Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Intestinal microbiota: its role in digestive diseases.

It is now well known that intestinal microbiota exerts not only several physiological functions, but has also been implied in the mechanisms of many conditions, both intestinal and extraintestinal. These advances, to the best of our knowledge, have been made possible by the development of new ways of studying gut flora. Metagenomics, the study of genetic material taken directly from environmental samples, avoiding individual culture, has become an excellent tool to study the human microbiota. Therefore, it has demonstrated an association between an altered intestinal microbiota and inflammatory bowel disease or irritable bowel syndrome, perhaps the most extensively studied conditions associated with this particular subject. However, microbiota has a potential role in the development of other diseases; their manifestations are not confined to the intestine only. In this article, an extensive updated review is conducted on the role intestinal microbiota has in health and in different diseases. Focus is made on the following conditions: inflammatory bowel disease, irritable bowel syndrome, celiac disease, hepatic encephalopathy, and obesity.

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs.

BACKGROUND: In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for the treatment of moderate-to-severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population have raised concerns about the risk of cardiovascular events with the use of tofacitinib, which was extrapolated to other immune-mediated diseases and other JAK inhibitors. S1P receptor modulation has been associated with potential cardiovascular events, especially bradycardia and cardiac conduction abnormalities. AIM: To review the incidence of cardiovascular events with the use of SMDs in patients with IBD and to provide practical recommendations on mitigation strategies. METHODS: Published literature was reviewed; recommendations were synthesised by experts in both cardiovascular diseases and IBD. RESULTS: Evidence from the IBD population does not indicate a higher risk of cardiovascular events with tofacitinib and other JAK inhibitors. The risk is higher in patients with intermediate to high cardiovascular risk. S1P modulators may be associated with a dose-dependent, first-dose effect, transient risk of conduction abnormalities (bradycardia and AV block). Screening and monitoring of cardiovascular risk factors should be done in all patients with IBD. Risk stratification for cardiovascular disease should be performed before starting treatment with SMDs. CONCLUSIONS: Available evidence of both JAK inhibitors and S1P modulators indicates a reassuring safety profile of SMDs from the cardiovascular perspective in the overall IBD population. Efforts should be made to identify patients with IBD at a higher risk of cardiovascular events.

Opportunistic Infections in Patients with Inflammatory Bowel Disease Treated with Advanced Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition. METHODS: Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided. RESULTS: Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs. CONCLUSION: Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.

[Bacteremia in patients hospitalized with cellulitis]. / Bacteriemia en pacientes internados con celulitis.

Cellulitis is an acute inflammation of dermis and subcutaneous tissue, usually complicating wounds, ulcers, or dermatosis. Even though in these cases it is recommended to perform culture from skin and soft tissue samples, the utility of blood cultures remains controversial due to the low frequency of positive results. Here we report the prevalence of bacteremia in patients with cellulitis admitted in our Hospital, and evaluate the presence of risk factors associated with the occurrence of this event. Clinical records of patients with diagnosis of cellulitis admitted between June 2007 and March 2010 were retrospectively reviewed. Patients without skin and soft tissue culture and/or blood cultures were excluded. Demographic data, presence of comorbidities, and culture results were analyzed. In this period, 140 patients were admitted with this diagnosis. Fifty six (40%) of them had positive skin and soft tissue cultures; where methicillin resistant Staphylococcus aureus (MRSA) was the most frequently isolated bacterium species (35.7%). Bacteremia was detected in 8.6% of these cases, where the most frequently isolated bacteria were Group G Beta haemolytic Streptococcus (33%). Bacteremia was significantly associated with longer hospital stay (10.5 ± 8.98 vs. 4.9 ± 6, p = 0.004). The following variables were significantly associated with the occurrence of positive blood cultures: diabetes (41.7% vs. 14.1%; p = 0.02; OR 4.4), positive skin and soft tissue culture (75% vs. 35.2%; p = 0.01; OR 5.5), alcoholism (16.7% vs. 3.9%; p = 0.01; OR 4.9), and chronic obstructive pulmonary disease (16.7% vs. 0.78%; p = 0.01; OR 25.4).

Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis.

BACKGROUND: There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small molecule drugs for the treatment of patients with moderate-to-severe ulcerative colitis. METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions for articles published between Jan 1, 1990, and July 1, 2021. Major congresses' databases from Jan 1, 2018, to July 3, 2021, were reviewed manually. Phase 3, placebo-controlled or head-to-head randomised controlled trials (RCTs) assessing the efficacy and safety of biologics or small molecule drugs as induction or maintenance therapies for patients with moderate-to-severe ulcerative colitis were included. Phase 2 RCTs were excluded because of their small sample sizes and inclusion of doses not further explored in phase 3 RCTs. Summary data from intention-to-treat analyses were extracted from included reports by JSL and PAO. The primary outcome was the induction of clinical remission. A network meta-analysis was done under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. The surface under the cumulative ranking (SUCRA) was used to rank the included agents for each outcome. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety. Maintenance data on efficacy for treat-straight-through and randomised responder trials are also presented. This study is registered with PROSPERO, CRD42021225329. FINDINGS: Our search yielded 5904 results, from which 29 studies (four being head-to-head RCTs) fulfilled our inclusion criteria and were included. Of these, 23 studies assessed induction therapy with either a biologic or small molecule drug, comprising 10 061 patients with ulcerative colitis. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib was significantly superior to all other interventions for the induction of clinical remission (infliximab [OR 2·70, 95% CI 1·18-6·20], adalimumab [4·64, 2·47-8·71], golimumab [3·00, 1·32-6·82], vedolizumab [3·56, 1·84-6·91], ustekinumab [2·92, 1·31-6·51], etrolizumab [4·91, 2·59-9·31], tofacitinib [2·84, 1·28-6·31], filgotinib 100 mg [6·15, 2·98-12·72], filgotinib 200 mg [4·49, 2·18-9·24], and ozanimod (2·70, 1·18-6·20), and ranked highest for the induction of clinical remission (SUCRA 0·996). No differences between active interventions were observed when assessing adverse events and serious adverse events. Vedolizumab ranked lowest for both adverse events (SUCRA 0·184) and serious adverse events (0·139), whereas upadacitinib ranked highest for adverse events (0·843) and ozanimod ranked highest for serious adverse events (0·831). INTERPRETATION: Upadacitinib was the best performing agent for the induction of clinical remission (the primary outcome) but the worst performing agent in terms of adverse events in patients with moderate-to-severe ulcerative colitis. Vedolizumab was the best performing agent for safety outcomes. With the paucity of direct comparisons in the published literature, our results might help clinicians to position drugs in treatment algorithms. FUNDING: None.

Safety of S1P Modulators in Patients with Immune-Mediated Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Sphingosine-1-phosphate modulators are approved for the treatment of multiple sclerosis and are under development for other immune-mediated conditions; however, safety concerns have arisen. OBJECTIVE: The objective of this systematic review was to investigate the safety profile of S1P modulators in patients with multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis, and systemic lupus erythematosus. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1 January, 1990 through 1 April, 2020. We also performed a manual review of conference databases from 2017 through 2020. The primary outcome was the occurrence of adverse events and serious adverse events. We also estimated the occurrence of serious infections, herpes zoster infection, malignancy, bradycardia, atrio-ventricular block, and macular edema. We performed a meta-analysis of controlled studies to assess the risks of such events. RESULTS: We identified 3843 citations; of these, 26 studies were finally included, comprising 9604 patients who were exposed to a sphingosine-1-phosphate modulator. A meta-analysis of randomized controlled trials showed an increased risk in herpes zoster infection [risk ratio, 1.75 (95% confidence interval 1.09-2.80)], bradycardia [2.64 (1.77-3.96)], and atrio-ventricular block [1.73 (1.03-2.91)] among subjects exposed to sphingosine-1-phosphate modulators as compared with a placebo or an active comparator. CONCLUSIONS: We found an increased risk of herpes zoster infection, and transient cardiovascular events among patients treated with sphingosine-1-phosphate modulators. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020172575.

Bacteriemia en pacientes internados con celulitis / Bacteremia in patients hospitalized with cellulitis

La celulitis es una inflamación aguda de la dermis y tejido celular subcutáneo de causa bacteriana, que generalmente complica a heridas, úlceras y dermatosis, aunque de manera frecuente no existe sitio de entrada. Se recomienda la realización de cultivo de punción de piel y partes blandas (PPB). Los hemocultivos raramente dan resultados positivos. El objetivo de este trabajo fue determinar la prevalencia de bacteriemia en pacientes internados en nuestra institución con diagnóstico de celulitis. Se analizaron retrospectivamente los registros clínicos de los pacientes con este diagnóstico al ingreso entre junio de 2007 y marzo de 2010. Se evaluaron los datos poblacionales, presencia de comorbilidades, y resultados de los cultivos. En ese período, se internaron 140 pacientes con diagnóstico de celulitis y a todos ellos se les realizó hemocultivo y cultivos de PPB. Setenta y cuatro eran varones (52.8%). La edad promedio: 47.5 ± 19.7 años (rango 16-94). El 40% tuvo cultivos positivos de PPB, en los que el Staphylococcus aureus meticilino resistente (SAMR) fue el germen más frecuentemente aislado (35.7%); la prevalencia de bacteriemia fue del 8.6%, en donde el germen más frecuente fue Streptoccocus Beta hemolítico, grupo G (33% del total de hemocultivos positivos). La bacteriemia se asoció significativamente a mayor estadía hospitalaria (10.5 ± 8.9 vs. 4.9 ± 6, p = 0.004). Se asoció con mayor riesgo de hemocultivo positivo a ser diabético, tener cultivo de PPB positivo, consumo de alcohol y/o enfermedad pulmonar obstructiva crónica.

Cellulitis is an acute inflammation of dermis and subcutaneous tissue, usually complicating wounds, ulcers, or dermatosis. Even though in these cases it is recommended to perform culture from skin and soft tissue samples, the utility of blood cultures remains controversial due to the low frequency of positive results. Here we report the prevalence of bacteremia in patients with cellulitis admitted in our Hospital, and evaluate the presence of risk factors associated with the occurrence of this event. Clinical records of patients with diagnosis of cellulitis admitted between June 2007 and March 2010 were retrospectively reviewed. Patients without skin and soft tissue culture and/or blood cultures were excluded. Demographic data, presence of comorbidities, and culture results were analyzed. In this period, 140 patients were admitted with this diagnosis. Fifty six (40%) of them had positive skin and soft tissue cultures; where methicillin resistant Staphylococcus aureus (MRSA) was the most frequently isolated bacterium species (35.7%). Bacteremia was detected in 8.6% of these cases, where the most frequently isolated bacteria were Group G Beta haemolytic Streptococcus (33%). Bacteremia was significantly associated with longer hospital stay (10.5 ± 8.98 vs. 4.9 ± 6, p = 0.004). The following variables were significantly associated with the occurrence of positive blood cultures: diabetes (41.7% vs. 14.1%; p = 0.02; OR 4.4), positive skin and soft tissue culture (75% vs. 35.2%; p = 0.01; OR 5.5), alcoholism (16.7% vs. 3.9%; p = 0.01; OR 4.9), and chronic obstructive pulmonary disease (16.7% vs. 0.78%; p = 0.01; OR 25.4).