Serious Infections Research Articles

795 Real World Safety of Vedolizumab and Anti-TNF Therapies in Biologic-Naïve Ulcerative Colitis and Crohn's Disease Patients: Results From the EVOLVE Study

INTRODUCTION: The GEMINI phase III clinical trials showed a favorable safety profile for vedolizumab (VDZ) in treating patients (pts) with moderate-to-severely active ulcerative colitis (UC) and Crohn's disease (CD). Real-world studies are needed comparing the safety of VDZ to anti-tumor necrosis factors (anti-TNF) agents in biologic (bio)-naïve pts. METHODS: This was a multi-country (Canada, Greece and the United States) and multi-center, retrospective study including bio-naïve pts (≥18 years old) with ≥6 months follow-up, initiating treatment (Tx) with VDZ or an anti-TNF (adalimumab, infliximab, golimumab, certolizumab pegol) as standard of care between May 2014-March 2018. Data were collected from Tx initiation to earliest of death, chart abstraction date or 6 months post-Tx discontinuation (Canada only). Serious adverse events (SAEs) and serious infections (SIs) (defined as either life threatening, requiring hospital admission, resulting in significant disability/incapacity, or recorded in the chart as an important medical event) occurring from Tx initiation up to five half-lives post-Tx discontinuation were assessed. Incidence rates (per 100 person-years [PYs]) of SAEs and SIs were estimated. A Cox proportional hazards model adjusted for baseline characteristics was used to compare incidence rates between Tx cohorts. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) are reported. RESULTS: This study included 1,095 pts (VDZ: 598 [UC: 380; CD: 218]; anti-TNF: 497 [UC: 224; CD: 273]) from 42 sites. Compared to anti-TNF pts, the VDZ cohort were older (mean [SD] age [years]: VDZ, 47.9 [17.4]; anti-TNF, 39.6 [15.2] [P < 0.01]), were proportionately more male (VDZ, 56.9%; anti-TNF, 49.9% [P = 0.02]) and had a longer disease duration (median [range: min-max] disease duration [years]: VDZ, 5.0 [0.04– 54.0]; anti-TNF, 2.0 [<0.1–49.0] [P < 0.01]). Median (range: min-max) follow-up (months) was: VDZ, 15.3 (3.0-47.0); anti-TNF, 16.3 (3.5-51.0). Incidence rates of first occurrence of SAEs and SIs (Table 1) were significantly lower in VDZ versus anti-TNF pts (adjusted HR: SAE, 0.42 [0.27-0.66]; SI, 0.33 [0.18-0.58]). Similar trends were shown when data were stratified by UC and CD, separately (Table 1). CONCLUSION: Bio-naïve pts treated with VDZ were significantly less likely to experience SAEs and SIs than those treated with anti-TNF therapies. These data support a favourable safety profile of VDZ versus anti-TNF in bio-naïve inflammatory bowel disease pts in real-world clinical practice.

706 Impact of Baseline Corticosteroid Therapy on Tofacitinib Induction Efficacy and Infection Risk in Patients With Ulcerative Colitis: Data From Global Clinical Trials

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Oral corticosteroids (CS) can be used as induction therapy, but side effects are a concern. 1 METHODS: We evaluated efficacy and infection risk with tofacitinib 10 mg twice daily (BID) based on baseline CS use in UC induction studies. Remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0), mucosal healing (Mayo endoscopic subscore ≤1) and clinical response (decrease from baseline total Mayo score of ≥3 points and ≥30%, and decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of 0 or 1) were evaluated in the 8-week, Phase 3 tofacitinib OCTAVE Induction 1 & 2 studies (NCT01465763 & NCT01458951; pooled data). Induction studies allowed stably dosed CS (25 mg/day maximum). Efficacy and safety data were summarized by oral CS use at induction baseline (BLC-Yes/No). Infections of interest included herpes zoster (HZ), serious infections (SIs), and adjudicated opportunistic infections (OIs). RESULTS: Of 1139 patients (pts) (placebo [PBO]: n = 234; 10 mg BID: n = 905) in OCTAVE Induction 1 & 2, 525 (46.1%) were on CS at baseline (<15 mg daily dose: 32.8%; ≥15 mg daily dose: 67.2%). A statistically significant treatment effect of tofacitinib 10 mg BID vs PBO was observed for remission, mucosal healing, and clinical response at Week 8, for both subgroups of pts with and without baseline oral CS use (Table 1). Differences vs PBO were numerically greater for pts not receiving oral CS at baseline. In OCTAVE Induction 1 & 2, infections of interest occurred with similar frequency among both subgroups of pts: the proportion of PBO-treated pts with HZ was 0.8% for BLC-No vs 0.0% for BLC-Yes; and 0.2% for BLC-No vs 1.0% for BLC-Yes with 10 mg BID. The proportion of PBO-treated pts with SIs was 0.0% for BLC-No vs 0.0% for BLC-Yes; and 1.0% for BLC-No vs 0.2% for BLC-Yes with 10 mg BID. The proportion of PBO-treated pts with OIs was 0.0% for BLC-No vs 0.0% for BLC-Yes; and 0.2% for BLC-No vs 0.5% for BLC-Yes with 10 mg BID. CONCLUSION: Tofacitinib demonstrated significant induction efficacy vs PBO for both subgroups of pts with and without baseline CS use. Proportions of HZ, SIs, and OIs in OCTAVE Induction 1 & 2 were generally similar for both subgroups of pts. The relatively small number of events and short duration of follow-up (8 weeks) are limitations.

The association between lymphopenia and serious infection risk in rheumatoid arthritis.

To investigate the relationship between occurrence of serious infection (SI) and lymphocyte counts in patients with RA using data from a single centre. We used routinely captured data from a single tertiary rheumatology centre to explore the relationship between lymphopenia and SI risk. Adult RA patients were included over a 5-year follow-up period. Admissions due to confirmed SI were considered. SI rate with 95% confidence intervals was calculated. The association between SI with baseline lymphocyte counts, time-averaged lymphocyte counts throughout all follow-up, and a nadir lymphocyte count was assessed using Cox proportional hazards regression. The relationship between lymphopenia over time and SI was analysed using a mixed-effect model of lymphocyte counts prior to SI. This analysis included 1095 patients with 205 SIs during 2016 person-years of follow-up. The SI rate was 4.61/100 patient-years (95% CI: 3.76, 5.65). Compared with patients with nadir lymphocyte counts >1.5 × 109 cells/l, nadir lymphopenia <1 × 109 cells/l was significantly associated with higher SI risk (HR 3.28; 95% CI: 1.59, 6.76), increasing to HR 8.08 (95% CI: 3.74, 17.44) in patients with lymphopenia <0.5 × 109 cells/l. Lymphocyte counts were observed to be reduced in the 30-day period prior to SI. Lymphocyte counts below <1.0 × 109 cells/l were associated with higher SI risk in RA patients; the strongest association between lymphopenia and SI was observed when lymphocyte counts were below <0.5 × 109 cells/l. Lymphopenia may be used as a measure to stratify patients at risk of SI.

Risk of Serious Infection in Patients With Rheumatoid Arthritis Treated With Biologic Versus Nonbiologic Disease-Modifying Antirheumatic Drugs.

ObjectiveThe objective of this study is to examine the risk of serious infections (SIs) associated with biological disease‐modifying antirheumatic drugs (bDMARDs) compared with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA).MethodsWe studied patients with RA who initiated bDMARDs or csDMARDs from 2001 to 2016 in FORWARD–The National Databank for Rheumatic Diseases. Disease‐modifying antirheumatic drugs (DMARDs) were categorized into three groups: (1) csDMARDs (bDMARD‐naïve; reference), (2) tumor necrosis factor α inhibitors (TNFis), and (3) non‐TNFi biologics (abatacept, rituximab, tocilizumab, and anakinra). SIs were defined as those requiring intravenous antibiotics or hospitalization or those resulting in death. We calculated the propensity score (PS), which reflected the probability of receiving a specific DMARD group, and estimated the hazard ratio (HR) (with the 95% confidence interval [CI]) for SI from multivariable Cox models, adjusting for PS and time‐varying confounders.ResultsA total of 694 (5.9%) first SIs were identified in 11 623 patients with RA during 27 552 patient‐years of follow‐up. The SI incidence rate per 1000 patient‐years was 22.4 (95% CI 19.2‐26.1) for csDMARDs, 26.9 (95% CI 24.5‐29.6) for TNFis, and 23.3 (95% CI 19.0‐28.5) for non‐TNFi bDMARDs. Adjusted HRs for SIs were 1.33 (95% CI 1.05‐1.68) for TNFis and 1.48 (95% CI 1.02‐2.16) for non‐TNFi bDMARDs, compared with csDMARDs. The SI risk with non‐TNFi bDMARDs versus TNFis was not different. Other risk factors for SI were older age, higher comorbidity burden (particularly pulmonary disease), higher weighted cumulative prednisone dose, disability and disease activity, and number of prior csDMARD failures.Conclusion TNFis and non‐TNFi bDMARDs were associated with an increased SI risk compared with csDMARDs in RA, even after accounting for risk‐associated patient characteristics.

P034 Assessment of age as a risk factor for adverse events in patients from the tofacitinib ulcerative colitis clinical program

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib were demonstrated in Phase (P) 2/3 induction studies (NCT00787202; NCT01465763; NCT01458951), a 52-week, P3 maintenance study (NCT01458574), and are being further investigated in an ongoing, open-label, long-term extension (OLE) study (NCT01470612). This analysis assessed age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical program. METHODS: Analyses of AEs were performed for 2 cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily in the maintenance study) and the Overall Cohort (all tofacitinib-treated patients in the P2/P3/OLE studies [as of December 2016]), stratified by age (≥65 years vs &lt;65 years). AEs of special interest included serious infections (SIs), opportunistic infections (OIs), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE), and gastrointestinal perforations. Risk factors (based on baseline characteristics) for SIs, OIs, HZ, and NMSC in the Overall Cohort were evaluated using multivariate Cox proportional regression models. RESULTS: AEs occurred in 75.3% (placebo) and 75.9% (tofacitinib) of patients in the Maintenance Cohort, and 82.1% in the Overall Cohort (in which 83.9% received predominantly tofacitinib 10 mg twice daily). Most patients (Maintenance Cohort: 180/198 [90.9%] and 364/394 [92.4%] receiving placebo and tofacitinib, respectively; Overall Cohort: 1,080/1,157 [93.3%]) were aged &lt;65 years. In both the placebo and tofacitinib groups of the Maintenance Cohort, rates of AEs, serious AEs, severe AEs, and discontinuations due to AEs were numerically higher in patients aged ≥65 years (placebo: 83.3%, 11.1%, 11.1%, and 22.2%; tofacitinib: 80.0%, 16.7%, 10.0%, and 16.7%) vs &lt;65 years (placebo: 74.4%, 6.1%, 9.4%, and 18.3%; tofacitinib: 75.5%, 4.4%, 7.1%, and 8.8%). AEs of special interest were generally infrequent in both the placebo and tofacitinib groups of the Maintenance Cohort. In the Overall Cohort, AE, serious AE, and severe AE rates were numerically higher in patients aged ≥65 years (88.3%, 19.5%, and 15.6%) vs &lt;65 years (81.7%, 14.3%, and 12.2%). OI, HZ, malignancies (excluding NMSC), NMSC, and MACE rates were numerically higher in patients aged ≥65 years (3.9%, 14.3%, 2.6%, 5.3%, and 2.6%) vs &lt;65 years (1.7%, 5.0%, 0.6%, 0.7%, and 0.2%); SI and gastrointestinal perforation rates were similar between age groups (≥65 years: 2.6% and 0.0%; &lt;65 years: 2.9% and 0.4%). In multivariate modeling in the Overall Cohort, increasing age (every 10 years) was associated with increased risk of OIs (hazard ratio [95% confidence interval] 1.54 [1.15, 2.08]) and HZ (1.58 [1.34, 1.87]), but not SIs or NMSC (univariate modeling: 1.0 [0.78, 1.27] and 2.31 [1.46, 3.66]). CONCLUSION(S): In the tofacitinib UC program, AE rates were higher among patients aged ≥65 years vs those aged &lt;65 years, regardless of whether they received tofacitinib or placebo. In multivariate analyses, older age was associated with increased OI and HZ risk. Although this is consistent with the general population, due to the small number of patients aged ≥65 years (&lt;10% of the total), these findings should be interpreted with caution.

Comorbid infections in rheumatic diseases (according to FSBI RIR named after V.A. Nasonova)

Aim. Study of spectrum, frequency and risk factors of comorbid infections in rheumatic diseases (RD) in the stationary contingent of patients hospitalized in the FSBI RIR named after V.A. Nasonova within 1 year.Patients and methods. The study included 245 patients with RD: 122 patients suffered from rheumatoid arthritis, 62 - systemic lupus erythematosus, 61 - systemic scleroderma. All patients were interviewed by a doctor-researcher and filled in a questionnaire. If necessary, additional information was obtained during the analysis of medical records.Results. In the spectrum of infections in patients with RD, respiratory tract and ENT infections prevailed. The frequency of serious infections (SI) during RD in the studied cohort was 23.7–38.1%. The frequency of certain infections, including SI, is influenced by the duration and variant of RD, comorbid diseases and immunosuppressive therapy.Conclusions: the data obtained indicate the importance of infections in rheumatology. A high percentage of RD exacerbation against the background of infection, the prevalence of respiratory tract infections, including SI, dictate the need for vaccine prophylaxis at the early stages of RD.

Serious infection risk in rheumatoid arthritis compared with non-inflammatory rheumatic and musculoskeletal diseases: a US national cohort study

ObjectivesTo identify serious infection (SI) risk by aetiology and site in patients with rheumatoid arthritis (RA) compared with those with non-inflammatory rheumatic and musculoskeletal diseases (NIRMD).MethodsPatients participating in FORWARD from...

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

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

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.

To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors. We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach. Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates. The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk. Prospero 2017 CRD4201707879.

Ten-year retrospective review of the incidence of serious infections in patients on biologic disease modifying agents for rheumatoid arthritis in three tertiary hospitals in Western Australia.

Biologic disease modifying anti-rheumatic drugs (bDMARDs) have significantly improved the prognosis for patients with rheumatoid arthritis (RA). However, due to their immunosuppressive nature, concerns remain about the potential for infection in patients receiving these medications. To evaluate the incidence of serious infections (SI) in a Western Australian cohort of patients with RA who are receiving bDMARDs. The role of confounders including age, gender, comorbidities and use of glucocorticoids was also evaluated. The incidence of SI was defined as any infection necessitating admission to the hospital and the use of antibiotics. A 10-year retrospective review was conducted of all patients with RA who were receiving bDMARDs at three tertiary hospitals in Western Australia. Discharge summaries and all available clinic letters were reviewed and patient demographics and clinical data were collected. Pearson Chi-squared test and Student's t-test were used for comparing demographic factors and clinical variables between the groups with SI and those without. One hundred and two patients met the inclusion criteria for the period 2006-2016, 25 of whom had been admitted with SI, accounting for a total of 46 admissions. Skin and soft tissue infections were the most common (28%) followed by respiratory infections (26%) and urinary tract infections (20%). The incidence rate of SI was 8.98 per 100 person years. The rate was lowest with adalimumab (5.27 per 100 person years) and highest with infliximab (34.5 per 100 person years). Those with SI were older (68 years vs 60 years; P = 0.02) and had been on bDMARDs for longer period of time (6.05 years vs 4.68 years; P = 0.04). There was no significant increase in length of stay due to co-administration of glucocorticoids. The presence of comorbidities did not play a significant role in increasing the risk of SI. Age and duration of bDMARD use were statistically significant factors associated with an increased risk of SI. Comorbidities did not play a significant role in increasing the incidence of SI. Patients who were on both glucocorticoids and bDMARDs did not have a significant increase in length of stay when compared with patients who were just on bDMARDs. More research is needed in this area with larger numbers to draw statistically significant conclusions regarding the role of comorbidities in SI risk and the individual infection risk associated with each bDMARD.

Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study

ObjectiveTo investigate the rate of serious bacterial, viral or opportunistic infection in patients with rheumatoid arthritis (RA) starting tocilizumab (TCZ) versus tumour necrosis factor inhibitors (TNFi) or abatacept.MethodsUsing claims data...

P060 COMBINATION THERAPY WITH TNF-INHIBITORS AND IMMUNOMODULATORS ARE ASSOCIATED WITH SHORTER DURATION TO FIRST SERIOUS INFECTION – THE DEVELOP EXPERIENCE

DEVELOP is a multicenter, international, prospective, observational registry of the long-term safety and clinical status of 6070 pediatric patients (pts) with inflammatory bowel disease (IBD) diagnosed prior to 18 years of age who were treated with anti-tumor necrosis factor biologics (aTNF) and/or other medical therapies for IBD. Our aim was to assess the risk factors that lead to first serious infection (SI): an infection requiring hospitalization and/or IV therapy. Physicians participating in the registry prescribe IBD treatments based on their usual clinical practice and standards of care. Pts are categorized into cohorts according to their IBD medication exposure representing prevalent or incident exposure. The registry started enrollment in 2007 and completed enrollment in 2017. After the initial enrollment visit, data are obtained by the registry physician or designee every 6 months. SI data includes infections that occurred within 91 days of exposure to aTNF relative to non-biologics. The most recent available data cut (June 30 2018) includes 33586 patient years (PY) of follow up in the registry. The analysis of the stepwise Cox regression model for time to first SI among aTNF only pts relative to the non-biologics cohort included 3,566 Crohn’s disease (CD) pts who had at least 1 post-baseline follow-up visit, complete baseline covariate data, and complete disease severity data at event. Covariates that were significantly associated with a shorter duration of time to first SI within 91 days of aTNF exposure (Table 1) included: PCDAI Score (Moderate to Severe vs. Inactive) monotherapy with corticosteroids (CS) combination therapy with aTNF and immunomodulators (IMM), Hospitalization in the year prior to enrollment monotherapy with aTNF, PCDAI Score (Mild vs. Inactive) Female gender Time since IBD was diagnosed The analysis of the stepwise Cox regression model included 1063 ulcerative colitis (UC) pts who also had at least 1 post-baseline follow-up visit, complete baseline covariate data, and complete disease severity data at event. The covariates that were significantly associated with shorter duration of time to first SI (Table 2) included: Monotherapy with CS Monotherapy with aTNF Hospitalization in the year prior to enrollment Partial Mayo Score (Mild vs. Inactive) Combination therapy with aTNF and IMM In CD pts, combination therapy with aTNF/IMM, monotherapy with aTNF or CS, disease severity, recent hospitalization, gender, length of diagnosis and geographic region were all significantly associated with shorter duration of time to first SI. In UC pts, only monotherapy with aTNF or CS, combination therapy with aTNF and IMM, disease severity and recent hospitalization were significantly associated with shorter duration of time to first SI.

Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden

ObjectiveTo estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with...

Adverse Cardiovascular Events in Patients with Rheumatic Conditions and Biologic Therapy Interruption

Background: Recent studies in patients with rheumatologic conditions support the importance of inflammation in the development of atherosclerosis. Moreover, targeting inflammation upstream with biological agents for atherosclerosis progression has become the focus of intense research. Whilst biologics suppress inflammation, they increase serious infection (SI) risk. We hypothesised that biologic therapy interruption due to SI in patients would lead to rebound inflammation and more major adverse cardiovascular events (MACE) compared to those with no interruption. Methods: We retrospectively analysed a cohort of 265 patients above the age 18 who received biologics for rheumatoid arthritis; ankylosing spondylitis; and psoriatic arthritis with regular follow-ups. Patient characteristics, biologic therapy interruptions, SIs and MACE (non-fatal MI, non-fatal stroke and cardiovascular death) were captured in detail. Patients were categorised into 3 groups for analysis: (1) pause AND SI, (2) pause AND no SI, and (3) no pause. Results: Baseline characteristics were similar between the groups. A total of 357 pauses in biologic therapy was noted among 152 patients, of which 39 (11%) were observed in 25 patients due to SI. A significantly higher rate of MACE was observed in the group who paused for SI compared to others (Figure). Also, whilst pausing biologic therapy due to SI was associated with an increased incremental odds of experiencing MACE [OR 4.08 (95% CI 1.21–13.74), p = 0.023], pausing biologics for other reasons was not [OR 1.17 (95% CI 0.41–3.29), p = 0.77].Conclusions: In rheumatic patients, biologic therapy interruption due to SI leads to increased MACEs.

Biologic prescribing decisions following serious infection: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.

To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.

Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

ObjectivesTo compare the incidence of serious infection (SI) across biologic drugs used to treat rheumatoid arthritis (RA) using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis...

DOP006 A multicentre cohort study to assess the safety of vedolizumab for inflammatory bowel disease

We aimed to quantify rates and identify predictors of serious adverse events (SAE) with vedolizumab (VDZ) for Crohn’s disease (CD) and ulcerative colitis (UC). This was a review of a multicentre, US-based consortium of CD and UC patients treated with VDZ. Serious infections (SI) were defined as those requiring antibiotics or hospitalisation, or resulting in discontinuation of VDZ or death. SAE were defined as SI or adverse events resulting in discontinuation of VDZ or death. Multivariable logistic regression analyses with odds ratio (OR) and 95% confidence intervals (CIs) are reported for independent predictors of SI and SAE. 1087 patients (n = 650 CD; 45% male) with a median follow-up of 302 days (interquartile range 171–434) were included. SI occurred in 66 patients (6%); the most common SI were C. difficile (n = 24), abscess (n = 11), respiratory tract infections (n = 10), zoster (n = 7), and bacteraemia (n = 6). SAE occurred in 73 patients (7%), with no reported malignancies. Transverse myelitis (n = 1) and optic neuritis (n = 1) were the only two reported central nervous system adverse events. SI and SAE were observed in 3.7% and 4.3% of patients on VDZ monotherapy, 6.1% and 6.7% of patients on VDZ in combination with steroids or an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate), and 9.8% and 10.7% of patients on VDZ in combination with both steroids and an immunomodulator. On multivariable analyses, after adjusting for inflammatory bowel disease type (CD vs. UC), age, and sex, concomitant immunosuppressive (steroid or immunomodulator) therapy was the only independent predictor of SI (OR 1.67 per number of immunosuppressive agents used, 95% CI 1.17–2.38) and SAE (OR 1.65 per number of immunosuppressive agents used, 95% CI 1.17–2.31). VDZ is well tolerated in clinical practice, with SI and SAE being reported in 6% and 7% of patients, respectively. The strongest predictor of SI or SAE is the use of concomitant steroids or immunomodulators, with the greatest risk seen in patients on triple therapy with VDZ, steroids, and immunomodulator therapy. Further studies are needed to identify patients who will most benefit from concomitant immunosuppressive therapy use with VDZ to optimise the safety profile in clinical practice.

Recurrent serious infections in patients with rheumatoid arthritis-results from the British Society for Rheumatology Biologics Register.

To establish the rate of recurrent infection in RA patients recruited to the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis. Secondary objectives were to establish whether the organ class of index infection predicted future serious infection (SI). Using data from the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis, a prospective observational cohort, we identified patients with at least one episode of SI. Incidence rates of SI, recurrent SI within the same organ class as the index infection and recurrent SI (of any class) were calculated. A Cox proportional hazards model was used to identify predictors of SI. In total, 5289 subjects with at least one SI contributing 19 431 patient-years follow-up were studied. The baseline annual rate of first SI was 4.6% (95% CI: 4.5, 4.7), increasing to 14.1% (95% CI: 13.5, 14.8) following an index infection. Respiratory infections were the most frequent (44% of all events). Recurrent infections mirrored the organ class of the index infection. Sepsis, increasing age and polypharmacy were significant predictors of infection recurrence in a fully adjusted model. The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent SI within 12 months, 19.7% (95% CI: 15.1, 25.7). Recurrent infections in RA are common. Understanding patterns and predictors of recurrent infection together with the differential infection risk associated with immunosuppressive agents will help personalize RA care, tailor treatment choices better and mitigate against episodes of SI.

A retrospective review of vital signs and clinical outcomes of febrile infants younger than 3 months old presenting to the emergency department.

ObjectivesFebrile infants younger than 3 months old present a diagnostic dilemma to the emergency physician. We aim to describe a large population of febrile infants less than 3 months old presenting to a pediatric emergency department (ED) and to assess the performance of current heart rate guidelines in the prediction of serious infections (SI).Materials and methodsWe performed a retrospective review of febrile infants younger than 3 months old, between March 2015 and Feb 2016, in a large tertiary pediatric ED. We documented the primary outcome of SI for each infant, as well as the clinical findings, vital signs, and Severity Index Score (SIS). We assessed the performance of the Paediatric Canadian Triage and Acuity Scale (PaedCTAS), Advanced Pediatric Life Support (APLS) guidelines and Fleming normal reference values, using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under receiver operating characteristics curve (AUC).Results1057 infants were analyzed, with 326 (30.6%) infants diagnosed with SI. High temperature, tachycardia, and low SIS score were significantly associated with SI. Item analysis showed that the SIS performance was driven by the presence of mottling (p = 0.003) and high temperature (p<0.001). The APLS guideline had the highest sensitivity (66.0%, 95% CI 60.5–71.1%), NPV (73.3%, 95% CI 69.7–76.5%) and AUC (0.538), while the PaedCTAS (2 standard deviation from normal) had the highest specificity (98.5%, 95% CI 97.3–99.3%) and PPV (55.2%, 95% CI 32.7–71.0%).ConclusionsCurrent guidelines on infantile heart rates have a variable performance. In our study, the APLS heart rate guidelines performed with the highest sensitivity, but no individual guideline predicted for SIs satisfactorily.

Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study

BackgroundRheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry...