The safety profile of mesenchymal stem cell therapy administered through intrathecal injections for treating neurological disorders: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Based on previous in vivo studies and human trials, intrathecal cell delivery is a safe and relevant therapeutic tool for improving patient's quality of life with neurological conditions. We aimed to characterise the safety profile of intrathecally delivered Mesenchymal stem cells (MSCs). METHODS: Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed. RESULTS: 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate. CONCLUSIONS: Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.

Safety and efficacy of mesenchymal stem cells therapy in the treatment of rheumatoid arthritis disease: A systematic review and meta-analysis of clinical trials.

BACKGROUND AND OBJECTIVES: Some patients have insufficient treatment response to conventional disease-modifying antirheumatic drugs (cDMARD); although biologics have proven to be an effective treatment for RA, the effects that bDMARDs have on integumentary, cardiac, and immune systems and the high costs associated with these treatments, make that mesenchymal stem cell-based therapies (MSCs) for RA are being considered potential treatment methods. This work analyses the performance in safety and efficacy terms of MSCs techniques. METHODS AND FINDING: A literature search was performed in PubMed, EMBASE, Cochrane Library, Web of Science, and Open Grey databases from inception to October 28, 2022. Three randomized controlled trials (RCTs) and one non-randomized controlled trial (non-RCTs), including 358 patients met our inclusion criteria and were included in qualitative synthesis; only RCTs were eligible for quantitative synthesis (meta-analysis). Meta-analysis of adverse events (AE) in RCTs showed no significant differences in the incidence of AE in the MSCs group compared to the control group (Risk ratio: 2.35; 95% CI, 0.58 to 9.58; I2 = 58.80%). The pooled Risk ratio for non-serious and serious adverse events showed no statistical difference between intervention and control groups concerning the incidence of non-serious and serious adverse events (Risk ratio: 2.35; 95% CI, 0.58 to 9.51; I2 = 58.62%) and (Risk ratio: 1.10; 95% CI, 0.15 to 7.97; I2 = 0.0%) respectively. The Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS28) decreased in agreement with the decreasing values of C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR). Additionally, a trend toward clinical efficacy was observed; however, this improvement was not shown in the studies after 12 months of follow-up without continuous treatment administration. CONCLUSION: This Systematic review and meta-analysis showed a favorable safety profile, without life-threatening events in subjects with RA, and a trend toward clinical efficacy that must be confirmed through high-quality RCTs, considerable sample size, and extended follow-up in subjects with RA.

Perfil lipídico e inhibidores de integrasa: revisión sistemática y metaanálisis / Lipid profile and integrase inhibitors: a systematic review and metaanalysis

Resumen Introducción: en pacientes con virus de inmunodeficiencia humana algunos antirretrovirales afectan el perfil lipídico incrementando el riesgo cardiovascular. Hay evidencia de que los inhibidores de integrasa afectan poco al perfil lipídico. El presente estudio buscó evaluar la mejor evidencia disponible sobre cambios en lípidos de pacientes con virus de inmunodeficiencia humana que cambiaron su terapia antirretroviral a esquemas con inhibidores de integrasa. Métodos: revisión sistemática de la literatura con intención metaanalítica. A partir de la pregunta: "En pacientes mayores de 16 años con virus de inmunodeficiencia humana, los esquemas antirretrovirales que incluyen inhibidores de integrasa comparados con aquellos esquemas antirretrovirales que no los incluyen, ¿presentan cambios en el perfil lipídico?" se extrajeron palabras clave para búsqueda de la evidencia publicada entre 1997 y diciembre 2019. Se incluyeron estudios experimentales y observacionales y su calidad fue evaluada. Se realizó análisis por inhibidor de integrasa y parámetro lipídico buscándose síntesis cuantitativa de la evidencia. Resultados: se identificaron 17 estudios relevantes susceptibles de síntesis de la evidencia con un total de 5 683 pacientes. De estos, 2 878 entraron a síntesis cuantitativa. Acorde a lo encontrado, los inhibidores de integrasa presentan mejor perfil lipídico comparados a otros antirretrovirales. Dolutegravir fue el que mostró mejor perfil lipídico cuando la comparación se hizo con inhibidores de proteasa. Raltegravir tuvo mejor perfil lipídico comparándolo con inhibidores de transcriptasa inversa no análogos de nucleósidos. Conclusiones: el uso de inhibidores de integrasa es un factor relevante en el control del riesgo cardiovascular en pacientes con virus de inmunodeficiencia humana.

Abstract Introduction: some antiretrovirals affect the lipid profile in human immunodeficiency virus patients increasing their cardiovascular risk. Integrase inhibitors generate little lipid alteration. The present study evaluated the best available evidence about changes in the lipid profile in human immunodeficiency virus patients who had switch from different antiretroviral therapies to schemes with integrase inhibitors. Methods: a systematic review with meta-analytic intention was carried out. From the question "How does antiretroviral schemes with integrase inhibitors impact in lipid profile in human immunodeficiency virus patients compared to antiretroviral schemes without integrase inhibitors?" an evidence search was done. Articles from experimental and observational studies were included and the quality was evaluated. An analysis by integrase inhibitor and lipid parameters was performed. Results: 17 relevant studies were identified and 2 878 patients were included in the quantitative synthesis. According to evidence, integrase inhibitors had a better lipid profile compared to other antiretrovirals. Dolutegravir had a better metabolic profile when it was compared with protease inhibitors. Raltegravir had a better lipid profile when it was compared to non-nucleoside analog reverse transcriptase inhibitors. Conclusions: integrase inhibitors are a relevant factor for cardiovascular risk control in patients with human immunodeficiency virus.