Efficacy and Safety of Interferon-Gamma in Chronic Granulomatous Disease: a Systematic Review and Meta-analysis.

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency with increased susceptibility to several bacteria, fungi, and mycobacteria, caused by defective or null superoxide production by the NADPH oxidase enzymatic complex. Accepted treatment consists mainly of antimicrobial prophylaxis. The role of human recombinant subcutaneous interferon-gamma (IFNγ) is less clear since the available evidence on its efficacy derives mainly from a single clinical trial that has been challenged. OBJECTIVE: We aimed to assess the efficacy and safety of IFNγ as an added treatment for CGD when compared to antimicrobial prophylaxis alone. METHODS: A literature search was conducted using MeSH terms "Chronic granulomatous disease" AND ("interferon gamma" OR "interferon-gamma"), as well as antibiotics, placebo, no therapy, clinical trial, and trial, on MEDLINE, EMBASE, LILACS, WHOs, CENTRAL, KOREAMED, The Cochrane Library, clinicaltrials.gov, and abstracts from meetings, from 1976 to July 2022. We included clinical trials (CT) and prospective follow-up studies and registered the number of serious infections (requiring hospitalization and IV antibiotics) and deaths, adverse events, and autoimmune complications, in patients treated for CGD with antimicrobial prophylaxis plus IFN-γ, versus antimicrobial prophylaxis alone. We assessed the quality of the studies using risk of bias and STROBE. We performed a meta-analysis by calculating both Peto's odds ratio (OR) and risk reduction (RR) through the Mantel-Haenszel method with a fixed-effect model, using Review Manager 5.4, and we reported the number needed to treat (NNT). RESULTS: We identified 54 matches from databases and 4 from other sources. We excluded 12 duplicates, 7 titles, and 9 abstracts for relevance, after which we had 30 eligible studies. Twenty-four were then excluded after reading the full text. Six papers were included: one randomized CT and 5 follow-up studies. In total, 324 patients with Chronic granulomatous disease were followed for 319 months under treatment with antibiotic prophylaxis plus interferon-gamma or placebo (or antibiotic prophylaxis alone), reported between the years 1991 and 2016. Three of the studies included a control group, allowing for the aggregate analysis of efficacy (prevention of serious infections). The aggregate OR was 0.49, with a 95% confidence interval of 0.19 to 1.23. The risk ratio for serious infection was 0.56 (95%CI 0.35-0.90) under IFN-γ. The meta-analysis thus favors interferon-gamma for a risk reduction of serious infection. DISCUSSION: The results from this meta-analysis support the use of IFN-γ in the treatment of patients with CGD. However, we found insufficient clinical evidence and believe more clinical trials are needed to better assess the efficacy and long-term safety of IFN-γ.

Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort.

AIM: The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. RESULTS: Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. CONCLUSIONS: Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

Changing rate of serious infections in biologic-exposed rheumatoid arthritis patients. Data from South American registries BIOBADABRASIL and BIOBADASAR.

OBJECTIVE: Most reports on serious infections (SI) in rheumatoid arthritis (RA) patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) are from the USA and Western Europe. Data from other regions are largely missing. We report data from South American countries with different backgrounds and health-care systems but similar registries. METHODS: We merged 2010-2016 data from two registries, BIOBADABRASIL (Brazil) and BIOBADASAR (Argentina), which share the same protocol, online platform and data monitoring process. Patients with active RA were included when they began the first bDMARD or a conventional synthetic DMARD (csDMARD, control group). The SI incidence rate (IR) per 1000 patient/years and adjusted IR ratio (aIRR) were estimated for bDMARDs and csDMARDs. RESULTS: Data were analysed for 3717 RA patients with an exposure of 13,380 patient/years. The 2591 patients treated with bDMARDs (64% tumour necrosis factor-α inhibitors (TNFi)) had a follow-up of 9300 years, and the 1126 treated with csDMARDs had an exposure of 4081 patient/years. The SI IR was 30.54 (CI 27.18-34.30) for all bDMARDs and 5.15 (CI 3.36-7.89) for csDMARDs. The aIRR between the two groups was 2.03 ([1.05, 3.9] p = 0.034) for the first 6 months of treatment but subsequently increased to 8.26 ([4.32, 15.76] p < 0.001). The SI IR for bDMARDs decreased over time in both registries, dropping from 36.59 (28.41-47.12) in 2012 to 7.27 (4.79-11.05) in 2016. CONCLUSION: While SI remains a major concern in South American patients with RA treated with bDMARDs, a favourable trend toward a reduction was observed in the last years.Key Points• New comprehensive data on biologic drugs safety from international collaboration in South America.• First proposal for national registries data merging in South America.• Serious infections remain a major concern in RA patients treated with biologics.• A significant reduction of serious infections in RA patients exposed to biologics was observed over a 7 years period.

Risk of Serious Infections Associated with Biologic Agents in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analyses.

OBJECTIVE: To assess whether treatment with biologic response modifying agents during clinical trial study periods increases the risk of serious infections in children with juvenile idiopathic arthritis (JIA). STUDY DESIGN: A systematic literature review using Medline, Embase, Cochrane library, and the clinical trial registry was performed up to July 2017. Random effects meta-analyses were used to compare rates of serious infections in children with JIA given biologic agents compared with controls, and the pooled relative risk calculated. Subanalyses were performed for different biologic agent classes. RESULTS: In total, 19 trials accounting for 21 individual studies were included (11 for tumor necrosis factor-alpha inhibitors [n = 814 patients], 3 for interleukin-6 inhibitors [n = 318], 6 for interleukin-1 inhibitors [n = 353], and 1 for selective T-lymphocyte costimulation modulators [n = 122]). Patients (68% female) had a mean age of 10.8 years. Seventeen serious infections were reported among 810 children receiving biologic agents and 15 among 797 controls. The most frequent infections were bronchopulmonary and varicella. No statistically significant difference in risk of serious infections was found between children receiving biologic agents compared with control groups (pooled relative risk = 1.13; 95% CI [0.63, 2.03]) during the trial study periods. The risk remained nonsignificant when evaluating the different classes of biologic agents separately. However, the analyses were underpowered to detect differences in the risk of serious infections overall or differences between classes of biologic agents. CONCLUSIONS: In this systematic review and meta-analyses, serious infections were uncommon and not significantly increased among patients with JIA receiving biologic agents compared with controls. However, the analyses were underpowered and study periods were relatively short. Ongoing careful monitoring for serious infections remains necessary for all patients with JIA, and particularly those receiving biologic agents.

Infecciones severas en pacientes con artritis reumatoide tratados con fármacos antagonistas del factor de necrosis tumor alfa / Serious infections in patients with rheumatoid arthritis treated with tumor necrosis factor alpha antagonist therapy

ResumenJustificación y objetivos:el uso de fármacos antagonistas del factor de necrosis tumoral alfa se asocia a infecciones severas en artritis reumatoide, con una alta morbi-mortalidad en la práctica clínica. No existe casuística publicada respecto al tema en nuestro país. Se pretende aportar información relacionada con la epidemiología local de las infecciones severas e identificar factores de riesgo asociados.Métodos:estudio observacional retrospectivo, que incluyó 50 pacientes tratados al menos un año en el periodo 2006-2012. Se evaluaron las características demográficas, así como las clínicas y epidemiológicas de la(s) infección(es) severa(s) desarrollada(s) y los factores de riesgo asociados.Resultados:la mayor parte de los pacientes fueron mujeres en edad media. Solo se documentó una infección severa, que correspondió a una infección de piel y tejido blando que resolvió con terapia antibiótica intravenosa. Se registraron factores de riesgo, especialmente en uso de terapia inmunosupresora esteroidal y el antecedente quirúrgico reciente, con una baja prevalencia de comorbilidades.Conclusiones:el perfil demográfico, así como el perfil clínico de las infecciones severas es similar a otras poblaciones, la baja incidencia de éstas en la cohorte podría relacionarse a una menor prevalencia de comorbilidades, no obstante se requiere investigaciones futuras para corroborar o descartar dicha observación.

AbstractAim and objetives:the use of tumour necrosis factor alpha therapy antagonist leads to an increased risk of serious infections in rheumatoid arthritis, with a high morbi-mortality in clinical practice. There are no published data in our country. This study pretends to provide knowledge about the local epidemiology of serious infections and to identify associated risk factors.Methods:An observational and retrospective study, included 50 patients treated at least for one year between 2006-2012. Demographic characteristics, clinical and epidemiological characteristics of serious infections and risk factors associated with serious infections were described.Results:A predominant female population in middle age was detected. Just one serious infection was described, corresponding to serious skin and soft tissue infection that resolved with intravenous antibiotics. Risk factors were described including inmunosuppresive therapy with steroids and prior surgery.Conclusions:Demographic profile of analized population and their clinic profile of serious infectios are similar to others populations. Low incidence of serious infections in this cohort could be related with less comorbilities than others populations, although, this topic needs further investigations to corroborate or discard this observation.

Estudos observacionais de infecções graves em artrite reumatoide: Uma revisão sistemática de medicamentos biológicos não anti-tnf-alfa / Observational studies of serious infections in rheumatoid arthritis: A systematic review of biological medicines not anti-TNF-alpha

Introdução. A segurança do emprego de Disease-Modifying Antirheumatic Drugs (DMARDs) biológicos não antagonistas do fator de necrose tumoral (TNF) em pacientes com artrite reumatóide ainda não está plenamente estabelecida. Evidências do risco de infeccções graves associado a estes medicamentos descritas por meio de relatos de casos ou ensaios clínicos não foram ainda extensivamente documentadas previamente em revisão de estudos mais longos. Objetivo. Avaliar o risco de infecções graves associado ao uso de DMARDs biológicos não anti-TNF (anakinra, rituximab, abatacept e tocilizumab) em pacientes com AR utilizando exclusivamente estudos observacionais. Método. Revisão sistemática (RS) de estudos observacionais utilizando as principais bases de dados bibliográficas para a busca de artigos publicados até julho de 2010 para avaliar o risco de infecções graves nos pacientes com AR que fizeram uso de anakinra, rituximab, abatacept e tocilizumab...

Resultados. Foram relatados em quatro estudos de 12 a 36 meses de acompanhamento relacionados ao anakinra 129 (5,1 por cento) infecções graves em 2.896 pacientes dos quais três evoluíram para óbito. Em relação ao rituximab, dois estudos relataram 72 infecções graves (5,9 por cento) em 1.224 pacientes (incluindo diabéticos e aqueles que usavam quaisquer DMARDS sintéticos) dos quais dois evoluíram para óbito. O abatacept foi avaliado em apenas um estudo de seis meses de duração no qual foram relatadas 25 infecções graves (2,4 por cento) em 1046 pacientes. Não foi selecionado nenhum estudo referente ao tocilizumab. O principal sítio de infecção para conjunto dos três medicamentos foi o trato respiratório. Conclusões. As freqüências maiores que 5 por cento de infecções graves detectadas no contexto do uso destes medicamentos são classificadas como eventos adversos “comuns”. Cautela na monitorização destes pacientes, principalmente diabéticos, devem ser tomadas considerando que estas incidências foram maiores que as divulgadas em revisões recentes baseadas em ensaios clínicos...