Serious Infectious Adverse Events Research Articles

Real-life drug retention rate and safety of rituximab when treating rheumatic diseases: a single-centre Swiss retrospective cohort study

BackgroundIn Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat other auto-immune diseases (AID), especially connective tissue diseases (CTD). We aimed to characterise the use of RTX in AID in a real-life Swiss setting and compare RTX retention rates and safety outcomes between patients treated for RA, CTD and AAV.MethodsA retrospective cohort study of patients who started RTX in the Rheumatology Department for RA or AID. The RTX retention rate was analysed using Kaplan–Meier survival curves. Occurrences of serious adverse events (SAE), low IgG levels and anti-drug antibodies (ADA) were reported.ResultsTwo hundred three patients were treated with RTX: 51.7% had RA, 29.6% CTD, 9.9% vasculitis and 8.9% other AIDs. The total observation time was 665 patient-years. RTX retention probability at 2 years (95%CI) was similar for RA and CTD 0.65 (0.55 to 0.73), 0.60 (0.47 to 0.72) and lower for vasculitis 0.25 (0.09 to 0.45). Survival curves for RTX retention matched closely (p = 0.97) between RA and CTD patients but were lower for patients with vasculitis due to a higher percentage of induced remission. Patients with vasculitis (95%) and CTD (75%) had a higher rate of concomitant glucocorticoid use than RA (60%). Moderate to severe hypogammaglobulinaemia was observed more frequently in patients with vasculitis (35%) than with RA (13%) or CTD (9%) and was associated with an increased risk of presenting a first infectious SAE (HR 2.01, 95% CI 1.04 to 3.91). The incidence rate of SAE was 23.3 SAE/100 patient-years (36% were infectious). When searched, ADAs were observed in 18% of the patients and were detected in 63% of infusions-related SAE. 10 patients died during RTX treatment and up to 12 months after the last RTX infusion, 50% from infection.ConclusionRTX retention rates are similar for patients with RA and CTD but lower for those with vasculitis due to more frequent remission. Patients treated with RTX for vasculitis present more SAE and infectious SAE than patients with RA and CTD, potentially due to a higher use of concomitant glucocorticoids and the occurrence of hypogammaglobulinaemia.

MULTIDISCIPLINARY MANAGEMENT, ANTI-TNF THERAPY, AND CLINICAL OUTCOMES OF INTERNALLY PENETRATING CROHN’S DISEASE COMPLICATION IN PEDIATRICS: INTERIM ANALYSES OF A MULTICENTER RETROSPECTIVE COHORT

Abstract BACKGROUND Internally penetrating Crohn’s disease (CD) complications (IPCDC; i.e. abscess and/or inflammatory mass) confer significant morbidity to pediatric patients with CD. Management strategies are heterogenous. Anti-tumor-necrosis-factor-a biologics (anti-TNF) are the mainstay of penetrating CD therapy and are most effective early in the treatment course. However, anti-TNF use among patients with IPCDC is limited by hesitancy concerning infectious risk. Recent studies show that this risk may be overstated. We hypothesized that early anti-TNF following IPCDC diagnosis, in the context of infection control, is 1) safe and 2) effective in pediatric patients. Here, we present interim results of an observational multi-center study. METHODS We performed a retrospective cohort study of pediatric patients with IPCDC, across 12 tertiary children’s hospitals. Patients (age 6+ years) were identified via radiology, ICD-coding, and ImproveCareNow searches. Patients admitted for an IPCDC diagnosed via MRI or CT from 2007-2021, with 1+ year of follow-up were included. Patients were excluded if complications were due to a non-CD-related process, solely perianal, if admission followed outpatient or outside institution treatment failure, or if surgery was required within 7 days of IPCDC (n=7). First, we measured the safety effect of anti-TNF following IPCDC diagnosis, prior to IPCDC resolution, on infectious serious adverse events (SAE) (i.e. new or enlarging IPCDC, or infection, requiring hospitalization or surgery), within 30 days. Next, we measured the effectiveness of anti-TNF within 30 days of IPCDC diagnosis on CD-related SAEs (i.e. non-infectious CD-related hospitalization or surgery), within one year. Kaplan-Meier curves were generated to describe outcomes over time. RESULTS 95 patients were included. Cohort characteristics, multidisciplinary treatment strategies, and outcomes are presented in Table 1. Kaplan-Meier curves are presented in Figure 1. 80% of patients received anti-TNF within one year of IPCDC (median 37 days [IQR 7-68]). Infectious SAEs within 90 days of IPCDC occurred in 37% (median 20 days [IQR 10-26]). Among patients initiating anti-TNF prior to IPCDC resolution, 27% had an infectious SAE within 90 days, compared to 49% of those not initiating anti-TNF prior to IPCDC resolution. Non-infectious CD-related SAEs within one year occurred in 44% (median 51 days [IQR 27, 89]). Among patients initiating anti-TNF within 30 days of IPCDC, 47% had a CD-related SAE, compared to 43% in those not receiving anti-TNF within 30 days. CONCLUSION Among a large multicenter pediatric cohort, IPCDC are associated with high rates of both infectious and CD-related SAE. Further data collection, implementation of causal inference methods, and subgroup analyses will be critical in isolating the relationship between timing of anti-TNF post-IPCDC and SAEs. Values represent Number (Percent) for categorical variables and Median (Interquartile Range) for continuous variables. Kaplan-Meier Survival Analyses for A) Infectious Serious Adverse Events and B) Crohn's Disease-Related Serious Adverse Events, stratified by exposure status. No censoring for lost-to-followup occured, as all patients had at least 1 year of follow-up avaialble.

Safety analysis of patients who received ruxolitinib for steroid-refractory acute or chronic graft-versus-host disease in an expanded access program.

Outside of clinical trials and before commercial availability for acute and chronic graft-versus-host disease (GVHD), the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was available to US patients with steroid-refractory GVHD through an open-label, multicenter expanded access program (EAP) sponsored by Incyte Corporation. To assess the safety of ruxolitinib, data on serious adverse events (SAEs) reported among patients in the EAP were collected. Patients ≥12 years old who received allogeneic hematopoietic cell transplantation for a hematologic malignancy and developed any-grade acute or chronic steroid-refractory GVHD received ruxolitinib at a starting dose of 5 mg twice daily (BID; acute GVHD) or 10 mg BID (chronic GVHD). At data extraction (May 8, 2020), 60 patients with acute GVHD and 549 with chronic GVHD were enrolled. In the acute and chronic GVHD cohorts, 41 (68.3%) and 186 (33.9%) patients, respectively, had ≥1 SAE. Sepsis (8.3%) and respiratory failure (6.7%) were the most common SAEs in the acute GVHD cohort, and pneumonia (4.9%), sepsis (3.8%), and lung infection (3.5%) in chronic GVHD. Infection SAEs were reported in 23.3% and 20.0% of patients with acute and chronic GVHD, respectively. Overall, these safety findings demonstrate the tolerability of ruxolitinib in steroid-refractory GVHD.

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil).

To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi). Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons. In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76-1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36-0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25-0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16-0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.

Incidence of Infectious Adverse Events in Patients With Rheumatoid Arthritis and Spondyloarthritis on Biologic Drugs-Data From the Brazilian Registry for Biologics Monitoring.

BackgroundThe safety profile of biologic drugs might present substantial regional differences. Since 2009, the Brazilian Society of Rheumatology has maintained BIOBADABRASIL (Brazilian Registry for Biologic Drugs), a registry for monitoring of biologic therapies in rheumatic diseases.ObjectivesThe aim of this study was to verify the incidence rate (IR) of serious infections in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biologic drugs.MethodsBIOBADABRASIL prospectively included patients with rheumatic diseases who started the first biologic drug or a synthetic disease-modifying antirheumatic drug as a parallel control group. This study focuses on serious infectious adverse events (SIAEs) in RA and SpA patients on biologic drugs compared with controls, from January 2009 to June 2015. Time of exposure was set from initiation of the drug to the date of last administration or censorship. Serious infectious adverse events IR was calculated per 1000 patient/years with 95% confidence interval (CI).ResultsA total of 1698 patients (RA, 1121; SpA, 577) were included, 7119 patient/years. Serious infectious adverse events were more common among patients on tumor necrosis factor inhibitors (TNFi's) than controls (adjusted IR ratio, 2.96 [95% CI, 2.01–4.36]; p < 0.001). Subsequent TNFi was associated with a higher SIAEs incidence when compared with first TNFI (adjusted IR ratio, 1.55 [95% CI, 1.15–2.08]; p = 0.004). Serious infectious adverse events were associated with age and corticosteroids intake. Serious infectious adverse events were more frequent in the respiratory tract in all subgroups.ConclusionsIn BIOBADABRASIL, biologic drugs, especially the subsequent TNFi, were associated with a higher risk of serious infections compared with synthetic DMARDs. Corticosteroid intake and age represented risk factors for SIAEs. Constant monitoring is required to follow the safety profile of drugs in the clinical setting of rheumatic conditions in Brazil.

Serious Adverse Events Associated with Anti-Tumor Necrosis Factor Alpha Agents in Pediatric-Onset Inflammatory Bowel Disease and Juvenile Idiopathic Arthritis in A Real-Life Setting.

Anti-tumor necrosis factor alpha (anti-TNF-α) agents are generally well tolerated, yet they can be associated with serious adverse events (SAEs) in a minority of patients. We examined the incidence of SAEs in a pediatric referral center for chronic rheumatologic and gastroenterological inflammatory disorders. Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) (n=78) or pediatric-onset inflammatory bowel disease (IBD) (n=105)seen at the Institutefor Maternal and Child Health IRCCS "Burlo Garofolo" in Trieste, Italy, between June 2001 and February 2016. Only SAEs grade 3-5 according to the Common Terminology Criteria for Adverse Events version 4.03 and/or requiring definitive therapy discontinuation were reported. Total anti-TNF-α exposure was 390.5 patient-years (PYs). The overall incidence rate of SAEs for etanercept was 4.14/100PYs. Four patients developed uveitis, two had anxiety disorders, one had a serious zoster infection, and one developed TNF-α antagonist-induced lupus-like syndrome (TAILS). The overall incidence rate of SAEs for infliximab was 22.49/100PYs. The most common SAEs were anaphylactoid reactions (n=18), followed by infectious events (n=9) and TAILS (n=3). The overall incidence rate of SAEs for adalimumab was 4.71/100PYs (two infectious SAEs). No malignancies or deaths were observed. A greater incidence rate of infectious SAEs was observed in IBD patients receiving infliximab compared to JIA patients receiving etanercept (8.11 vs 0.52 per 100PYs). Anti-TNF-α therapy was generally well tolerated. SAEs leading to anti-TNF-α discontinuation were rare and non-fatal. Infliximab was associated with the highest incidence of SAEs. Infectious SAEs were more frequently observed in IBD patients treated with infliximab than in JIA patients receiving etanercept.