Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis.

BACKGROUND: In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials. OBJECTIVES: To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE. MAIN RESULTS: We included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. AUTHORS' CONCLUSIONS: The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

The comparative efficacy and safety of factor Xa inhibitors and warfarin for primary thromboprophylaxis in multiple myeloma patients undergoing immunomodulatory therapy.

There are limited data on the optimal choice of anticoagulation in multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs). We conducted a propensity score-matched cohort study using the TriNetX database to compare the efficacy and safety of factor Xa inhibitors and warfarin in this patient population. Compared to warfarin, factor Xa inhibitors had a similar risk of deep vein thrombosis (hazard ratio [HR]: 1.11 [95% CI: 0.50-2.46]) or pulmonary embolism (HR: 1.08 [95% CI: 0.59-2.00]). There were no differences in the risk of gastrointestinal or intracranial bleeding. Factor Xa inhibitor-treated patients had lower all-cause mortality (HR: 0.56 [95% CI: 0.36-0.86]) compared with warfarin. These data suggest that factor Xa inhibitors had similar safety and efficacy compared with warfarin for MM patients on IMiDs.

Systemic Immunomodulatory Treatments for Atopic Dermatitis: Living Systematic Review and Network Meta-Analysis Update.

Importance: There are multiple approved systemic treatments for atopic dermatitis. Lebrikizumab is a newly licensed biologic medication that has been compared to placebo in clinical trials but not to other systemic treatments. Objective: To compare reported measures of efficacy and safety of lebrikizumab to other systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Latin American and Caribbean Health Science Information database, the Global Resource of Eczema Trials database, and trial registries were searched from inception through November 3, 2023. Study Selection: Randomized clinical trials evaluating 8 or more weeks of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis. Titles, abstracts, and full texts were screened in duplicate. Data Extraction and Synthesis: Data were abstracted in duplicate and random-effects bayesian network meta-analyses were performed. Minimal important differences were used to define important differences between medications. Certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). The updated analysis was completed from December 13, 2023, to February 20, 2024. Main Outcome Measures: Efficacy outcomes were the Eczema Area and Severity Index (EASI), the Patient Oriented Eczema Measure (POEM) Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS) and were compared using mean difference (MD) with 95% credible intervals (CrI). Safety outcomes were serious adverse events and withdrawal due to adverse events. Other outcomes included the proportion of participants with 50%, 75%, and 90% improvement in EASI (EASI-50, -75, -90) and the proportion with success on the Investigator Global Assessment compared using odds ratios with 95% CrI. Results: The study sample included 97 eligible trials, with a total of 24 679 patients. Lebrikizumab was associated with no important difference in change in EASI (MD, -2.0; 95% CrI, -4.5 to 0.3; moderate certainty), POEM (MD, -1.1; 95% CrI -2.5 to 0.2; moderate certainty), DLQI (MD, -0.2; 95% CrI -2.1 to 1.6; moderate certainty), or PP-NRS (MD, 0.1; 95% CrI -0.4, 0.6; high certainty) compared to dupilumab among adults with atopic dermatitis who were treated for up to 16 weeks. Dupilumab was associated with higher odds of efficacy in binary outcomes compared with lebrikizumab. The relative efficacy of other approved systemic medications was similar to that found by previous updates of this living study, with high-dose upadacitinib and abrocitinib demonstrating numerically highest relative efficacy. For safety outcomes, low event rates limited useful comparisons. Conclusions and Relevance: In this living systematic review and network meta-analysis, lebrikizumab was similarly effective to dupilumab for the short-term treatment of atopic dermatitis in adults. Clinicians and patients can use these comparative data to inform treatment decisions.

Acute hypoxic respiratory failure due to Lenalidomide-induced interstitial pneumonitis in a patient with multiple myeloma.

BACKGROUND: Patients with multiple myeloma are immunosuppressed due to both the disease itself and immunosuppressive therapies. Thus, when presenting with respiratory failure and pulmonary opacities, pneumonia must be considered. However, while rare, immunomodulating medications used in the treatment of multiple myeloma can also cause potentially life-threatening respiratory failure, a distinction which has important treatment implications. CASE PRESENTATION: An 80-year-old male with recently diagnosed multiple myeloma undergoing treatment with lenalidomide and daratumumab presented with acute, rapidly progressive hypoxic respiratory failure ultimately requiring intubation and mechanical ventilatory support. Imaging revealed bilateral pulmonary opacities, however infectious workup was negative, and he was ultimately diagnosed with lenalidomide-induced interstitial pneumonitis, a rare but serious adverse effect of this medication. He was treated with drug discontinuation and methylprednisolone, and quickly recovered. CONCLUSION: Lenalidomide is an immunomodulating medication used in the treatment of multiple myeloma, and is associated with rare but serious cases of drug-induced interstitial pneumonitis. Thus, if a patient receiving lenalidomide develops shortness of breath and/or hypoxia, drug-induced pneumonitis must be on the differential. Permanent drug discontinuation with or without corticosteroids is the mainstay of treatment, and patients are often able to fully recover, underscoring the need for early recognition of this condition.

Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

BACKGROUND AND OBJECTIVES: Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. METHODS: We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. RESULTS: Incidence of HSVE was ∼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. DISCUSSION: In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach. METHODS: The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test. RESULTS: A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I2 = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2 = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID. CONCLUSIONS: A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

Thrombosis events in Chinese patients with newly diagnosed multiple myeloma.

A high risk of thrombosis is seen in patients with newly diagnosed multiple myeloma (NDMM), particularly those treated with immunomodulatory drugs (IMiDs). Large cohorts addressing the thrombosis issue of NDMM patients in Asia are lacking. We retrospectively analyzed the clinical information of NDMM patients diagnosed in Zhongshan Hospital Fudan University, a national medical center, from January 2013 to June 2021. Death and thrombotic events (TEs) were the endpoints. To investigate risk factors for TEs, the Fine and Gray competing risk regression models were created, in which unrelated deaths were labeled as competing risk events. A total of 931 NDMM patients were recruited in our study. The median follow-up was 23 months [interquartile range (IQR): 9-43 months]. Forty-two patients (4.51%) developed TEs, including 40 cases (4.30%) of venous thrombosis and 2 cases (0.21%) of arterial thrombosis. The median time from taking first-line treatment to TEs occurrence was 2.03 months (IQR: 0.52-5.70 months). The cumulative incidence of TEs was higher in patients treated with IMiDs than in those without IMiDs (8.25 vs. 4.32%, p = 0.038). There was no difference in the incidence of TEs between lenalidomide-based and thalidomide-based groups (7.80 vs. 8.84%, p = 0.886). Besides, TEs occurrence did not adversely affect OS (p = 0.150) or PFS (p = 0.210) in MM patients. Chinese NDMM patients have a lower incidence of thrombosis than those in western countries. The risk of thrombosis was particularly increased in patients treated with IMiDs. TEs were not associated with inferior progression-free survival or overall survival.

Pathophysiology and human cancer risk assessment of pharmaceutical-induced thymoma in carcinogenicity studies.

Thymoma, a tumor of thymic lymphocytes or thymic epithelial cells (TECs), is a common spontaneous tumor in Wistar Han rats, especially in females with up to 18% incidence in controls. In addition to sex, there are rat strain differences in background incidence of thymomas such as Sprague Dawley versus Wistar Han rats. Human thymomas are very rare and without clear differences in incidence between males and females. Immunomodulatory and anti-inflammatory pharmaceutical drug classes, including Janus kinase inhibitors, increase the incidence of benign thymoma in two-year rat carcinogenicity studies. Potential non-genotoxic mechanisms that might contribute to the pathogenesis of thymoma development in one sex (female) Wistar Han rats include: (1) hormonal differences, (2) high proliferation rate of TECs, (3) delayed physiologic thymic involution, and/or (4) significant level of immunosuppression at high doses of a pharmaceutical drug. Factors to consider in the human cancer risk assessment of pharmaceutical-induced thymoma are: the genotoxicity of the test article, sex and strain of rats, exposure safety margins, and pathophysiologic differences and similarities of thymoma between rats and humans. Totality of weight of evidence approach and available data suggest thymomas observed in carcinogenicity studies of pharmaceutical drugs are not relevant for human risk at clinically relevant therapeutic doses.

Reporting of COVID-19 Reinfection and Potential Role of Immunosuppressant/Immunomodulating Agents: A Cross-Sectional Observational Analysis Based on a Spontaneous Reporting Database.

BACKGROUND: The enduring presence of COVID-19 and subsequent increasing incidence of COVID-19 reinfection has prompted evaluation of associated risk factors, particularly the role of immunosuppression. OBJECTIVE: The objective of this study was to characterize cases indicative of COVID-19 reinfection with respect to their reported use of immunosuppressant/immunomodulating agents. METHODS: This cross-sectional observational study leveraged the Pfizer global safety database (SDB) containing adverse event data collected in association with use of Pfizer products between 1 October 2019, and 30 June 2022. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms were used to identify COVID-19 cases; the search was further refined to comprise cases that subsequently reported events potentially indicative of COVID-19 reinfection. RESULTS: Of the cumulative total of 218,242 COVID-19 cases reported into the SDB, 4590 cases (2.1%) involving potential COVID-19 reinfection were identified. Of these 4590 cases of potential Covid-19 reinfection, a total of 134 cases reported COVID-19 specifically during treatment with pharmaceutical products, of which approximately 16% (21/134) of cases reported use of immunosuppressant/immunomodulating agents. Likewise, in the overall dataset (213,652 cases; excluding the 4590 cases involving potential COVID-19 recurrence), the percentage of reported immunosuppressant/immunomodulating agents was low (12%). In applying similar parameters to a dataset that excludes COVID-19 vaccine cases, 18% of cases reported use of immunosuppressant/immunomodulating agents (similar to the aforementioned 16% of cases reported from the overall total dataset that was inclusive of vaccine cases). CONCLUSION: This pharmacovigilance study provides a characterization of cases indicative of COVID-19 reinfection with respect to reported use of immunosuppressant/immunomodulating agents. The observations generated from this cross-sectional observational analysis may prompt further research into the role of immunosuppression in COVID-19 reinfection, in an effort to better inform clinical practice and patient management.

A systematic review on disease-drug-drug interactions with immunomodulating drugs: A critical appraisal of risk assessment and drug labelling.

AIM: Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling. METHOD: For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions. RESULTS: Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases. CONCLUSION: This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-α) and interleukin-1 bèta (IL-1ß) in diseases with systemic inflammation.

The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer and Neurological Diseases.

Cereblon (CRBN) mediates the teratogenic effect of thalidomide in zebrafish, chickens, and humans. It additionally modulates the anti-myeloma effect of the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide. IMiDs bind to CRBN and recruit neo-substrates for their ubiquitination and proteasome-mediated degradation, which significantly expands the application of proteolysis-targeting chimeras (PROTACs) for targeted drug discovery. However, the underlying molecular mechanisms by which CRBN mediates the teratogenicity and anti-myeloma effect of IMiDs have not been fully elucidated. Furthermore, the normal physiological functions of endogenous CRBN have not been extensively studied, which prevents the thorough assessment of side effects of the CRBN ligand-based PROTACs in the treatment of cancer and neurological diseases. To advance our understanding of the diverse functions of CRBN, in this review, we will survey the ubiquitination-dependent and -independent functions of CRBN, summarize recent advances in the discovery of constitutive substrates and neo-substrates of CRBN, and explore the molecular functions of CRBN in cancer treatment and in the development of neurological diseases. We will also discuss the potential future directions toward the identification of CRBN substrates/interacting proteins and CRBN ligand-based drug discovery in the treatment of cancer and neurological diseases.

Immune interventions in COVID-19: a matter of time?

As the COVID-19 pandemic is still ongoing, and considering the lack of efficacy of antiviral strategies to this date, and the reactive hyperinflammation leading to tissue lesions and pneumonia, effective treatments targeting the dysregulated immune response are more than ever required. Immunomodulatory and immunosuppressive drugs have been repurposed in severe COVID-19 with contrasting results. The heterogeneity in the timing of treatments administrations could be accountable for these discrepancies. Indeed, many studies included patients at different timepoints of infection, potentially hiding the beneficial effects of a time-adapted intervention. We aim to review the available data on the kinetics of the immune response in beta-coronaviruses infections, from animal models and longitudinal human studies, and propose a four-step model of severe COVID-19 timeline. Then, we discuss the results of the clinical trials of immune interventions with regards to the timing of administration, and finally suggest a time frame in order to delineate the best timepoint for each treatment.

COVID-19: can we treat the mother without harming her baby?

Medical care is predicated on 'do no harm', yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.

Terapias biológicas y tuberculosis en pediatría / Biological therapies and tuberculosis in pediatrics

En los últimos años, ha habido un aumento sostenido del uso de terapias inmunomoduladoras como las terapias biológicas y en un período más reciente, de las terapias con moléculas pequeñas. Estos tratamientos constituyen un factor de riesgo más para enfermar de tuberculosis en adultos y aunque en menor grado, también en niños, especialmente con el uso de anti TNF-α, por lo que antes de iniciar una terapia biológica, hay que descartar la tuberculosis activa y la latente. En el tratamiento de una tuberculosis activa producida por un biológico se debe prolongar la etapa de continuación a 9 meses. Es importante el seguimiento clínico prolongado en años de quienes usan o han completado el uso de estas terapias. Hay que posponer la vacunación BCG en los hijos de madres que usaron terapias biológicas durante la gestación hasta la edad 6 a 12 meses de los niños. El foco de esta revisión está centrado en la tuberculosis por progresión de una forma latente a una activa o por un contacto estrecho con una persona con tuberculosis pulmonar en pacientes que reciben terapias biológicas anti TNF alfa de uso inmunoreumatológico.

In recent years, there has been a sustained increase in the use of immunomodulatory therapies such as biologic therapies and, more recently, small molecule therapies. Those therapies have become another risk factor for tuberculosis in adults and, although to lesser degree, also in children, especially some of them, such as anti-TNF α. Before starting biological therapy, active tuberculosis and latent tuberculosis must be ruled out. In the treatment of active tuberculosis caused by a biologic, the continuation stage should be extended to 9 months. Long-term clinical follow-up in years of those who use them or have completed their use, is important. BCG vaccine should be postponed in children of mother who used biologic therapies during pregnancy until the children ́s age 6 to 12 months. The focus of this review is centered on tuberculosis due to progression from a latent to an active form or due to close contact with a person with pulmonary tuberculosis in patients receiving anti-TNF alpha biological therapies for immunorheumatology use.

Evidences suggesting a possible role of Vitamin D in COVID 19: The missing link.

The severe acute respiratory syndrome coronavirus 2 is spreading like wildfire with no specific recommended treatment in sight. While some risk factors such as the presence of comorbidities, old age, and ethnicity have been recognized, not a lot is known about who the virus will strike first or impact more. In this hopeless scenario, exploration of time-tested facts about viral infections, in general, seems to be a sound basis to prop further research upon. The fact that immunity and its various determinants (e.g., micronutrients, sleep, and hygiene) have a crucial role to play in the defense against invading organisms, may be a good starting point for commencing research into these as yet undisclosed territories. Herein, the excellent immunomodulatory, antiviral, and anti-inflammatory roles of Vitamin D necessitate thorough investigation, particularly in COVID-19 perspective. This article reviews mechanisms and evidence suggesting the role Vitamin D plays in people infected by the newly identified COVID-19 virus. For this review, we searched the databases of Medline, PubMed, and Embase. We studied several meta-analyses and randomized controlled trials evaluating the role of Vitamin D in influenza and other contagious viral infections. We also reviewed the circumstantial and anecdotal evidence connecting Vitamin D with COVID-19 emerging recently. Consequently, it seems logical to conclude that the immune-enhancing, antiviral, anti-inflammatory, and lung-protective role of Vitamin D can be potentially lifesaving. Hence, Vitamin D deserves exhaustive exploration through rigorously designed and controlled scientific trials. Using Vitamin D as prophylaxis and/or chemotherapeutic treatment of COVID-19 infection is an approach worth considering. In this regard, mass assessment and subsequent supplementation can be tried, especially considering the mechanistic evidence in respiratory infections, low potential for toxicity, and widespread prevalence of the deficiency of Vitamin D affecting many people worldwide.

Therapeutic immunoglobulin A antibody for dysbiosis-related diseases.

Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in microbial taxa. Dysbiosis, especially in the gut, has also been proposed to play a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. A body of evidence has shown that intestinal polymeric immunoglobulin A (IgA) antibodies are important to regulate the gut microbiota as well as to exclude pathogenic bacteria or viral infection such as influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) at mucosal sites. Since the 1970s, trials for oral administration of therapeutic IgA or IgG have been performed mainly to treat infectious enteritis caused by pathogenic Escherichia coli or Clostridium difficile. However, few of them have been successfully developed for clinical application up to now. In addition to the protective function against intestinal pathogens, IgA is well known to modulate the gut commensal microbiota leading to symbiosis. Nevertheless, the development of therapeutic IgA drugs to treat dysbiosis is not progressing. In this review, the advantages of therapeutic IgA antibodies and the problems for their development will be discussed.

Lipoic acid. Kinetics and pluripotent biological properties and derivatives.

Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.