Serious Infections In Patients Research Articles

Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function

ABSTRACT Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer

Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus.

ObjectivesThe incidence of serious infections is poorly defined in patients with lupus nephritis (LN). It is also unclear if LN influences risk of serious infections in a longitudinal analysis. The aim of this study was to determine the incidence of serious infections in patients with SLE and LN, compared with patients with SLE without LN.MethodsA multicentre retrospective cohort study was conducted. Patients with LN identified at two tertiary centres were matched where possible with age and gender-matched patients with SLE without LN.Any infection requiring inpatient admission, occurring in the 6 months following index clinical visit, was considered serious. Cox regression was employed to investigate the association between risk of serious infection and LN status, and other relevant covariates.ResultsA total of 173 patients were included within the analysis (n=87 LN, n=86 SLE only). A total of 9.2% (n=8) of patients with LN experienced at least one serious infection within the study period, compared with 5.8% (n=5) of patients without LN, equivalent to 19.5 and 12.0 infections per 100 patient-years with and without LN, respectively. Univariable and multivariable analyses found no significant increased risk of serious infection in patients with LN versus controls (HR 1.61; 95% CI 0.53 to 4.92 and adjusted HR (aHR) 0.91; 95% CI 0.27 to 3.06, respectively). Increased prednisone dose and modified SLE comorbidity index were strongly associated with serious infection (aHR (per 5 mg) 1.21; 95% CI 1.07 to 1.37; p=0.003 and aHR 1.13; 95% CI 1.02 to 1.25; p=0.018, respectively).ConclusionsIn this cohort, adjusting for cofactors, the presence of LN alone does not appear to increase the risk of serious infections compared with patients with SLE without LN. However, increased prednisone dose at baseline visit and increasing comorbidity were independently associated with the incidence of serious infection.

In silico integrative analysis predicts relevant properties of exotoxin-derived peptides for the design of vaccines against Pseudomonas aeruginosa

Pseudomonas aeruginosa (PA) is an opportunistic human pathogen responsible for causing serious infections in patients with cystic fibrosis. Infections caused by PA are difficult to treat and eradicate due to intrinsic and added resistance to antibiotic therapy. Therefore, it is necessary to establish effective prevention strategies against this infectious agent. In this study, a combination of immunoinformatic tools was applied to predict immunogenic and immunodominant regions in the structure of exotoxins commonly secreted as virulence factors in PA infection (ExoA, ExoS, ExoT, ExoU and ExoY). The peptides derived from exotoxins were evaluated for the potential affinity for human leukocyte antigen (HLA) I and HLA-II molecules, antigenicity score and toxicity profile. From an initial screening of 941 peptides, 13 (1.38%) were successful in all analyzes. The peptides with relevant immunogenic properties were mainly those derived from Exo A (10 / 76.9%). All peptides selected in the last analysis present a high population coverage rate based on the interaction of HLA alleles (95.36 ± 7.83%). Therefore, the peptides characterized in this study are recommended for in vitro and in vivo studies and can provide the basis for the rational design of a vaccine against PA.

Malignancy and infection risk during adalimumab therapy in hidradenitis suppurativa.

The association of adalimumab therapy with malignancy and infection is established in other inflammatory diseases; however, rates of hidradenitis suppurativa (HS) are based on case reports or retrospective healthcare data and the effect of adalimumab therapy on these rates is unknown. Previously reported rates in the PIONEER OLE Phase 3 study reported on rates only in a subpopulation of 88 participants rather than the entire cohort. To quantify rates of malignancy and serious infection in all patients with HS treated with adalimumab 40mg weekly. Reanalysis was undertaken of individual patient data from the PIONEER 1, PIONEER 2 and PIONEER open-label extension Phase 3 trial data encompassing 591 unique patients with HS administered adalimumab 40mg weekly without concurrent antibiotic exposure. Incidence rates of serious infection and malignancy were calculated. Incidence rates of serious infection and malignancy were 2.14 and 0.46 per 100 patient-years, respectively. Rates of infection and malignancy were comparable to those in other inflammatory conditions examined. Incidence of serious infection in patients with HS on adalimumab is comparable to those with psoriasis and inflammatory arthropathies, but the incidence of malignancy is increased. This may reflect disease-specific malignancy risk rather than an effect of adalimumab.

Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients

Introduction: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. Methods: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3–5) infections in univariate and multivariable logistic regression models. Results: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2–40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8–30.4) having a serious infection and 7 (6.3%; 95% CI 2.6–12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02–1.60; p = 0.03) as an independent risk factor for serious infection. Conclusion: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

PRO96 BURDEN OF HOSPITALIZATIONS AND SERIOUS INFECTIONS IN ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIS: AN ANALYSIS OF US NATIONAL IN-PATIENT SAMPLE DATABASE

The objective of this study was to examine burden of hospital stay and rate of serious infections in patients with ANCA Vasculitis. The 2016 National Inpatient Sample (NIS) data set was analyzed to estimate the burden of hospital admissions in patients with ANCA Vasculitis and two subtypes, Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). Patients ≥ 18 years old and with an ICD-10 diagnosis code M31.3, M31.31 or M31.7 were included (M30.1 was excluded). The rate of serious infections was estimated based on co-existing diagnosis for 70 different types of infections that were previously reported. In 2016, there were an estimated 13,535 hospital admissions with a diagnosis of ANCA Vasculitis (16% with principal diagnosis). The mean age was 62.6 years (SD: 16.3) and 54% of the patients were female. The mean length of stay (LOS) for patients with a diagnosis of ANCA Vasculitis was 7.6 days (SD: 9.0). The mean LOS was 9.6 (SD: 8.9), 9.2 (SD: 8.9) and 11.3 (SD: 8.3) days in patients with principal diagnosis of ANCA Vasculitis, GPA and MPA, respectively. The mean hospital charges for patients with a diagnosis of ANCA Vasculitis were $88,726 (SD: $144,020). The mean charges were $114,249 (SD: $ 148,382), $107,529 (SD: $140,486) and $145,766 (SD: $178,683) in patients with principal diagnosis of ANCA Vasculitis, GPA and MPA, respectively. The rates of serious infections were 37% in patients with any diagnosis of ANCA Vasculitis, and 27%, 27% and 30%, in patients with principal diagnosis of ANCA Vasculitis, GPA and MPA, respectively. Analysis of NIS database shows that patients with ANCA Vasculitis pose significant burden of hospitalizations and suffer from high rate of serious infections and mortality. There is an urgent need for new treatment options to improve outcomes for patients with ANCA Vasculitis.

Efficacy and safety of multiple doses of NEPA without dexamethasone in preventing nausea and vomiting induced by multiple-day and high-dose chemotherapy in patients with non-Hodgkin\u2019s lymphoma undergoing autologous hematopoietic stem cell transplantation: a phase IIa, multicenter study

Despite the availability of several antiemetics, clinical findings show that control of chemotherapy-induced nausea and vomiting (CINV) continues to be a serious concern for hematological patients, mainly for those receiving multiple-day (MD) and high-dose (HD) chemotherapy (CT). For CINV prophylaxis, 5-hydroxytryptamine type-3 receptor antagonists (5HT3-RAs) and neurokinin 1 receptor antagonists (NK1-RAs) are usually administered together with dexamethasone, which may increase the risk of serious infections in patients undergoing myeloablative treatment. The rationale of this multicenter, open-label and phase IIa study was to explore the efficacy of multiple doses of NEPA (netupitant/palonosetron) given as an every-other-day regimen without dexamethasone in preventing CINV in patients with relapsed-refractory aggressive non-Hodgkin’s lymphoma (R/R-NHL), eligible for autologous stem cell transplantation (ASCT) and treated with MD-HD-CT. Seventy patients participated to the study. According to the adopted Fleming one-stage design, the primary endpoint of this study was achieved. The CR values were 87.1% (primary endpoint, overall phase: days 1–8), 88.6% (acute phase: days 1–6), and 98.6% (delayed phase: days 7–8), while complete control (CR with no more than mild nausea) was 85.7% (overall phase), 88.6% (acute phase), and 95.7% (delayed phase). Moderate and severe episodes of nausea were reported by less than 10% of patients in the overall phase and less than 5% in both the acute and delayed phases. Regarding safety, NEPA was well tolerated with only one adverse event (constipation) evaluated as possibly related to NEPA administration. In conclusion, our study demonstrated that multiple alternate dosing of NEPA without the addition of dexamethasone is highly effective for preventing nausea and vomiting in this difficult setting, with a good tolerability profile.

Serious infections in patients with myasthenia gravis: population-based cohort study.

To characterize the frequency and risk of serious infections in patients with myasthenia gravis (MG) relative to age/sex/area-matched comparators. This was a population-based cohort study in Ontario, Canada of patients with newly-diagnosed MG and 1:4 age/sex/area-matched general population comparators accrued from 1 April 2002 to 31 December 2015. The main outcome was a serious infection, defined by a primary diagnosis code on a hospitalization or emergency department record. We computed crude overall and sex-specific rates of infection among patients with MG and comparators, and the frequency of specific types of infection. Adjusted hazard ratios and 95% confidence intervals were estimated using Cox regression. Among 3823 patients with MG, 1275 (33.4%) experienced a serious infection compared with 2973/15292 (19.4%) of comparators over a mean follow-up of over 5years. Crude infection rates among patients with MG were twice those in comparators (72.5 vs. 35.0 per 1000 person-years, respectively). The most common infection types were respiratory infections, particularly bacterial pneumonia. After adjustment for potential confounders, MG was associated with a 39% increased infection risk (adjusted hazard ratio, 1.39; 95% confidence intervals, 1.28-1.51). Patients with MG are at a significantly higher absolute and relative risk of serious infections compared with age/sex/area-matched comparators. This needs to be considered when selecting MG treatments and when planning vaccination/prophylaxis. Determining whether this risk is due to the use of immunosuppressive medications (vs. MG itself) is an important area for future research.

Risk of admission to hospital for serious infection after initiating tofacitinib versus biologic DMARDs in patients with rheumatoid arthritis: a multidatabase cohort study.

The risk of serious infection is a major concern when prescribing a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. Little evidence exists with regard to serious infection risk associated with tofacitinib, a targeted synthetic (ts)DMARD, compared with biologic DMARDs (bDMARDs) among patients with rheumatoid arthritis. We compared the risk of serious infection in patients with rheumatoid arthritis initiating tofacitinib versus one of the seven bDMARDs. In this multidatabase cohort study, we identified eight mutually exclusive groups of patients with rheumatoid arthritis initiating tofacitinib or one of the seven bDMARDs using US public (Medicare 20012-15) and private (Optum Clinformatics 2012-18 and IBM MarketScan 2012-17) health insurance programmes. Eligible patients were aged 18 years or older, and had one inpatient visit or two or more outpatient visits (7-365 days apart) for rheumatoid arthritis using International Classification of Diseases 9th and 10th revision codes. The primary outcome was a composite endpoint of admission to hospital for serious infection including bacterial, viral, or opportunistic infection based on the inpatient principal diagnosis code. Secondary outcomes were individual types of serious infections and herpes zoster. We adjusted for more than 60 potential confounders through propensity score-based inverse probability treatment weighting in each database. Database-specific adjusted hazard ratios (aHRs) were combined using a fixed-effects meta-analysis. We identified 130 718 patients with rheumatoid arthritis across the three databases. During 100 790 person-years of follow-up, 3140 serious infections occurred (crude incidence rate per 100 person-years 3·12, 95% CI 3·01-3·23). The aHR for serious infection associated with tofacitinib was 1·41 (95% CI 1·15-1·73) versus etanercept, 1·20 (0·97-1·49) versus abatacept, 1·23 (0·94-1·62) versus golimumab, and 1·17 (0·89-1·53) versus tocilizumab. The serious infection risk with tofacitinib was similar to adalimumab (1·06, 0·87-1·30) and certolizumab (1·02, 0·80-1·29), and was lower than infliximab (0·81, 0·65-1·00). Tofacitinib was associated with a 2-fold higher risk of herpes zoster versus all bDMARDs. This study found potential differences between tofacitinib and several bDMARDs in the risk of admission to hospital for serious infection, as well as herpes zoster, in patients with rheumatoid arthritis. These results contribute to the evolving understanding of the overall risk-benefit profile of tofacitinib. Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Harvard University, MA, USA.

Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics

BackgroundPatients with psoriatic arthritis (PsA) have increased risk of adverse events, including serious infections (SI), compared with psoriasis patients.MethodsPatients eligible for, or receiving conventional systemic and biologic agents for psoriasis were followed prospectively using PSOLAR. Cohorts included: ustekinumab, tumor necrosis factor (TNF) inhibitors; infliximab; etanercept; adalimumab; non-biologic/methotrexate (MTX) (reference group); and non-biologic/non-MTX. Multivariate analyses using Cox hazard regression were used to identify factors associated with time to first SI. Rates of SI in PSOLAR psoriasis patients with self-reported PsA and possible risks with biologic therapy were evaluated.ResultsPSOLAR enrolled 4315 psoriasis patients with self-reported PsA. The overall population (N = 2401) included patients (n): 628 ustekinumab; 1413 TNF inhibitors; 258 infliximab; 481 etanercept; 674 adalimumab; 54 other biologics, 98 non-biologic/MTX; 208 non-biologic/non-MTX. Overall, 138 SI were reported with incidence rates per 100 patient-years as follows: a) ustekinumab: 1.00; b) TNF inhibitors: 2.22; c) infliximab: 2.12; d) etanercept: 2.58; e) adalimumab: 1.99; f) non-biologic/MTX: 3.01; g) and non-biologic/non-MTX: 2.31. Age, time-dependent disease activity Physician’s Global Assessment (PGA) of 4, 5, history of infection, and diabetes were associated with increased risk for SI (p < 0.05) in self-reported PsA patients. Biologic groups, other than ustekinumab, had numerically higher rates of SI.ConclusionsPSOLAR psoriasis patients with self-reported PsA in the TNF inhibitors, infliximab, adalimumab, etanercept, and MTX cohorts had numerically higher SI rates than the ustekinumab cohort, although not statistically significant. Age, PGA 4, 5, history of infection, and diabetes were associated with an increased risk for SI, irrespective of biologic exposure.Trial registrationNCT00508547; Registered July 30, 2007.

Risk of Serious Infections with Carfilzomib in Patients with Multiple Myeloma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Infections are an important cause of morbidity and mortality in multiple myeloma [MM]. Infections can be a result of the underlying disease or toxicity of anti-myeloma therapy or both. Proteasome inhibitors [PI] are associated with a risk of infection due to several mechanisms including decreased cytotoxic T-cell and natural killer cell proliferation, inhibition of dendritic cell function, and suppression of polyclonal immunoglobulins. Carfilzomib is an irreversible PI, with a higher potency compared to bortezomib in preclinical studies. Although infections are frequently reported as adverse events with carfilzomib-based combination regimens, definitive data on increased infection risk with carfilzomib is lacking. Hence, we conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to estimate the relative risk of serious infections associated with the use of carfilzomib-based regimens in MM. Methods: A systematic electronic search was performed in Ovid MEDLINE, Ovid EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov with appropriate search terms through March 20, 2019. We included RCTs comparing carfilzomib-based regimens with non-carfilzomib based regimens in MM. Primary outcome of our analysis was to estimate the relative risk of serious infections with carfilzomib. Data on primary outcome was obtained from ClinicalTrials.gov records of the included studies. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method of the random-effects model by Der Simonian and Laird. Heterogeneity of effect size was quantified using I2 statistic. Publication bias was assessed by the Egger's regression test. All statistical analyses were performed with Review Manager (RevMan Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration). Results: A total of 3,683 unique records were screened, among which, four RCTs including a total of 2954 patients (1486 in carfilzomib arm and 1468 in control arm) were included in the final analysis. Characteristics of studies included in the analysis are summarized in table 1. All but one study (CLARION) were conducted in relapsed/refractory MM. Carfilzomib was administered twice weekly in all trials, with dose ranging from 20/27 to 20/56 mg/m2. The median duration of treatment ranged from 16 to 88 weeks. Other than FOCUS trial which had single-agent carfilzomib, all had carfilzomib-based combination regimens in the intervention arm, namely, carfilzomib-dexamethasone, carfilzomib-lenalidomide-dexamethasone, and carfilzomib-melphalan-prednisone. The risk of total serious infections was significantly elevated with carfilzomib-based regimens compared to other agents [pooled RR 1.40, 95% CI: 1.17 - 1.69, p = 0.0003, I2 = 57%, figure 1]. In the carfilzomib arm, 65% of all serious infections involved the respiratory tract, and 38% were serious pneumonia. Patients on carfilzomib-based regimens were at a significantly higher risk of serious respiratory tract infections (RTI) in comparison with those on other treatments [pooled RR 1.30, 95% CI: 1.12 - 1.50, p = 0.0004, I2 = 0%, figure 2]. However, there was no significant difference in the incidence of serious pneumonia between carfilzomib and control groups [pooled RR 1.14, 95% CI: 0.92 - 1.41, p = 0.23, I2 = 15%, figure 3]. None to substantial levels of heterogeneity were noted across trials, depending on the type of analysis. Subgroup analysis based on carfilzomib dose (≤ 27 vs. &gt;27 mg/m2) and treatment setting (relapsed/refractory vs. newly diagnosed) did not reveal any statistically significant subgroup effect. There was no publication bias among studies. Conclusion: In our meta-analysis, carfilzomib is associated with a 40% increased relative risk of serious infections in patients with MM. The most common site of infection is the respiratory tract. Although carfilzomib leads to a higher risk of serious RTIs, the risk of serious pneumonia was not significantly different compared to controls. These findings will assist clinicians with risk-benefit assessment prior to initiation of carfilzomib-based regimens. Future studies should investigate patient-related and disease-related risk factors for serious infections and the utility of prophylactic antibiotic or intravenous immunoglobulin in high-risk patients. Disclosures No relevant conflicts of interest to declare.

Nutritional status as the risk factor of serious infection in patients with rheumatoid arthritis

Objectives: The aim of this study was to identify the risk factors associated with severe infection in RA patients, with a particular focus on the association of the nutritional status.Methods: We retrospectively analyzed data from 74 patients with RA (male, n = 21; female, n = 53; age 74.2 ± 12.4) admitted to our hospital between 2016 and 2017 for infection (infection group). We also recruited control RA patients (n = 222) who were matched for age, gender and disease duration, with a match ratio of 1:3 (non-infection group). The nutritional condition was assessed based on controlling nutrition status (CONUT) score, and prognostic nutritional index (PNI). The data of the infection group were obtained from the most recent visit prior to the present admission, and non-infection group from the last regular visit in 2017.Results: The respiratory tract was the most frequent site of infection. The BMI and PNI were significantly lower and the CONUT score significantly higher in the infection group than in the non-infection group. A logistic regression analysis revealed that the CONUT score, underlying lung disease and use of prednisolone and biological disease-modifying anti-rheumatic drugs were independent and significant risk factors for serious infection.Conclusion: Poor nutritional status increases the risk of serious infection.

688 Probability of Vedolizumab Response as Defined by Clinical Decision Support Tool Is Associated With Lower Risk of Serious Infection in Patients With Inflammatory Bowel Disease

INTRODUCTION: Disease activity is an independent predictor of infection in patients receiving biologics; non-response to a therapy might therefore present a higher risk of serious infection due to persistence of disease activity. We hypothesized that a clinical decision support tool (CDST) predicting lower treatment response may be predictive of a higher risk of infection. METHODS: Two validated CDSTs predicting vedolizumab (VDZ) response in ulcerative colitis (UC) and Crohn's disease (CD) were used on GEMINI phase 3 clinical trial data. After stratification by baseline variables into low, intermediate, or high probability of response to VDZ, time-to-event with Cox proportional hazard models was used to compare the risk of infection across groups and to identify independent predictors of infections among subgroups. RESULTS: 618 UC and 1023 CD patients were included. Those categorized as having low-intermediate probability of response (n = 479 UC, n = 814 CD) to VDZ were more likely to develop infectious complications while on therapy than those categorized as having high probability (n = 139 UC, n = 209 CD) response to VDZ (UC: hazard ratio [HR] 1.383, 95% confidence interval [CI] 1.024−1.868; CD: HR 1.458, 95% CI 1.124−1.893). Serious infections were observed in 1% of UC and 3% of CD patients in the high probability of response groups vs 2% of UC and 5% of CD patients in the low-intermediate groups. Among the low-intermediate probability of response UC group, independent predictors of developing infection were: baseline extraintestinal manifestations (no vs yes; HR 0.755, 95% CI 0.569−1.001); previous tumor necrosis factor antagonist exposure (no vs yes; HR 0.671, 95% CI 0.497−0.906); and baseline fecal calprotectin (log transformed; HR 1.135, 95% CI 1.016−1.268). Among the low-intermediate probability of response CD group, an independent predictor of developing infection was exposure to opioids during treatment (yes vs no; HR 1.829, 95% CI 1.469−2.277). CONCLUSION: This analysis confirms a pattern of inverse correlation between CDST-predicted efficacy and risk of infection. Data are consistent with the VDZ safety profile and suggest that infectious events seen were related to persistence of disease activity as opposed to drug-related mechanisms.

1395P - Opportunist and serious infections in patients with neuroendocrine tumours treated with everolimus: A multicenter study of real world patients

BackgroundThe incidence of infections is poorly studied in patients (pts) with neuroendocrine (NET) tumors treated with everolimus (eve) outside of clinical trials. We aimed to evaluate the incidence and risk factors for opportunistic infections (OpI) or any serious infection among eligible pts. MethodsRetrospective multicenter Latin American cohort of consecutive pts with advanced NET who received at least one dose of eve. Duration of eve, comorbidities, organ dysfunctions, institution, type of prior treatment and concurrent immunosuppressive condition were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. Results111 pts from 5 centers were included: most were men (57.7%) and had pancreatic NET (49.5%). The median duration of eve treatment was 8.9 months and 30 (27%) pts required a dose reduction of eve due to any toxicity. The median overall survival of pts was 54.3 months. In a median follow-up of 32.9 months, 34 (30.6%) pts experienced infections of any grade, 24 (21.6%, 95% confidence interval [CI]: 12.9 – 28.5%) pts had a serious infection and 8 (7.2%, 95% CI: 2.6 – 12.6%) had at least one OpI. Among pts with OpI, the pathogens were Candida sp, Toxoplasma gondi, Pneumocystis sp and Cryptococcus sp; the most common serious infections were pneumonia and gastrointestinal infection. Eight pts (7.2%) died and all deaths were deemed as related to eve. The multivariable analysis identified eve duration (every 6-month increase; Odds Ratio [OR]: 1.26, 95%CI: 1.02-1.55; p=0.04) and Charlson comorbidity score (OR: 1.47, 95% CI: 1.03-2.08; p=0.03) as independent risk factors for serious infection. ConclusionsInfections are more frequent in NET pts using eve than previously reported by clinical trials - 2% had serious infections in the RADIANT-3 trial. Pts on eve should be closely monitored for infections, especially those receiving eve for several months. Legal entity responsible for the studyRachel Riechelmann. FundingHas not received any funding. DisclosureJ.M. O’Connor: Honoraria (self): Novartis. R.P. Riechelmann: Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

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.

Outcomes of renal transplantation in patients with previous hematologic malignancies

Recommendations regarding the appropriateness of renal transplantation in patients with prior hematologic malignancies are limited. Given the lack of available data, studies are needed to assess which of these patients will maximally benefit from renal transplantation. This study was undertaken to describe the incidence of new or recurrent malignancy as well as patient and allograft survival, acute rejection, and serious infections in patients with prior hematologic malignancies receiving renal transplantation. This was a single center retrospective review of all adult patients with a previous hematologic malignancy who received a living or deceased renal transplantation between January 2009 and January 2016. Eight renal transplantation recipients with prior hematologic malignancies were identified and followed for a minimum of 3 years. Six patients received prior chemotherapy and five had a prior hematopoietic stem cell transplant. Median time from remission to transplant was 2.6 years. Three-year patient and allograft survival were 87% and 75%, respectively. Three patients were diagnosed with new cancers within 3 years post-renal transplantation; one of which died from cancer-related complications with a functioning allograft. There was concern for recurrent hematologic malignancies in two patients based on serologic studies, but, both of these patients were alive with functioning allografts at 3-year follow-up. Our experience suggests that renal transplantation can be successfully performed in select patients with prior hematologic malignancy but with a significant risk for de novo malignancy post-transplant, which may be associated with an overall poor prognosis. Decisions regarding renal transplantation candidacy should be made based on risk stratification and multidisciplinary discussions with patients, hematologists, and transplant providers.

Associated clinical factors for serious infections in patients with systemic lupus erythematosus

Infection occurs frequently in patients with systemic lupus erythematosus (SLE), and has been a major cause of morbidity and mortality. However, no large-scale comprehensive studies have estimated the effect of clinical characteristics on serious infection in actual clinical practice yet. We investigated the influence of clinical characteristics on serious infections using electronic medical records data. We conducted a nested case-control study. Patients with SLE who developed serious infection which needs hospitalization or intravenous antibiotics (n = 120) were matched to controls (n = 240) who didn’t. Odds ratios (OR) and 95% confidence intervals (CIs) for infection associated with clinical features were obtained by conditional logistic regression analyses. The conditional logistic regression analysis with adjustment showed that serositis (OR, 2.76; 95% CI, 1.33–5.74), hematologic involvement (OR, 2.53; 95% CI, 1.32–4.87), and use of higher than the low dose of glucocorticoids (GCs; >7.5 mg/d prednisolone-equivalent) (OR, 2.65; 95% CI, 1.31–5.34) were related to serious infections in SLE. Serositis, hematologic involvement, and use of higher than the low dose of GCs were associated with serious infections in patients with SLE.

Association between vildagliptin and risk of angioedema, foot ulcers, skin lesions, hepatic toxicity, and serious infections in patients with type 2 diabetes mellitus: A European multidatabase, noninterventional, postauthorization safety study.

ObjectivesThis noninterventional, multidatabase, analytical cohort study explored whether vildagliptin is associated with an increased risk of specific safety events of interest, namely angioedema, foot ulcers, or skin lesions, adverse hepatic events, or serious infections compared with other noninsulin antidiabetic drugs (NIADs) using real‐world data from five European electronic healthcare databases.DesignPatients with type 2 diabetes mellitus aged ≥18 years on NIAD treatment were included between January 2005 and June 2014. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest were estimated using negative binomial regression.PatientsApproximately 2.8% of the included patients (n = 738 054) used vildagliptin at any time during the study, with an average follow‐up time of 1.4 years.ResultsThe adjusted IRRs (vildagliptin vs. other NIADs) were in the range of 0.87‐3.71 (angioedema), 0.73‐1.19 (foot ulcers), 0.37‐1.18 (skin lesions), 0.24‐1.14 (composite of foot ulcer or skin lesions), 0.29‐0.55 (serious hepatic events), and 0.59‐1.04 (serious infections), with no lower bound of the 95% CIs > 1.ConclusionsOverall, there was no increased risk of the events of interest in association with vildagliptin use compared with other NIADs.

Risk of Serious Infection in Patients Receiving Systemic Medications for the Treatment of Psoriasis

There is a need for better understanding of the comparative safety of systemic medications used in the treatment of psoriasis. To compare the risk of serious infection associated with biologic and nonbiologic systemic medications in patients with psoriasis. An observational cohort study was conducted using medical and outpatient pharmacy claims from 2 large US health insurance claims databases from January 1, 2003, through September 30, 2015. We included patients with a diagnosis of psoriasis who were new users of systemic medications for psoriasis. Prescription claims for acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, or ustekinumab. The primary outcome was serious infection, defined by inpatient discharge diagnosis International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Cox proportional hazards regression was used to compare rates of serious infection for each exposure (acitretin, adalimumab, apremilast, etanercept, infliximab, and ustekinumab) with the referent group (methotrexate). We used pairwise 1:1 propensity score (PS) matching to adjust for potential confounders, which were assessed during a 180-day baseline period prior to study drug initiation. Results from the 2 databases were pooled via fixed-effects analysis. The databases included 31 595 patients in the Optum Clinformatics Data Mart and 76 112 patients in Truven MarketScan who were new users of acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, and ustekinumab. Users of acitretin, apremilast, infliximab, and methotrexate were older and had higher baseline comorbidity scores than subcutaneous biologic users (adalimumab, etanercept, and ustekinumab). The pooled PS-matched analysis yielded a decreased rate of overall serious infection in users of apremilast (hazard ratio [HR], 0.50; 95% CI, 0.26-0.94), etanercept (HR, 0.75; 95% CI, 0.61-0.93), and ustekinumab (HR, 0.65; 95% CI, 0.47-0.89) compared with methotrexate. We did not find a different rate of overall serious infection among users of acitretin, adalimumab, and infliximab compared with methotrexate. Subanalysis by type of serious infection showed a significantly increased risk of cellulitis among users of acitretin compared with methotrexate (PS-adjusted HR, 1.76; 95% CI, 1.11-2.80). Among patients with psoriasis treated with systemic medications in 2 large US claims databases, new users of apremilast, etanercept, and ustekinumab had a decreased rate of serious infection compared with methotrexate.

189 Risk of serious infection in patients on systemic medications for the treatment of psoriasis: an observational comparative cohort study

189 Risk of serious infection in patients on systemic medications for the treatment of psoriasis: an observational comparative cohort study