Serious Infectious Events Research Articles

Relationship between lymphocyte count and risk of infection in Japanese rheumatoid arthritis patients treated with tofacitinib.

We characterised changes in absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs), and their relationship to incidence of serious infection events (SIEs) and herpes zoster (HZ) events in Japanese patients with moderate to severe rheumatoid arthritis enrolled in the tofacitinib clinical programme. Data included 765 patients receiving tofacitinib in Phase 2, Phase 3, and long-term extension studies. ALCs/LSCs and incidence rates (patients with events/100 patient-years) of SIEs and HZ were analysed over 75 months. Median ALCs were generally stable over 75 months of treatment. Transient numerical increases from baseline in median LSCs were observed at Month 3; LSCs were generally lower than baseline for Months 36-75. SIE/HZ incidence rates were higher in patients with ALC <0.5 × 103 cells/mm3 versus those with ALC ≥0.5 × 103 cells/mm3 during tofacitinib treatment. Baseline LSCs were similar in patients with/without SIEs or HZ events. SIE/HZ risk was highest in patients with ALC <0.5 × 103 cells/mm3, supporting this threshold as clinically relevant for defining increased SIE/HZ risk in Japanese patients with rheumatoid arthritis receiving tofacitinib. However, SIEs and HZ events did not necessarily occur simultaneously with confirmed lymphopenia, preventing conclusions on possible causal relationships being drawn.

Incidence of Serious Infection Events in People With Chronic Neutropenia—Analysis of Real-World Data From Patients in the United States

BackgroundChronic neutropenia (CN) encompasses multiple blood disorders with different etiologies resulting in absolute neutrophil counts (ANC) < 1500/µL for >3 months. To our knowledge, the association between annual incidence of serious infection events (SIEs) and severity of CN in the US has not been previously reported. ObjectiveDetermine estimated annual incidence of SIE in people with CN with frequent SIEs (≥2/y), defined as events requiring hospitalization or intravenous antibiotics, or resulted in disability or death, in a real-world US population. MethodsThis retrospective, cross-sectional cohort study identified people with ≥2 clinical visits and laboratory values recorded in the Dataworks USA Network electronic medical record (EMR) database for each calendar year from 2014–2019. To establish chronicity, people with CN were required to have ≥2 ANC tests < 1500/µL recorded in the 2 years before study entry. If frequent SIEs occurred, index date was defined as the second SIE of that calendar year of interest. General population was the non-neutropenic (ANC ≥ 1500/µL) EMR population who had ≥2 clinical visits and laboratory values. Neutropenia diagnoses were categorized using ICD-10 codes. People infected with HIV or receiving chemotherapy/drugs known to induce transient neutropenia were excluded. Primary outcome was annual SIE incidence in people with ≥2 ANC collected. ResultsDemographics are presented in Table 1. Annual estimated incidence rate of SIEs per 100,000 person-days for people with CN ranged between 51.1–83.4, 23.1–44.5, and 14.4–38.0 for ANC < 500/µL, 500– <1000/µL, and 1000–< 1500/µL, respectively, and was consistently 2-fold greater overall and 3- to 4-fold greater in people with severe CN (ANC < 500/µL) than general population (Figure 1). Increased estimated incidence of SIEs was observed in both age groups of people with CN evaluated, including pediatric (aged < 12 years) and adolescents/adults (aged ≥12 years). [Display omitted] Table 1(abstract: 189) Demographic and Laboratory Characteristics of People Included in the Analysisa201420152016201720182019People in the database, N33,556,84638,127,26943,568,14350,741,23957,211,95563,145,385People included in the analysis'5, n43,21880,904100,330128,823145,924149,144Agec, n (%)<12 y4837 (11.2)9438 (11.7)11,906 (11.9)14,220 (11.0)15,434 (10.6)15,556 (10.4)≥12 y37,479 (86.7)70,034 (86.6)86,793 (86.5)112,803 (87.6)128,576 (88.1)131,696 (88.3)Sex at birthc,d, n (%)Male16,747 (38.8)31,508 (38.9)39,988 (39.9)51,008 (39.6)58,763 (40.3)60,696 (40.7)Female26,471 (61.2)49,394 (61.1)60,340 (60.1)77,805 (60.4)87,149 (59.7)88,434 (59.3)Racec, n (%)White34,089 (78.9%)61,234 (75.7)74,728 (74.5)92,038 (71.5)103,363 (70.8)104,811 (70.3)African American5665 (13.1)11,799 (14.6)14,787 (14.7)20,542 (16.0)23,142 (15.9)23,703 (15.9)Asian724 (1.7)1351 (1.7)1761 (1.8)2506 (2.0)2952 (2.0)3061 (2.1)Others102 (0.2)279 (0.3)382 (0.4)698 (0.5)815 (0.6)831 (0.6)Unknown2638 (6.1)6240 (0.4)8672 (8.6)13,039 (10.1)15,652 (10.7)16,738 (11.2)ANCc, n (%)<500/μL122 (0.3)237 (0.3)288 (0.3)408 (0.3)441 (0.3)479 (0.3)500–1000/μL205 (0.5)444 (0.5)622 (0.6)789 (0.6)908 (0.6)946 (0.6)1000–1500/μL762 (1.8)1513 (1.9)1938 (1.9)2464 (1.9)2841 (1.9)2926 (2.0)≥1500/μL42,129 (97.5)78,710 (97.3)97,482 (97.2)125,162 (97.2)141,734 (97.1)144,793 (97.1)ANC, absolute neutrophil count; CN, chronic neutropenia.aAll percentages were rounded to 1 decimal place.bIncluded people with CN who (1) did not receive chemotherapy nor (2) were treated with specific drugs that increase the risk of transient neutropenia prior to their first ANC < 1500/μL and people that were not neutropenic with ANC> 1500/μL.cPercentages may not equal 100 due to rounding.dSex unknown for <15 patients for each year. ConclusionsIn this real-world analysis of US EMR data, people with CN were found to have a higher estimated annual incidence of SIEs compared with general population, providing evidence of the burden of SIEs in people with CN. To our knowledge, this is the first large EMR-based analysis of incidence of SIEs in both adults and children with CN in the US.

Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial

ObjectivesTo characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance.MethodsIn this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib...

Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Characteristics, Including Corticosteroid Use and Body Mass Index.

ObjectiveTo investigate the impact of baseline and time‐varying factors on the risk of serious adverse events (SAEs) in patients during long‐term certolizumab pegol (CZP) treatment.MethodsSafety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time‐varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO.ResultsData were pooled from 8747 CZP‐treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO.ConclusionAge, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP‐treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.

Postapproval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States-Based Rheumatoid Arthritis Registry.

ObjectiveTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5‐year adverse event (AE) incidence rates (IRs) between patients initiating tofacitinib and those initiating new biological disease‐modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry.MethodsIRs (number of first events/100 patient‐years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow‐up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable‐adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events [VTEs]) and long‐term (malignancy and death) events. VTEs were assessed descriptively.ResultsFor MACE, SIEs, and HZ, 1999 (3152.1 patient‐years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient‐years) and 6354 (16 670.8 patient‐years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS‐trimmed adjusted HR 2.32; 95% confidence interval [CI] 1.43‐3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13‐0.54) and 0.33 (0.24‐0.45) for tofacitinib and bDMARDs, respectively.ConclusionIn this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.

SAT0139 AGE-BASED (&lt;65 VS ≥65 YEARS) INCIDENCE OF INFECTIONS AND SERIOUS INFECTIONS IN TOFACITINIB-, ADALIMUMAB- AND PLACEBO-TREATED PATIENTS WITH RHEUMATOID ARTHRITIS: A POST HOC ANALYSIS OF PHASE 2, PHASE 3 AND PHASE 3B/4 TOFACITINIB STUDIES

Background:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). A recent ad hoc safety analysis (as of August 2019; may be subject to change) from an ongoing, open-label, randomised, post-authorisation safety study, Study A3921133 (NCT02092467), conducted in RA patients (pts) aged ≥50 years with ≥1 cardiovascular risk factor has shown that incidence rates (IRs) of serious infection events (SIEs) were higher with tofacitinib 10 mg BID vs tumour necrosis factor inhibitors (TNFi; adalimumab [ADA] and etanercept) and this difference was more pronounced in pts aged ≥65 years (Pfizer Inc; data on file).Objectives:To assess the IRs of overall infection events and SIEs in pts from Phase (P)2, P3 and P3b/4 tofacitinib RA trials which had a TNFi (ADA) active control or comparator arm.Methods:This is a post hoc analysis of Month 0–12 data pooled from P2 (A3921035;NCT00550446[first 12-week randomised parallel treatment period only]), P3 (ORAL Standard;NCT00853385) and P3b/4 (ORAL Strategy;NCT02187055) studies. Pts randomised to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, ADA 40 mg subcutaneously every other week and placebo (PBO) were included and assessed overall and by age (&lt;65 or ≥65 years). SIEs were defined as infections requiring hospitalisation or parenteral antimicrobial therapy, or meeting other criteria for a serious adverse event. IRs (pts with events/100 pt-years of exposure [PY]) and 95% confidence intervals (CIs) were calculated for all infection events and SIEs; only the first infection events that occurred up to 28 days after the last dose or to the data cut-off date were considered.Results:Of 2180 pts included in the pooled studies (tofacitinib 5 mg BID: N=1064 [943.4 PY]; tofacitinib 10 mg BID: N=306 [236.6 PY]; ADA: N=643 [554.3 PY]; PBO: N=167 [108.1 PY]), 1841 (84.4%) were aged &lt;65 years and 339 (15.6%) were aged ≥65 years. In general, the IRs for all infection events and SIEs were higher with tofacitinib 5 mg BID, tofacitinib 10 mg BID and ADA in pts aged ≥65 years compared with pts aged &lt;65 years. Overall and when stratified by age, IRs for all infection events were similar across the active treatment groups (Figure 1); IRs with PBO were lower vs the active treatment groups overall and in pts aged &lt;65 years, and numerically lower vs the active treatment groups in pts aged ≥65 years. IRs for SIEs were comparable across active treatment groups in pts aged &lt;65 years, while among pts aged ≥65 years, IRs were numerically higher for tofacitinib 10 mg BID vs ADA, and appeared to be similar for tofacitinib 5 mg BID and ADA (Figure 2).Conclusion:In this analysis of data pooled from P2, P3 and P3b/4 tofacitinib RA studies which included a TNFi arm (ADA), the risk of SIEs or infections overall was similar for tofacitinib and ADA with the exception of a numerically higher rate of SIEs with tofacitinib 10 mg BID vs ADA in pts aged ≥65 years. In most countries, tofacitinib 10 mg BID is not an approved dose for the treatment of RA. This post hoc comparison is limited by variation in sample size and PY of exposure between treatment and age groups, and a small number of cases of SIEs in the ≥65-year age group resulting in wide 95% CIs; interpretation of results should be made with caution. The findings in the present analysis are consistent with increasing age being a known risk factor for infections.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc.Disclosure of Interests: :Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, David Gold Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dan Henrohn Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Andrea Shapiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Hendrik Schulze-Koops Grant/research support from: Pfizer Inc

Serious Infectious Events and Immunoglobulin Replacement Therapy in Patients With Autoimmune Disease Receiving Rituximab: A Retrospective Cohort Study

Rituximab (RTX) is widely administered to patients with autoimmune disease (AID). This study aimed to estimate the incidence of serious infectious events (SIEs) after RTX initiation in patients with AID. We also described the characteristics and risk factors of SIEs, and immunoglobulin replacement therapy (IgRT) strategies. Patients treated between 2005 and 2016 were included in this retrospective monocentric cohort study. An RTX course was defined as the complete RTX treatment regimen received by a given patient for AID. SIEs and IgRT were right-censored at 24 months after RTX initiation. Two hundred twenty-one patients were included (corresponding to 276 RTX courses). Reasons for RTX initiation included connective tissue disease (38%), systemic vasculitis (36%), and autoimmune cytopenia (22%). The 1- and 2-year incidences of SIEs were 17.3 (95% confidence interval [CI], 12.0-22.5) and 11.3 (95% CI, 8.1-14.5) per 100 person-years, respectively. Forty-seven SIEs were observed, mostly comprising pneumonias (45%) and bacteremias (21%). When documented, the microorganisms were bacterial (55%) and fungal (12%). Identified risk factors of SIEs were age, history of diabetes, history of cancer, concomitant steroid treatment, and low CD4 lymphocyte count at RTX initiation. IgRT was started in 22 RTX courses (8%). In patients with AID treated with RTX, the 1- and 2-year incidence of SIE was 17.3 and 11.3 per 100 person-years, respectively. Reports of SIE characteristics, risk factors, and IgRT strategies highlight the need for an appropriate and individualized assessment prior to and following RTX to prevent SIEs, particularly in patients with comorbidities.

Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases.

To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs). A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4-6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2-4, a mixed-effects logistic regression model was used. A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody-associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person-years). Predictors of SIEs included non-RTX-specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX-specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX-associated neutropenia, higher IgM, and longer time to RTX re-treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person-years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person-years) versus those with normal IgG (9.7 per 100 person-years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease-modifying antirheumatic drugs. Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk-benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.

One-year risk of serious infection in patients treated with certolizumab pegol as compared with other TNF inhibitors in a real-world setting: data from a national U.S. rheumatoid arthritis registry

BackgroundRegistry studies provide a valuable source of comparative safety data for tumor necrosis factor inhibitors (TNFi) used in rheumatoid arthritis (RA), but they are subject to channeling bias. Comparing safety outcomes without accounting for channeling bias can lead to inaccurate comparisons between TNFi prescribed at different stages of the disease. In the present study, we examined the incidence of serious infection and other adverse events during certolizumab pegol (CZP) use vs other TNFi in a U.S. RA cohort before and after using a methodological approach to minimize channeling bias.MethodsPatients with RA enrolled in the Corrona registry, aged ≥ 18 years, initiating CZP or other TNFi (etanercept, adalimumab, golimumab, or infliximab) after May 1, 2009 (n = 6215 initiations), were followed for ≤ 12 months. A propensity score (PS) model was used to control for baseline characteristics associated with the probability of receiving CZP vs other TNFi. Incidence rate ratios (IRRs) of serious infectious events (SIEs), malignancies, and cardiovascular events (CVEs) in the CZP group vs other TNFi group were calculated with 95% CIs, before and after PS matching.ResultsPatients were more likely to initiate CZP later in the course of therapy than those initiating other TNFi. CZP initiators (n = 975) were older and had longer disease duration, more active disease, and greater disability than other TNFi initiators (n = 5240). After PS matching, there were no clinically important differences between CZP (n = 952) and other TNFi (n = 952). Before PS matching, CZP was associated with a greater incidence of SIEs (IRR 1.53 [95% CI 1.13, 2.05]). The risk of SIEs was not different between groups after PS matching (IRR 1.26 [95% CI 0.84, 1.90]). The 95% CI of the IRRs for malignancies or CVEs included unity, regardless of PS matching, suggesting no difference in risk between CZP and other TNFi.ConclusionsAfter using PS matching to minimize channeling bias and compare patients with a similar likelihood of receiving CZP or other TNFi, the 1-year risk of SIEs, malignancies, and CVEs was not distinguishable between the two groups.

Use of a baseline risk score to identify the risk of serious infectious events in patients with rheumatoid arthritis during certolizumab pegol treatment

BackgroundThe risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age-adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP).MethodsData of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment.ResultsAmong 1224 RCT CZP patients, 40 reported ≥ 1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported ≥ 1 SIE (IR 3.66/100 PY). Age ≥ 70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups.ConclusionsAACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients’ likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA.Trial registrationClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005).

Morbidity in relation to feeding mode in African HIV-exposed, uninfected infants during the first 6 mo of life: the Kesho Bora study

Refraining from breastfeeding to prevent HIV transmission has been associated with increased morbidity and mortality in HIV-exposed African infants. The objective was to assess risks of common and serious infectious morbidity by feeding mode in HIV-exposed, uninfected infants ≤6 mo of age with special attention to the issue of reverse causality. HIV-infected pregnant women from 5 sites in Burkina Faso, Kenya, and South Africa were enrolled in the prevention of mother-to-child transmission Kesho Bora trial and counseled to either breastfeed exclusively and cease by 6 mo postpartum or formula feed exclusively. Maternal-reported morbidity (fever, diarrhea, and vomiting) and serious infectious events (SIEs) (gastroenteritis and lower respiratory tract infections) were investigated for 751 infants for 2 age periods (0-2.9 and 3-6 mo) by using generalized linear mixed models with breastfeeding as a time-dependent variable and adjustment for study site, maternal education, economic level, and cotrimoxazole prophylaxis. Reported morbidity was not significantly higher in nonbreastfed compared with breastfed infants [OR: 1.31 (95% CI: 0.97, 1.75) and 1.21 (0.90, 1.62) at 0-2.9 and 3-6 mo of age, respectively]. Between 0 and 2.9 mo of age, never-breastfed infants had increased risks of morbidity compared with those of infants who were exclusively breastfed (OR: 1.49; 95% CI: 1.01, 2.2; P = 0.042). The adjusted excess risk of SIEs in nonbreastfed infants was large between 0 and 2.9 mo (OR: 6.0; 95% CI: 2.2, 16.4; P = 0.001). Between 3 and 6 mo, the OR for SIEs was sensitive to the timing of breastfeeding status, i.e., 4.3 (95% CI: 1.2, 15.3; P = 0.02) when defined at end of monthly intervals and 2.0 (95% CI: 0.8, 5.0; P = 0.13) when defined at the beginning of intervals. Of 52 SIEs, 3 mothers reported changes in feeding mode during the SIE although none of the mothers ceased breastfeeding completely. Not breastfeeding was associated with increased risk of serious infections especially between 0 and 2.9 mo of age. The randomized controlled trial component of the Kesho Bora study was registered at Current Controlled Trials (www.controlled-trials.com) as ISRCTN71468401.

Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program

ObjectiveThe objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).MethodsThis was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.ResultsOverall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3–4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03–3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.ConclusionsIn placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.Trial RegistrationSTAGE Clinical Trials.gov NCT00406419 SCRIPT Clinical Trials.gov NCT00476996 FILM Clinical Trials.gov NCT00485589 FEATURE Clinical Trials.gov NCT00673920

Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials.

ObjectiveTo report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011.DesignData from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented.Results4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04–7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY).ConclusionsNo new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.

THU0048 Radius 1: Correlation between serious infection events (SIES) and rheumatoid arthritis (RA) disease activity in patients requiring a change in therapy

BackgroundThe RA Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study–1 (RADIUS 1) was a real-world, prospective, 5-year, observational study of 4968 patients (aged ≥18 y) with RA (per 1987 American...

Rheumatoid Arthritis Disease-modifying Antirheumatic Drug Intervention and Utilization Study: Safety and Etanercept Utilization Analyses from the RADIUS 1 and RADIUS 2 Registries

to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.