Infection-related Adverse Events Research Articles

Factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor agent use in patients with ankylosing spondylitis: a retrospective cohort study

ObjectTo investigate the factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor (TNF) agent use in patients with ankylosing spondylitis (AS).MethodsAS patients who initiated first-line anti-TNF treatment between 2004 and 2018 and continued treatment for at least two years were enrolled in the study. Enrolled patients were observed until the last visit, discontinuation of treatment, or September 2022. Reasons for discontinuation of the first-line anti-TNF agent were categorized into the following: (1) clinical remission, (2) loss of efficacy, (3) adverse events, and (4) other reasons including loss to follow-up, cost, or reimbursement issues. A cumulative incidence function curve was used to visualize the cumulative failure rates over time for each specific reason. Univariable and multivariable cause-specific hazard models were utilized to identify factors associated with cause-specific discontinuation of the first-line anti-TNF agent.ResultsA total of 429 AS patients was included in the study, with 121 treated with adalimumab (ADA), 176 with etanercept (ETN), 89 with infliximab (INF), and 43 with golimumab (GLM). The median overall survival on the first-line anti-TNF agent was 10.6 (7.9–14.5) years. Among the patients, 103 (24.0%) discontinued treatment, with 36 (34.9%) due to inefficacy, 31 (30.1%) due to clinical remission, 15 (14.6%) due to adverse events, and 21 (20.4%) due to other reasons. Patients treated with ETN had a lower risk of discontinuation due to clinical remission compared to those receiving ADA (hazard ratio [HR] 0.45 [0.21–0.99], P = 0.048). Higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; HR 1.31 [1.04–1.65], P = 0.023) and INF use were linked to a higher risk of treatment discontinuation for inefficacy compared to ADA use (HR 4.53 [1.45–14.16], P = 0.009). Older age was related to an increased risk of discontinuation due to infection-related adverse events (HR 1.07 [1.02–1.12], P = 0.005), and current smoking was a risk factor for discontinuation due to other reasons (HR 6.22 [1.82–21.28], P = 0.004).ConclusionAS patients on their first anti-TNF treatment for at least two years demonstrated a favorable long-term treatment retention rate, with a 24.0% discontinuation rate over a 10.6-year overall survival period. The predictors for discontinuation varied by causes, underscoring the complexity of treatment response and the importance of personalized approaches to treatment management.

Efficacy and Safety of Bendamustine-Rituximab as Frontline Therapy for Indolent Non-Hodgkin Lymphoma: A Real-World, Single-Center, Retrospective Study.

Background The use of bendamustine with an anti-CD20 monoclonal antibody as frontline therapy for indolent non-Hodgkin lymphoma(NHL)has become a standard of care.We aimed to evaluate the real-world efficacy and safety of bendamustine-rituximab (BR) frontline therapy for indolent NHL. Patients and methods Patients with indolent NHL treated with frontline BR therapy in Hôpital du Sacré-Coeur de Montréal, from January 2015 to August 2018 were included in this retrospective study. Results Our cohort included 42 adults with a median age of 63 years. Follicular lymphoma was the most common histology (n = 31, 74%). Most patients had advanced disease (Lugano stage III or IV, 88%). The overall response rate was 84% (complete response = 62% and partial response = 22%). Median progression-free survival (PFS) was not reached. At 30 months, PFS was 74.8% and overall survival was 90%. Grade 3-4 neutropenia occurred in 21% of patients. Infection-related adverse events were observed in 17 patients (40%). Most were grade 1 and 2 events (84%).One case of grade 5 progressive multifocal leukoencephalopathy related to John Cunningham (JC) virus reactivation was observed. The most common non-infectious-related adverse events were mild nausea and fatigue. Conclusions The efficacy and safety of BR treatment for indolent NHL were comparable in our real-life cohort compared to prior studies. This supports BR as a standard of care for indolent NHL. Future studies should assess whether the use of granulocyte-colony stimulating factors as primary prophylaxis effectively mitigates the hematological and infection-related adverse events related to BR therapy.

PCSK9 Inhibitors and Infection-Related Adverse Events: A Pharmacovigilance Study Using the World Health Organization VigiBase.

Protein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are novel lipid-lowering agents used in patients with cardiovascular disease. Despite reassuring safety data from pivotal trials, increasing evidence from real-world studies suggests that PCSK9i increase the risk of bacterial and viral infections. Therefore, this study aimed to identify signals of infection-related adverse events (AEs) associated with PCSK9i. We performed an observational pharmacovigilance study using the World Health Organization's VigiBase, recorded up to December 2022. We included individual case safety reports (ICSRs) of PCSK9 inhibitors, alirocumab and evolocumab, and compared them with those of other drugs. Infection-related ICSRs were retrieved from the Medical Dictionary for Regulatory Activities System Organ Class 'infections and infestations.' Among 114,293 reports (258,099 drug-AE pairs) related to PCSK9 inhibitors, 54% included female patients, 41% included patients aged ≥65 years, and 82% included patients who received evolocumab. Additionally, beyond AEs recognized by regulatory authorities, organ infections such as influenza (reporting odds ratio [ROR] 2.89, 95% confidence interval [CI] 2.74-3.05), gastric infections (ROR 2.47, 95% CI 1.63-3.75), and kidney infections (ROR 1.36, 95% CI 1.06-1.73) were observed. Sensitivity analysis indicated a heightened risk of infection-related AEs associated with PCSK9i regardless of the specific drug type. In addition to the labelled respiratory infections, six infection-related symptoms in the gastrointestinal, urinary, and renal organs were identified. Our findings support the need for systematic surveillance of infections among PCSK9i users.

Infection associated with CDK4/6 inhibitors: a pharmacovigilance analysis of the FDA adverse event reporting system database.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are first-line treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. With their increasing clinical use, infection-related adverse events (AEs) associated with CDK4/6 inhibitors have been widely reported in recent years. This study aimed to analyze the occurrence of infections associated with the CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) based on the real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Data were extracted from the FAERS database between 2015Q1 and 2022Q3. The clinical characteristics of patients with primary suspected infection-related AEs were analyzed. A disproportionality analysis was performed to investigate the potential association between AEs and CDK4/6 inhibitors. The influencing factors were evaluated using Pearson's chi-square test. Reports of infection-related AEs associated with ribociclib accounted for 8.58% of the total reports of AEs associated with ribociclib, followed by palbociclib (2.72%) and abemaciclib (1.24%). Ribociclib (67.65%) was associated with more serious outcome events than palbociclib (30%) or abemaciclib (48.08%). The sex and age were not associated with outcome severity. Disproportionality analysis showed that fourteen, sixteen and two infection-related preferred terms were detected for palbociclib, ribociclib and abemaciclib, respectively. Infection-related AEs were highly associated with three CDK4/6 inhibitors, especially palbociclib and ribociclib, based on the real-world data from the FAERS database. However, further causality assessment is required.

#1800 Cascade filtration in severe pulmonary-kidney syndrome: an one-center experience

Abstract Background and Aims In some forms of rapidly progressive glomerulonephritis (RPGN), the effect of plasma exchange (PE) is not well understood. Cascade filtration (CF) differs from standard PE in that it uses a double filter system, where the first filter is used to separate plasma from whole blood and the second filter is used to filter high-molecular weight substances. In this study, we investigated the efficacy and safety of CF in patients with ANCA-associated vasculitis (AAV) and Goodpasture's syndrome (GPS). Method During one year we included 18 patients with RPGN whose received CF in the study. The eligibility criteria was eGFR ≤15 ml/min/1.73 m2 and/or diffuse alveolar hemorrhage (DAH), presence of antineutrophilic antibodies or anti-GBM-antibodies. CF was performed on a Plasauto Sigma using a Plasmaflo OP-05W plasma separator and a Cascadeflo EC-30W separator with a fresh frozen plasma or 25% albumin solution. All patients received immunosuppressive therapy with steroids and cyclophosphamide, one patient with AAV received rituximab due to anemia and thromobocytopenia. All data were obtained from one hospitalization with the median of 43 days. Results Eight patients with AAV and three patients with GPS met the eligibility criteria. The median age of the patients in the AAV group was 59.8 (48; 66) years, with a female to male ratio of 1:1. All patients had evidence of systemic disease: seven patients had lung damage, including DAH, two patients had arthralgia, one had purpura and one had severe sinonasal involvement. The median creatinine level was 588 µmol/l (382; 1352), dialysis was initiated in 6 patients, and the median Birmingham Vasculitis Activity Score (BVAS) was 17 (15; 20). After three procedures of CF, all patients showed positive changes on CT scan, and dialysis was stopped in three patients. The immunological response to CF was observed quite rapidly in seven patients, with decreasing ANCA titer after three exchanges and decreasing antibody levels after six exchanges in one patient. There was a significant decrease in inflammatory markers, median C-reactive protein at baseline 179 (147; 226) decreased to 23 (2.8; 30.9) mg/l (p = 0.041). The CF was well tolerated with no significant adverse events. One patient receiving rituximab died after 4 months due to a severe COVID 19 infection. Three patients with GPS, one male 23 years old and two females 56 and 60 years old, also received CF. Creatinine concentrations at baseline were 1285, 1299 and 661 µmol/l, BVAS scores were 18, 20 and 15, respectively. After three procedures of CF, there was an immunological response: decrease in antibody levels from 121 U/ml to 15 U/ml, from 88.2 to 18.4 U/ml, from > 200.0 to 85.4 U/ml, CRP from 252 to 0.7 mg/l, from 120 to 5 mg/l, from 81.9 to 12.58 mg/l. There were no deaths and all three patients remained on dialysis. Conclusion CF was an effective and well tolerated method of treating severe AAV and GPS in addition to immunosuppressive treatment. Possibly due to the different filtration principle and the absence of donor plasma, we did not observe any infection-related adverse events and a lower number of procedures of CF was required compared to standard plasma exchanges. Further larger studies are needed to evaluate the benefits and safety of CF in combination with immunosuppressive treatment in RPGN patients.

Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}

BackgroundThe World Health Organization recommends universal iron supplementation for children aged 6–23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation.MethodsThis will be a two-arm, randomised controlled trial. Gambian children aged 6–12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor).DiscussionThis study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6–12 months.Trial registrationPan African Clinical Trial Registry PACTR202210523178727

Biologicals for the treatment of lupus nephritis: a Bayesian network meta-regression analysis.

Previous studies comparing the efficacy and safety of different treatment regimens for lupus nephritis are scarce. Moreover, confounding factors such as the duration of follow-up were hardly adjusted in those studies, potentially compromising the results and their extents to clinical settings. To rigorously investigate the efficacy and safety of biologics in patients with lupus nephritis using Bayesian network meta-regression analyses that adjust for the follow-up period, in order to provide more robust evidence for clinicians. Databases comprising PubMed, Embase, MedlinePlus, Cochrane Library, Google Scholars, and Scopus were retrieved for eligible articles from inception to February 29, 2024. The primary endpoint was the complete response rate, the secondary endpoint was the partial response rate, the tertiary endpoints were the adverse events, and infection-related adverse events. Napierian Logarithm of hazard ratio (lnHR) and the standard error of lnHR (selnHR) were generated for dichotomous variants by STATA 18.0 MP and then put into Rstudio 4.3.2 to conduct Bayesian network meta-analysis as well as network meta-regression analysis to yield hazard ratio (HR) as pairwise effect size. Ten studies involving 2138 patients and 11 treatment regimens were ultimately included. In the original analysis, for the primary endpoint, compared to the control group, obinutuzumab (22.6 months), abatacept-30mg (20.5 months), abatacept-10mg (17.8 months), and belimumab (23.3 months) demonstrated significant superiority (HR ranged from 1.6 to 2.5), more ever, their significance regarding relative efficacy was correlated with follow up period, namely "time window" (shown in parentheses above). For the secondary endpoint, compared to the control group, obinutuzumab and abatacept-30mg showed conspicuous preponderance (HR ranged from 1.6 to 2.4), "time window" was also detected in abatacept-30mg (20.5 months), whereas obinutuzumab remained consistently obviously effective regardless of the follow-up period (shown in parentheses above). For the tertiary endpoint, there were no differences among active regimens and control. Considering the efficacy and safety and "time window" phenomenon, we recommend obinutuzumab as the preferred treatment for LN. Certainly, more rigorous head-to-head clinical trials are warranted to validate those findings.

Biologic therapies committee. What does it provide?

ObjectiveTo assess the general healthcare impact of a Biological Therapies Commitee (immune-mediated inflammatory diseases) through prescription habits, pre-biological studies and immunization. MethodA quasi-experimental study was conducted on all naive patients of legal age who started treatment with a biological agent for an immune-mediated inflammatory disease the year before and the year after the creation of the Biological Therapies Committee. ResultsA total of 31 patients treated in 2016 and 40 patients treated in 2018 were included. Prescriptions of tumor necrosis factor alpha inhibitor drugs decreased in 2018 (from 80.6% to 45.0%, p < 0.05), while prescriptions of interleukin 12/23 inhibitors increased (from 12.9% to 35.0%, p < 0.05). Tuberculosis screening was statistically different between the two periods: the number of interferon gamma release assays performed was higher in 2018 (from 9.7% to 80.0%, p < 0.01) and the proportion of patients who successfully underwent chemoprophylaxis was higher in 2018 (from 36.4% to 81.8%, p < 0.05). The proportion of tests requested for the study of viral pathologies and the number of vaccines administered were also higher in 2018. ConclusionsThe development of a specific Biological Therapies Committee allows healthcare improvements, contributing to a deeper understanding of the medications and to preventing the infection-related adverse events. It would therefore seem advisable to develop specialized committees akin to the Biological Therapies Committee in other domains.

Meta-Analysis of Efficacy and Safety of Intravenous Iron in Patients With Iron Deficiency and Heart Failure With Reduced Ejection Fraction

Iron deficiency is an independent risk factor for heart failure (HF) exacerbation. We aim to study the safety and efficacy of intravenous (IV) iron therapy in patients with HF with reduced ejection fraction (HFrEF). A literature search was conducted on MEDLINE (Embase and PubMed) using a systematic search strategy by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) until October 2022. CRAN-R software (The R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis. The quality assessment was performed using the Cochrane Risk of Bias and Newcastle-Ottawa Scale. We included 12 studies with a total of 4,376 patients (IV iron n=1,985 [45.3%]; standard of care [SOC] n=2,391 [54.6%]). The mean age was 70.37±8.14years and 71.75±7.01years in the IV iron and SOC groups, respectively. There was no significant difference in all-cause mortality and cardiovascular mortality (risk ratio [RR] 0.88, 95% confidence interval [CI]0.74 to 1.04, p<0.15). However, HF readmissions were significantly lower in the IV iron group (RR 0.73, 95% CI0.56 to 0.96, p=0.026). Non-HF cardiac readmissions were not significantly different between the IV iron and SOC groups (RR 0.92, 95% CI0.82 to 1.02, p=0.12). In terms of safety, there was a similar rate of infection-related adverse events in both arms (RR 0.86, 95% CI0.74 to 1, p=0.05). IV iron therapy in patients with HFrEF is safe and shows a significant reduction in HF hospitalizations compared with SOC. There was no difference in the rate of infection-related adverse events. The changing landscape of HFrEF pharmacotherapy in the last decade may warrant a re-demonstration of the benefit of IV iron with current SOC. The cost-effectiveness of IV iron use also needs further study.

Timing of Immune Reconstitution in Patients With Congenital Athymia After Treatment With Allogeneic Processed Thymus Tissue-agdc

Congenital athymia is a rare pediatric condition characterized by the absence of a functioning thymus resulting in extremely low naïve T-cell numbers and severe immune deficiency. Allogeneic processed thymus tissue-agdc is approved for immune reconstitution in these patients. In clinical studies, naïve T-cell numbers increased from baseline through year 2 after allogeneic processed thymus tissue-agdc implantation. Based on these studies, immune reconstitution sufficient to overcome infection (>100 naïve CD4+ T cells/mm3) is unlikely to develop before 6–12 months after implantation and may take 2 years in some patients (Figure 1). This analysis aims to identify clinical features associated with delayed naïve T-cell development and impacts on clinical outcomes. In this post hoc analysis of data at year 1 (Y1) after allogeneic processed thymus tissue-agdc implantation, we evaluated clinical features of patients with < 100 naïve CD4+/mm3. Of 95 patients implanted in clinical trials, all 65 patients with baseline measurements had < 50 naïve CD4+/mm3. Of patients with Y1 measurements, 30/45 (66.7%) achieved >100 naïve CD4+/mm3 and 15/45 (33.3%) had < 100 naïve CD4+/mm3 (Tables 1, 2). Among patients with < 100 naïve CD4+/mm3 at Y1, 11/15 (73.3%) had atypical complete DiGeorge Syndrome (cDGS); all 11 atypical patients received glucocorticoids pre-implantation and calcineurin inhibitors pre- and post-implantation, and 6/11 received glucocorticoids post-implantation. Four of 15 patients (26.7%) with < 100 naïve CD4+/mm3 at Y1 had typical cDGS; 1 received calcineurin inhibitors pre- and post-implantation and 2 received glucocorticoids (pre-implantation only). Of 15 patients with < 100 naïve CD4+/mm3 at Y1, 10 (66.7%) experienced infection-related adverse events starting >1 year post-implantation. These events were reported for 8 atypical patients (all on pre-or post-implantation immunosuppressive therapy) and 2 typical patients (with no immunosuppressive therapy); most events resolved. At the time of last follow-up, 93.3% of patients (14/15) were alive; 1 patient died 7.6 years post-treatment (respiratory failure). In summary, most patients (66.7%) with available data achieved >100 naïve CD4+/mm3 by Y1 after allogeneic processed thymus tissue-agdc implantation. Amongst patients who did not, many had atypical cDGS and received immunosuppressive medications. No infection-related deaths were reported in patients with delayed naïve CD4+ T-cell reconstitution. [Display omitted] Table 1(abstract: 100) Characteristics of Patients With < 100 Naïve CD4+ T Cells/mm3 at Year 1 and Year 2 After ImplantationPatientAge at implantation, yearscDGS phenotypeGenetic backgroundaAlive at last follow-upInfection-related AE>1 year post-implantationImmunosuppression useCIPatients with <100 cells/mm3 at the year 1 visit10.8AtypicalHemizygous 22q11.2 deletion✓✓✓✓21.1AtypicalHemizygous 22q11.2 deletion✓No✓✓32.2AtypicalNo known mutation✓No✓✓40.7AtypicalCHARGE✓✓✓✓50.8AtypicalNo known mutation✓✓✓✓60.7AtypicalCHARGE✓✓✓✓71.3AtypicalCHARGE✓✓✓✓80.7TypicalHemizygous 22q11.2 deletion✓No✓✓92.3TypicalHemizygous 22q11.2 deletion✓NoNo✓10c0.2TypicalCHARGE✓✓NoNo110.4TypicalNo known mutationNod✓NoNoPatients with <100 cells/mm3 at the year 1 and year 2 visits121.4AtypicalHemizygous 22q11.2 deletion✓✓✓✓131.2AtypicalCHARGE✓No✓✓140.7AtypicalNo known mutation✓✓✓✓151.8AtypicalCHARGE✓✓✓✓Patients with <100 cells/mm3 at the year 2 visite160.3TypicalHemizygous 22q11.2 deletion✓✓NoNo170.9TypicalHemizygous 22q11.2 deletion✓✓NoNoAE, adverse event; cDGS, complete DiGeorge syndrome; CHARGE, coloboma, heart defect, choanal atresia, growth and developmental delay, genital hypoplasia, and ear anomalies or deafness syndrome; CHD7, chromodomain-helicase DNA-binding protein 7; CI, calcineurin inhibitor; EAS, efficacy analysis set; GC; glucocorticoids. Data based on EAS population (N = 95).aCHARGE includes CHD7mutation or other unknown CHARGE mutations.bIncludes methylprednisolone with anti-thymocyte globulin [rabbit] administered just before implantation.cPatient had renal impairment (defined as serum creatinine levels >0.4 mg/dL at baseline).dPatient died 7.6 years after allogeneic processed thymus tissue-agdc implantation (due to respiratory failure).eNaïve CD4+ T-cell data at the year 1 visit was not available for these patients.Table 2Naive CD4+ T cells/mm3 Over Time After Allogeneic Processed Thymus Tissue-agdc ImplantationaPatientNaïve CD4+ T cells/mm30.5–0.9 years1.0–1.4 years1.5–1.9 years≥2 yearsPatients with <100 cells/mm3 at the year 1 visit165.5NA48721046, 80NA2813101475NA4NA90, 521NA454511.9,51.0NA119.9, 219.3356.662.7,22.954.0NA218.5711,0NA7481250,100276NA9NA27NA10NA67.6359.9NA11NA47.9294.4NAPatients with <100 cells/mm3 at the year 1 and year 2 visits1246456454131068NA94.7, 149144,2339.934.466.4,1091518.534.072.939.9Patients with <100 cells/mm3 at the year 2 visitb1616273355173.9NA6967EAS, efficacy analysis set; NA, not available.Data based on EAS population (N = 95).aBased on available naïve CD4+ T-cell data.bNaïve CD4+ T-cell data at the year 1 visit was not available for these patients.

Incidence Of Infections In Patients With Severe, Uncontrolled Asthma Treated With Tezepelumab: A Pooled Analysis Of The Phase 2b PATHWAY And Phase 3 NAVIGATOR Studies

Tezepelumab is a humanized monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in asthma pathogenesis. This post hoc analysis describes the incidence of infection-related adverse events (AEs) in patients treated with tezepelumab, using pooled data from the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial

Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 μg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 μg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. Netherlands Organisation for Health Research and Development.

P526 A prediction model for successful increase of adalimumab dose intervals: analysis of the pragmatic open-label randomised controlled non-inferiority LADI trial

Abstract Background We showed in the pragmatic open-label randomised controlled non-inferiority LADI trial that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in CD patients in stable remission, while infection-related adverse events (AE) were reduced. This was counterbalanced by lower rates of clinical remission and more gastro-intestinal AEs after 48 weeks. In the current study we aimed to develop a prediction model to identify patients who could successfully increase their ADA dose interval. Methods This is a secondary analysis of the intervention group of the LADI trial. In this group, patients in steroid-free clinical remission for ≥ 9 months (Harvey-Bradshaw Index (HBI) &amp;lt; 5, CRP &amp;lt; 10 mg/L and faecal calprotectin (FCP) &amp;lt; 150 µg/g), on conventional ADA dosing increased ADA intervals to 3 and then to 4 weeks. A successful dose interval increase was defined as: no persistent flare (&amp;gt;8 weeks), no intervention-related severe AE, no rescue medication use, and an increased dose interval while in clinical and biochemical remission at week 48. Candidate baseline predictors were selected after a study group consensus meeting (Table 1). Prediction models were based on logistic regression. Four variable selection strategies were used: inclusion of all variables as a naïve reference model, stepwise backwards regression, LASSO with minimal lambda, and LASSO using the ‘one standard error’ rule. Models were evaluated on discrimination and calibration. Missing data were multiply imputed and models were internally validated using bootstrap optimism correction. Results The four models were developed on 109 patients, of which 59.1% experienced the outcome of successful dose interval increase (Table 1). Apparent performance of the models was adequate, with areas under the receiver operating characteristic curves (AUC) between 0.60 and 0.67 (Table 2 and Figure 1). Predicted probabilities from LASSO-based models were too modest (Table 2 and Figure 2). Internal validation showed optimism-corrected AUCs around 0.5 (Table 2), meaning that models could not identify patients who successfully increased their ADA dose interval. Optimism-corrected calibration estimates for the naïve model and backwards selection showed overfitting on the data. Internally validated predicted probabilities from LASSO-based models were too modest. Conclusion After 48 weeks, approximately 60% of patients could successfully increase their ADA dose interval without major negative clinical impact, but these could not be identified with a series of different prediction models. Risks and benefits of this strategy should be discussed with individual patients based on their risk perception and medication preferences.

Voluntary medical male circumcision in selected provinces in South Africa: Outcomes from a programmatic setting.

Voluntary medical male circumcision (VMMC) remains an effective biomedical intervention for HIV prevention in high HIV prevalence countries. In South Africa, United States Agency for International Development VMMC partners provide technical assistance to the Department of Health, at national and provincial levels in support of the establishment of VMMC sites as well as in providing direct VMMC services at site level since April 2012. We describe the outcomes of the Right to Care (RTC) VMMC program implemented in South Africa from 2012 to 2017. This retrospective study was undertaken at RTC supported facilities across six provinces. Young males aged ≥10 years who presented at these facilities from 1 July 2012 to 31 September 2017 were included. Outcomes were VMMC uptake, HIV testing uptake and rate of adverse events (AEs). Using a de-identified observational database of these clients, summary statistics of the demographic characteristics and outcomes were calculated. There were a total 1,001,226 attendees of which 998,213 (99.7%) were offered VMMC and had a median age of 15 years (IQR = 12-23 years). Of those offered VMMC, 99.6% (994,293) consented, 96.7% (965,370) were circumcised and the majority (46.3%) were from Gauteng province. HIV testing uptake was 71% with a refusal rate of 15%. Of the newly diagnosed HIV positives, 64% (6,371 / 9,972) referrals were made. The rate of AEs, defined as bleeding, infection, and insufficient skin removal) declined from 3.26% in 2012 to 1.17% in 2017. There was a reduction in infection-related AEs from 2,448 of the 2,602 adverse events (94.08%) in 2012 to 129 of the 2,069 adverse events (6.23%) in 2017. There was a high VMMC uptake with a decline in AEs over time. Adolescent men contributed the most to the circumcised population, an indication that the young population accesses medical circumcision more. VMMC programs need to implement innovative demand creation strategies to encourage older males (20-34 years) at higher risk of HIV acquisition to get circumcised for immediate impact in reduction of HIV incidence. HIV prevalence in the total population increased with increasing age, notably in clients above 25 years.

Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial

Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

Impact of frailty on mortality and morbidity in bridge to transplant recipients of contemporary durable mechanical circulatory support.

Frailty is associated with adverse outcomes in advanced heart failure. We studied the impact of frailty on postoperative outcomes in bridge to transplant (BTT) durable mechanical circulatory support (MCS) recipients. Patients undergoing left ventricular assist device (LVAD, n=96) or biventricular support (BiV, n=11) as BTT underwent frailty assessment. Frailty was defined as ≥ 3 physical domains of the Fried's Frailty Phenotype (FFP) or ≥ 2 physical domains of the FFP plus cognitive impairment on the Montreal Cognitive Assessment (MoCA). No difference in mortality at 360 days was observed in frail (n=6/38, 15.8%) vs non-frail (n=4/58, 6.9%) LVAD supported patients, p=0.19. However, there was a significant excess mortality in frail BiV (n=4/5) vs non-frail BiV (n=0/6) supported patients, p=0.013. In all patients, frail patients compared to non-frail patients experienced longer intensive care unit stay, 12 vs 6 days (p < 0.0001) and hospital length of stay, 48 vs 27 days (p < 0.0001). There was no difference in hemocompatibility and infection related adverse events. The majority (n=22/29, 75.9%) of frail patients became non-frail following MCS; contrastingly, a minority (n=3/42, 7.1%) became frail from being non-frail (p=0.0003). Abnormal markers of frailty are common in patients undergoing BTT-MCS support and those used herein predict mortality in BiV-supported patients, but not in LVAD patients. These findings may help us better identify patients who will benefit most from BiV-BTT therapy.

Glucocorticoid Therapy in ANCA Vasculitis: Using the Glucocorticoid Toxicity Index as an Outcome Measure.

ANCA-associated vasculitis (AAV) is an autoimmune disease. Induction remission and maintenance treatment typically includes high-dose, tapering glucocorticoids (GC), in addition to other immunosuppressive medication. The use of theGlucocorticoid Toxicity Index (GTI) provides a global, quantifiable assessment tool in which clinicians can assess GC-associated morbidity. Recent trials in AAV have exposed the need for systemic assessment of GC burden. In this small cohort study, we look to address these issues and the justification of newer GC sparing agents, such as C5a inhibitors. A retrospective cohort study of 43 patients with biopsy AAV was constructed from a single center between 2012-2016, and followed up for 48 months. The GTI table made up of adverse features was used to quantify patients' GC toxicity. Electronic patient records were reviewed and scores calculated according to published methods. GTI scores were compared with cumulative steroid doses at separate intervals and incidences of adverse features in relation to the treatment timeline. The mean age was 65.9 (±11.06) years and treatment regimens consisted of glucocorticoids alongside cyclophosphamide or rituximab. Our results showed statistical significance in the association of cumulative GC doses and GTI scores (P=0.008; 95% CI, 1.31 to 8.05). Adverse features relating to mood disturbance and GC-induced psychosis occurred early, in contrast to adrenal insufficiency, which typically presented later in the follow-up. Infection-related adverse events were consistent throughout. We demonstrated that higher cumulative doses of steroids in AAV lead to worse glucocorticoid-related toxicity. Using the GTI creates the potential to individualize and quantify the adverse effects patients experience as a result of GC treatment and permits more patient-centered management. Although glucocorticoids remain the main adjunctive immunosuppression of AAV treatment, the narrow therapeutic window supports the need for GC-sparing treatments.

FC 049A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims In patients (pts) with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. This study assessed the efficacy and safety over 52 weeks (wks) of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in pts with active proliferative LN (ClinicalTrials.gov number: NCT02770170). Method Overall, 121 pts with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 wks, followed by dosing every 2 wks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (&amp;lt;3 vs ≥3). The primary efficacy endpoint was complete renal response (CRR), defined as 24 h proteinuria &amp;lt;0.5 g/day and stable eGFR at Wk 52. Results The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Wk 52 compared with placebo. However, CRR at Wk 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Wk 4. Time to CRR was shorter in the 180 mg group (17.3 wks) vs placebo (20.4 wks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Wks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five pts treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Wks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively.

Vaccination in multiple sclerosis patients treated with highly effective disease-modifying drugs: an overview with consideration of cladribine tablets.

Infectious diseases are an important consideration in autoimmune conditions such as multiple sclerosis. Infective episodes may trigger relapses and significantly deteriorate the course of the disease. Some immunotherapies may cause increased rates of infection-related adverse events. Thus, infection and vaccine-related issues should be included in the individualized patient-specific treatment strategy and counseling before starting therapy and regularly on treatment. Clinical and epidemiological studies as well as pharmacovigilance data repeatedly demonstrated the safety of the great majority of vaccines in multiple sclerosis patients. Moreover, studies have shown that vaccinations with killed/inactivated vaccines do not increase the short-term risk of relapse or deterioration in multiple sclerosis, whereas infections have been shown to provoke relapses. The available evidence indicates reduced humoral vaccination efficacy on treatment with MS drugs acting on the S1P receptor, natalizumab, and B-cell depleting therapies. Recent data for cladribine tablets suggest the potential of effective immunization in the interval of the two treatment courses and after completion of therapy. Regardless of treatment, vaccine efficacy may be optimized with proper timing of application. Multiple sclerosis patients receiving highly effective therapies should be vaccinated according to general recommendations for healthy adults. Immunization against COVID-19 is highly recommended for all multiple sclerosis patients regardless of age and comorbidities. Preliminary data show the potential of adequate responses in patients treated with cladribine tablets.

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)