inconclusive (odds ratio [OR], 0.65; 95% CI, 0.39-1.07; I2 = 9%). Restriction to exact 28-day mortality also remained inconclusive (OR, 0.84; 95% CI, 0.50-1.43; I2 = 0%). An alternative risk-ratio model was similarly nonsignificant (risk ratio, 0.76; 95% CI, 0.55-1.06; I2 = 0%). Statistically significant estimates arose only in exploratory post hoc analyses: the language-inclusive Pentaglobin sensitivity analysis (OR, 0.57; 95% CI, 0.34-0.95; I2 = 16%) and the exploratory formulation-class model including CIGMA (OR, 0.64; 95% CI, 0.43-0.94; I2 = 5%). Safety reporting was incomplete in most Pentaglobin reports.ConclusionsCurrent randomized adult evidence does not justify routine use of IgM-enriched immunoglobulin in unselected sepsis or septic shock. Direct Pentaglobin evidence remains statistically inconclusive, whereas statistically significant estimates appear only after exploratory expansion to historical or indirect formulation-level evidence. Efficacy remains unproven, but the recurrent direction of effect supports a modern, adequately powered, phenotype-guided trial with standardized day-28 mortality and rigorous safety assessment.

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