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PURPOSE Fluctuations in weight have been linked to cardiovascular (CV) outcomes in the general population. We evaluated whether weight fluctuation was independently predictive of CV events in patients with rheumatoid arthritis (RA). METHODS We studied patients with RA from the Corrona registry. Weight change was categorized as loss of ≥10%, loss of 5-10%, stable, gain of 5-10%, and gain of ≥10%. We also categorized patients by quintile of variability in weight in prior observation periods. Cox proportional hazard models explored independent associations between time-varying weight change and weight variability and risk of CV events before and after adjusting for CV risk factors, RA disease features, and disability. RESULTS Among 31,381 participants, those that lost or gained 10% of their weight had greater disease activity, worse physical function, and were more likely to smoke, have diabetes, use corticosteroids, and be disabled. In adjusted models, a greater risk of CV events was observed in those that experienced 10% weight loss [HR: 1.18 (1.03,1.36) p=0.02] or weight gain [HR 1.20 (1.04,1.38) p=0.01]. The association between weight change and CV events was stronger among participants with BMI

Background Evaluating the performance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays and clearly articulating the utility of selected antigens, isotypes, and thresholds is crucial to understanding the prevalence of infection within selected communities. Methods This cross-sectional study, implemented in 2020, screened PCR–confirmed coronavirus disease 2019 patients (n = 86), banked prepandemic and negative samples (n = 96), healthcare workers and family members (n = 552), and university employees (n = 327) for anti–SARS-CoV-2 receptor-binding domain, trimeric spike protein, and nucleocapsid protein immunoglobulin (Ig)G and IgA antibodies with a laboratory-developed enzyme-linked immunosorbent assay and tested how antigen, isotype and threshold choices affected the seroprevalence outcomes. The following threshold methods were evaluated: (i) mean + 3 standard deviations of the negative controls; (ii) 100% specificity for each antigen-isotype combination; and (iii) the maximal Youden index. Results We found vastly different seroprevalence estimates depending on selected antigens and isotypes and the applied threshold method, ranging from 0.0% to 85.4%. Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3% to 25.9%. Conclusions This study revealed the importance of evaluating serosurvey tools for antigen-, isotype-, and threshold-specific sensitivity and specificity, to interpret qualitative serosurvey outcomes reliably and consistently across studies.

Background Likelihood of Neisseria gonorrhoeae infection in women exposed to male sex partners with increasing N. gonorrhoeae burdens and enhancement by Chlamydia trachomatis is not defined. Methods We identified men with urethritis and their regular female sex partners. Exposure to N. gonorrhoeae burdens in men was compared in N. gonorrhoeae-infected versus -uninfected partners. Association of N. gonorrhoeae infection in women with burdens in male partners was estimated using logistic regression. Association of C. trachomatis coinfection and N. gonorrhoeae burdens in women adjusted for burdens in male partners was estimated by linear regression. Results In total, 1816 men were enrolled; 202 had ≥2 partners, 91 who confirmed monogamy and were enrolled; 77% were married. Seventy were partners of N. gonorrhoeae-infected men; 58 (83%) were N. gonorrhoeae infected, 26 (45%) C. trachomatis coinfected. Infected women had partners with 9.3-fold higher N. gonorrhoeae burdens than partners of uninfected women (P = .0041). Association of N. gonorrhoeae infection in women with upper quartiles of N. gonorrhoeae burdens in partners increased (odds ratios ≥ 2.97)compared to the first quartile (P = .032). N. gonorrhoeae burdens in C. trachomatis-coinfected women were 2.82-fold higher than in C. trachomatis-uninfected women (P = .036). Conclusions N. gonorrhoeae infections increased in women whose partners were infected with higher N. gonorrhoeae burdens. C. trachomatis coinfection was associated with increased N. gonorrhoeae burdens in women.

Introduction No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. Methods This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. Results Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. Conclusions In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. Funding Pfizer Inc Electronic supplementary material The online version of this article (10.1007/s40744-019-00177-4) contains supplementary material, which is available to authorized users.

Dose escalation of infliximab in both primary and secondary nonresponders is widely reported; however, the usefulness of dose escalation has been disputed. The objective of this analysis is to evaluate trends in clinical efficacy following multiple infliximab dose escalations in patients with rheumatoid arthritis (RA). Patients enrolled in a US RA registry were included if they initiated infliximab at 3 mg/kg every 8 weeks, received ≥ 1 infliximab dose escalation within 12 months of initiation, and had ≥ 1 visit following dose escalation. Trends in mean Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores from visits following dose escalations were evaluated. In patients who received 2 or 3 dose escalations, the initial (1 or 2) dose escalations resulted in reduced mean CDAI scores, but subsequent escalations did not further reduce disease activity. In patients who received ≥ 4 dose escalations, mean CDAI scores did not further reduce disease activity over time. Mean HAQ scores were stable over time in patients who received 2 or 3 dose escalations. In patients who received ≥ 4 dose escalations, mean HAQ scores decreased following 1 dose escalation but progressively increased following subsequent dose escalations. Initial dose escalations (from 3 mg/kg to the equivalent of approximately 5 to 7 mg/kg) may be useful in controlling disease activity; however, there may be diminishing clinical benefit of further escalations, which can also increase the potential risk for infection and increase incremental drug costs. • Initial infliximab dose escalations (1 to 2) may be useful in lowering disease activity in patients with rheumatoid arthritis. • There does not appear to be a clinical benefit in infliximab dose escalations above the equivalent of 5 to 7 mg/kg.

Background Mycoplasma genitalium (MG) causes symptomatic urethritis in men, and can infect alone or together with other sexually transmitted infection (STI) agents. Methods The prevalence of MG and other STIs was determined in 1816 men with symptomatic urethritis. Resistance of MG to macrolides and fluoroquinolones was determined by sequencing; the impact of recent antimicrobial usage on the distribution of MG single or mixed infections was determined. Results Overall, prevalence of MG infection was 19.7% (358/1816). Fifty-four percent (166/307) of MG infections occurred alone in the absence of other STI agents. Men with single MG infection self-administered or were prescribed antibiotics more often in the 30 days prior to enrollment than subjects with urethritis caused by MG coinfection (P < .0001). Higher rates (96.7%) of infection with macrolide resistance in MG were identified in men who had taken macrolides prior to enrollment (P < .03). Overall, 88.9% (303/341) of 23S ribosomal RNA (rRNA) genes contained mutations responsible for macrolide resistance; 89.5% (308/344) of parC and 12.4% (42/339) of gyrA genes had mutations responsible for fluoroquinolone resistance. Approximately 88% (270/308) of MG had combined mutations in 23S rRNA and parC genes; 10.4% (32/308) had mutations in all 3 genes. Conclusions MG was the single pathogen identified in 11% of men with symptomatic urethritis. Overall, nearly 90% of MG infections were resistant to macrolides and fluoroquinolones. Men who took macrolides in the 30 days prior to enrollment had higher rates (97%) of macrolide-resistant MG. Resistance was associated with numerous mutations in 23SrRNA, parC, and gyrA genes.

Key Points Question Can video capsule endoscopy be safely used as an alternative to standard endoscopic procedures for the initial evaluation of gastrointestinal bleeding during the COVID-19 pandemic? Findings In this cohort study of 146 patients (74 with COVID-19), active bleeding was more frequently identified with video capsule endoscopy as the first strategy (59.5%) compared with conventional endoscopic evaluation (25.0%). The number of invasive procedures was significantly decreased with video capsule endoscopy without increased risk of rebleeding or compromising safety. Meaning The results of this study suggest that video capsule endoscopy can serve as a safe alternative to the standard endoscopic evaluation of gastrointestinal bleeding because it reduces the number of invasive procedures, personnel involved, and use of personal protective equipment., Importance Evaluation of acute gastrointestinal (GI) bleeding using invasive endoscopic procedures comprising the standard of care (SOC)—upper endoscopy and colonoscopy—can expose the endoscopy staff to SARS-CoV-2. Video capsule endoscopy (VCE) does not generate aerosols and only requires 1 person to manage the procedure. Objective To examine the safety of VCE for the initial evaluation of GI bleeding at the peak of the COVID-19 pandemic to identify signs of active bleeding while minimizing patient and personnel exposure, saving personal protective equipment, and avoiding invasive or unnecessary procedures. Design, Setting, and Participants A multicenter (UMass Memorial Medical Center and Louisiana State University Health Sciences Center) retrospective cohort study including 146 patients with COVID-19 who received VCE as the first-line diagnostic modality was conducted from March 15 to June 15, 2020, compared with SOC in January 2020 for evaluation of GI bleeding. The association between treatment and outcomes was estimated using multivariable regression adjusting for potential confounders. Propensity score matching was used to verify the results. Main Outcomes and Measures The primary end point was detection of active bleeding or stigmata of recent bleeding. Secondary end points included the number of patients requiring any invasive procedures, number of additional procedures, rates of rebleeding and rehospitalization, transfusion requirements, and mortality. Results Among 146 patients, 92 (63.0%) were men; mean (SD) age was 64.93 (14.13) years in the COVID-19 group and 61.33 (13.39) years in the SOC group. Active bleeding or stigmata of recent bleeding was observed in 44 (59.5%) patients in the COVID-19 group compared with 18 (25.0%) in the SOC group (adjusted odds ratio, 5.23; 95% CI, 2.23 to 12.27). Only 36 patients (48.7%) in the COVID-19 group required any invasive procedure during the hospitalization compared with 70 (97.2%) in the SOC group (adjusted odds ratio, 0.01; 95% CI, 0.001 to 0.08). The mean (SD) number of invasive procedures was 0.59 (0.77) per patient in the COVID-19 group compared with 1.18 (0.48) per patient in the SOC group (adjusted difference, −0.54; 95% CI, −0.77 to −0.31). Both approaches appeared to be safe and there was no significant difference in transfusion requirements, rebleeding, rehospitalization, or in-hospital mortality. No mortality was attributed to GI bleeding in either group. Conclusions and Relevance In this cohort study, first-line diagnostic evaluation of acute GI bleeding using VCE appeared to be a safe and useful alternative to the traditional approach of upper endoscopy and colonoscopy. Use of VCE was associated with increased detection of active bleeding and a reduced number of invasive procedures and unnecessary exposure of personnel to SARS-CoV-2 and use of personal protective equipment., This cohort study examines the use of video capsule endoscopy vs standard invasive diagnostic procedures to evaluate gastrointestinal (GI) bleeding in patients with COVID-19.

Neisseria gonorrhoeae has become resistant to most antibiotics in clinical use. Currently, there is no safe and effective vaccine against gonorrhea., Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical Neisseria gonorrhoeae isolates and mediates complement-dependent bactericidal activity. We recently showed that a recombinant human IgG1 chimeric variant of MAb 2C7 containing an E430G Fc modification (2C7_E430G), which enhances complement activation, outperformed the parental MAb 2C7 (2C7_WT) in vivo. Because natural infection with N. gonorrhoeae often does not elicit protective immunity and reinfections are common, approaches that prolong bacterial control in vivo are of great interest. Advances in DNA-based approaches have demonstrated the combined benefit of genetic engineering, formulation optimizations, and facilitated delivery via CELLECTRA-EP technology, which can induce robust in vivo expression of protective DNA-encoded monoclonal antibodies (DMAbs) with durable serum activity relative to traditional recombinant MAb therapies. Here, we created optimized 2C7-derived DMAbs encoding the parental Fc (2C7_WT) or complement-enhancing Fc variants (2C7_E430G and 2C7_E345K). 2C7 DMAbs were rapidly generated and detected throughout the 4-month study. While all complement-engaging 2C7 variants facilitated rapid clearance following primary N. gonorrhoeae challenge (day 8 after DMAb administration), the complement-enhancing 2C7_E430G variant demonstrated significantly higher potency against mice rechallenged 65 days after DMAb administration. Passive intravenous transfer of in vivo-produced, purified 2C7 DMAbs confirmed the increased potency of the complement-enhancing variants. This study highlights the ability of the DMAb platform to launch the in vivo production of antibodies engineered to promote and optimize downstream innate effector mechanisms such as complement-mediated killing, leading to hastened bacterial elimination.

ObjectivesRheumatoid arthritis (RA), along with glucocorticoid use, is associated with cardiovascular disease. Cardiovascular safety of glucocorticoids in RA is controversial and may be related to dose and duration of use. We determined if initiating glucocorticoids in steroid-naive RA patients would increase cardiovascular event (CVE) risk in a dose and duration-dependent manner over short-term intervals.MethodsPatients enrolled in CorEvitas (formerly Corrona) RA registry. Cox proportional-hazards models estimated adjusted HRs (aHR) for incident CVE in patients who initiated glucocorticoid treatment, adjusting for RA duration, traditional cardiovascular risk factors and time-varying covariates: Clinical Disease activity Index, disease-modifying antirheumatic drugs use and prednisone-equivalent use. Glucocorticoid use assessed current daily dose, cumulative dose and duration of use over rolling intervals of preceding 6 months and 1 year.Results19 902 patients met criteria. 1106 CVE occurred (1.66/100 person-years). Increased aHR occurred at current doses of ≥5–9 mg 1.56 (1.18–2.06) and ≥10 mg 1.91 (1.31–2.79), without increased risk at 0–4 mg 1.04 (0.55–1.59). Cumulative dose over preceding 6 months showed increased aHR at 751–1100 mg 1.43 (1.04–1.98) and >1100 mg 2.05 (1.42–2.94), without increased risk at lower doses; duration of use over preceding 6 months exhibited increased aHR for >81 days of use 1.54 (1.08–2.32), without increased risk at shorter durations. One-year analyses were consistent.ConclusionsOver preceding 6-month and 1-year intervals, initiating glucocorticoids in steroid-naïve RA patients is associated with increased risk of CVE at daily doses ≥5 mg and increased cumulative dose and duration of use. No association with risk for CVE was found with daily prednisone of ≤4 mg or shorter cumulative doses and durations.

OBJECTIVE Comparative effectiveness research can inform treatment decisions regarding the choice of biologics for rheumatoid arthritis (RA). The objective of this study is to compare the efficacy of tumor necrosis factor inhibitors (TNFis) and non-TNFis (nTNFis) in real-world patients with RA and past TNFi experience. METHODS Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) was nested within the United States Corrona registry. Adult patients with RA with moderate to high disease activity (Clinical Disease Activity Index [CDAI] >10) with exposure to one or more prior TNFis who were switching to a new TNFi or nTNFi (choice of therapy per physician choice) were enrolled. The primary outcome was the achievement of low disease activity (LDA) at 12 months (CDAI ≤10; disease activity score in 28 joints based on C-reactive protein [DAS28-CRP]

Drs. Pincus, Bergman, and Yazici have raised some concerns about our published article comparing the Clinical Disease Activity Index (CDAI) with simultaneous measures of the Routine Assessment of Patient Index Data 3 (RAPID3).1 We believe our publication has clearly established that the validated CDAI scores provide a fundamentally different evaluation of disease status compared with the RAPID3.

ObjectivesTo determine the effect of hydroxychloroquine on the incidence of new respiratory infections in a large registry of rheumatoid arthritis (RA) patients compared with a matched cohort receiving other conventional disease-modifying antirheumatic drugs (csDMARDs).MethodsWe reviewed physician-reported infections including upper respiratory infections (URI), bronchitis and pneumonia in the Corrona RA registry from June 2008 to February 2020 with the goal of comparing infections in biologic/targeted synthetic (b/ts) DMARDs naive HCQ starts compared with starts of other csDMARDs and no HCQ. Patients on different interventions were compared using time-varying adjusted Cox models adjusting for age, sex, duration of RA, BMI, disease activity, smoking status, concurrent medications, season of the year, year of onset and history of serious infections, diabetes or cardiovascular disease (CVD). A secondary analysis in a set of propensity-matched starts were also compared adjusting for time-varying covariates. The analysis was repeated including URI and bronchitis only and also for serious respiratory infections only.ResultsNo evidence of differences was found in the incidence of any respiratory infection (URI, bronchitis, pneumonia) in patients receiving HCQ compared with other csDMARDs: HR=0.87 (0.70 to1.07) in adjusted analyses and HR=0.90 (0.70 to 1.17) in adjusted matched analysis. Similar results were found in the analysis of URI and bronchitis only and for serious respiratory infections only.ConclusionsIn patients with RA, the risk for respiratory infections was similar among patients using HCQ as compared to other non-biologic DMARDs.

Introduction Controlled clinical studies have shown that the efficacy of tocilizumab (TCZ) monotherapy is superior to that of tumor necrosis factor inhibitor (TNFi) monotherapy and comparable to that of TCZ plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). This study compared the real-world effectiveness of TCZ monotherapy vs. TNFis plus MTX in US patients with RA. Methods TCZ-naïve patients from the Corrona RA registry with prior exposure to ≥ 1 TNFi who initiated TCZ monotherapy or TNFi + MTX were included. Outcomes included mean change in Clinical Disease Activity Index (CDAI), achievement of low disease activity (LDA; CDAI ≤ 10), achievement of modified American College of Rheumatology (mACR) 20/50 responses, and mean change in modified Health Assessment Questionnaire (mHAQ) at 6 months. Patients initiating TNFi + MTX were grouped by MTX dose (≤ 10 mg; > 10 to ≤ 15 mg; > 15 to ≤ 20 mg; > 20 mg); outcomes in each group were compared with TCZ monotherapy using trimmed populations (excluding patients outside the propensity score distribution overlap). Results Patients in all groups experienced improvement in CDAI at 6 months (mean change, − 6.9 to − 9.7), with no significant differences between the TCZ monotherapy and TNFi + MTX groups. Achievement of LDA and mACR responses at 6 months were comparable between the TCZ monotherapy and TNFi + MTX groups; overall, 26.8–38.0% of patients achieved LDA, 24.3–37.6% achieved mACR20 response and 13.2–20.8% achieved mACR50 response. The mean change in mHAQ at 6 months was − 0.1 in all groups. Conclusions In this real-world population of US patients with RA who had prior TNFi exposure, there was no evidence of a difference in the effectiveness of TCZ monotherapy compared with that of TNFi + MTX, regardless of MTX dose, at 6 months for improving RA disease activity. Funding Corrona, LLC. Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s40744-018-0127-1) contains supplementary material, which is available to authorized users.

Objective To assess the feasibility and efficacy of implementing a treat‐to‐target approach versus usual care in a US‐based cohort of rheumatoid arthritis patients. Methods In this behavioral intervention trial, rheumatology practices were cluster‐randomized to provide treat‐to‐target care or usual care. Eligible patients with moderate/high disease activity (Clinical Disease Activity Index [CDAI] score >10) were followed for 12 months. Both treat‐to‐target and usual care patients were seen every 3 months. Treat‐to‐target providers were to have monthly visits with treatment acceleration at a minimum of every 3 months in patients with CDAI score >10; additional visits and treatment acceleration were at the discretion of usual care providers and patients. Coprimary end points were feasibility, assessed by rate of treatment acceleration conditional on CDAI score >10, and achievement of low disease activity (LDA; CDAI score ≤10) by an intent‐to‐treat analysis. Results A total of 14 practice sites per study arm were included (246 patients receiving treat‐to‐target and 286 receiving usual care). The groups had similar baseline demographic and clinical characteristics. Rates of treatment acceleration (treat‐to‐target 47% versus usual care 50%; odds ratio [OR] 0.92 [95% confidence interval (95% CI) 0.64, 1.34]) and achievement of LDA (treat‐to‐target 57% versus usual care 55%; OR 1.05 [95% CI 0.60, 1.84]) were similar between groups. Treat‐to‐target providers reported patient reluctance and medication lag time as common barriers to treatment acceleration. Conclusion This study is the first to examine the feasibility and efficacy of a treat‐to‐target approach in typical US rheumatology practice. Treat‐to‐target care was not associated with increased likelihood of treatment acceleration or achievement of LDA, and barriers to treatment acceleration were identified.

Implementation of a treat-to-target strategy is challenging when the patient and physician prioritize different goals. This study aimed to “translate” improvements in Clinical Disease Activity Index (CDAI) to concepts that resonate with patients (such as pain, fatigue, morning stiffness) by examining the association between changes in disease activity and patient-reported outcomes (PROs) in a national cohort of patients with rheumatoid arthritis (RA) initiating their first biologic treatment. Patients in the Corrona registry with moderate or high disease activity (M/HDA) (defined by a CDAI score > 10), prior use of at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), 12-month follow-up, and initiating their first tumor necrosis factor inhibitor (TNFi) between 1 January 2006 through 1 November 2015 were identified. Patients were stratified on the basis of CDAI during follow-up, and changes in PROs were compared with a test of trend using CDAI-defined groups. Of 1570 patients, 37% achieved sustained remission or low disease activity (remission/LDA), 15% had improving remission/LDA, 12% had worsening M/HDA, and 35% were in sustained M/HDA during 12-month follow-up. Those in sustained remission/LDA had greater magnitude of improvement in physical functioning, pain, fatigue, morning stiffness, patient’s global assessment, and quality of life compared with patients in sustained M/HDA (p

Tocilizumab (TCZ) monotherapy has been proven as an effective treatment for rheumatoid arthritis (RA) in clinical trials. However, there are limited data available regarding the effectiveness of TCZ monotherapy in real-world clinical settings in the United States. The objective of this study was to evaluate the impact of TCZ monotherapy on disease activity and patient-reported outcomes (PROs) in a US-based observational cohort of patients with RA seen in routine clinical practice. Eligible patients had active RA, no prior use of TCZ, and initiated TCZ as monotherapy. Changes in disease activity and PROs were assessed 1 year after TCZ initiation for the overall cohort and stratified by number of prior tumor necrosis factor inhibitors (TNFis; 0, 1, or ≥2). Primary outcomes were change in Clinical Disease Activity Index (CDAI); change in patient global disease activity, pain, fatigue; and the proportions of patients with improvement in modified Health Assessment Questionnaire (mHAQ), morning stiffness, and EQ-5D. Of 255 eligible TCZ monotherapy initiators, 9.4% were TNFi naive, 36.5% had one prior TNFi, and 54.1% had ≥2 prior TNFis. Clinical and PRO measures indicated that patients were substantially impacted by their disease at baseline. The median decrease in CDAI from baseline to 1 year was 9.8 and median patient global and pain scores improved by 10 mm, indicative of clinically meaningful improvement; the median fatigue score improved by 5 mm. Approximately 26% of patients reported clinically meaningful improvement in mHAQ, 54% experienced improvement in morning stiffness, and 20% to 36% experienced improvement in EQ-5D domains (walking, self-care, usual activities, pain/discomfort, and anxiety/depression). Improvements were similar across TNFi groups. Patients with active, refractory RA who initiated TCZ monotherapy experienced improvements in both composite disease activity scores and PROs at 1 year, regardless of prior TNFi exposure. Corrona, LLC and Genentech.

Current recommendations for the management of rheumatoid arthritis (RA) focus on a treat-to-target approach with the objective of maximizing long-term health-related quality-of-life in patients with RA. Published studies from randomized clinical trials have reported limited data regarding the long-term efficacy and safety of adalimumab in patients with RA. This study aims to evaluate the long-term (10+ years) persistency and effectiveness of adalimumab in patients with RA in a real-world setting. Included in this study were biologic-naive adults with RA initiating adalimumab during follow-up enrolled in the Corrona RA registry. More than 10 years of data on persistency of adalimumab and rheumatologist-supplied reasons for discontinuation were examined. Among patients who persisted on adalimumab over the years, clinical [e.g., clinical disease activity index scores (CDAI), physician global assessment, tender joint count, and swollen joint count] and patient-reported outcomes (PRO), such as physical function, pain, fatigue, and morning stiffness, were examined. Of 1791 biologic-naive patients treated with adalimumab who had ≥1 follow-up registry visit, 64.1% were still on therapy at 1 year and 10.2% were still on therapy by the end of year 12. Among patients who persisted on adalimumab for at least 1 year (77.1% female, mean age 53.9 years), 67.0% were in low disease activity (LDA)/remission (CDAI ≤10) and had clinically meaningful improvements from baseline in all clinical assessments and PROs. Initial improvements in LDA/remission and in clinical and PRO assessments observed at year 1 were sustained in those patients who remained on adalimumab over 10 years of follow-up. Among patients who discontinued adalimumab, 61.6% were not in LDA/remission and 41.9% switched to another biologic within 12 months after discontinuing adalimumab. Real-world data demonstrate a sustained effectiveness of adalimumab in the treatment of RA for patients who remained on therapy for 10 years. Corrona, LLC and AbbVie.

To compare clinical outcomes and treatment patterns among patients with moderate vs severe RA following biologic DMARD initiation.Biologics-naive patients with moderate to severe RA [Clinical Disease Activity Index (CDAI)10] who initiated a biologic DMARD were selected from the Corrona registry (2001-13). CDAI, functional status [modified HAQ (mHAQ)] and patterns of drug use were compared at 1 and 2 years post-initiation between patients with moderate (CDAI10⩽22) vs severe (CDAI22) baseline disease activity.A total of 1596 patients (817 severe, 779 moderate) had ⩾1 year of follow-up and 1269 (635 severe, 634 moderate) had ⩾2 years of follow-up. Patients with severe vs moderate baseline disease activity experienced greater improvements in disease activity [mean change in CDAI -18.9 vs -6.0 at year 1; -21.0 vs -7.1 at year 2 ( P0.0001)] and physical function [mean change in mHAQ -0.2 vs -0.1 ( P0.0001) at year 1; -0.2 vs -0.1 ( P = 0.0013) at year 2]. Greater proportions of patients with moderate vs severe disease activity achieved remission (CDAI ⩽2.8) [22.7 vs 15.8% ( P = 0.0003) at year 1; 25.9 vs 20.9% ( P = 0.0396) at year 2] or low disease activity (CDAI10) [60.1 vs 41.2% at year 1; 66.7 vs 49.4% at year 2 ( P0.0001)]. Most patients remained on the original biologic drug (70% at year 1;62% at year 2).With biologic therapy, RA patients with higher baseline disease activity achieved greater improvements in measures of disease activity than those with lower levels of disease, but less often achieved the common targets of remission or low disease activity.

Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo. Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine., The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. The 2C7 epitope is (i) broadly expressed as a gonococcal antigenic target in human infection, (ii) a critical requirement for gonococcal colonization in the experimental setting, and (iii) a virulence determinant that is maintained and expressed by gonococci. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 μg/dose in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1-promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains. Similarly, a 3-dose biweekly schedule (50 μg TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model.

Objective Though randomized controlled trials have demonstrated relatively comparable clinical outcomes with triple therapy (methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) compared to combination therapy (tumor necrosis factor inhibitor [TNFi] and MTX), real-world experiences comparing these strategies have not been well studied. Methods We evaluated the clinical effectiveness and effects of medication discontinuation of triple therapy with MTX/SSZ/HCQ versus combination therapy with TNFi/MTX in rheumatoid arthritis (RA) patients enrolled in the Corrona RA Drug Safety & Effectiveness Registry. Propensity score matching was used to match patients up to a ratio of 1:3 to adjust for imbalances between treatment groups, with stratification performed according to biologics-naive or biologics-exposed status of study participants. Results Patients eligible for analysis in this study included biologics-naive RA patients (3,926 who received combination therapy with TNFi/MTX and 262 who received triple therapy with MTX/SSZ/HCQ) and biologics-exposed RA patients (3,365 who received combination therapy with TNFi/MTX and 130 patients who received triple therapy with MTX/SSZ/HCQ). Before propensity score matching, numerous factors were imbalanced between the treatment groups, with triple therapy patients generally being older, having a longer disease duration of RA and lower RA disease activity, and more likely having a history of malignancy and other comorbidities. After matching, almost all (93-98%) triple therapy patients could be matched to TNFi/MTX therapy patients, and cohort characteristics were generally well balanced. Discontinuation of medication was greater in triple therapy patients referent to TNFi/MTX therapy patients (adjusted hazard ratio [HR] of 2.17 [95% confidence interval 1.63-2.88] in the biologics-naive group; adjusted HR of 1.51 [95% confidence interval 1.06-2.15] in the biologics-exposed group). At 6 months, the proportion of biologics-naive patients attaining low disease activity was significantly greater in the TNFi/MTX treatment group (49.2% in TNFi/MTX therapy patients versus 33.3% in triple therapy patients), as was the mean change in Clinical Disease Activity Index scores (-9.3 units versus -5.5 [95% confidence interval -1.5, -6.1]). Corresponding results in the biologics-exposed patients numerically favored TNFi/MTX therapy compared to triple therapy but did not reach statistical significance. Conclusion Few patients receive triple therapy with MTX/SSZ/HCQ in the US. In the present study, drug persistence and clinical effectiveness outcomes were less favorable in triple therapy patients compared to TNFi/MTX therapy patients.

Objective To assess whether the time between the last rituximab infusion and initiation of a different biologic agent influenced infection risk in patients with rheumatoid arthritis (RA). Methods Patients with RA who newly initiated rituximab within the Consortium of Rheumatology Researchers of North America registry were included if they switched to a nonrituximab biologic agent and had ≥1 followup visit within 12 months of switching. Patients were categorized by duration of time between their last rituximab infusion and initiation of a subsequent biologic agent (≤5 months, 6–11 months, and ≥12 months). The primary outcome was time to first infectious event. Adjusted Cox regression models estimated the association between time to starting a subsequent biologic agent and infection. Results A total of 44 overall infections (7 serious, 37 nonserious) were reported during the 12-month followup in the 215 patients included in this analysis (104 switched at ≤5 months, 67 at 6–11 months, and 44 at ≥12 months). Median (interquartile range) time to infection was 4 (2–5) months. Infection rates per patient-year in the ≤5-month, 6–11-month, and ≥12-month groups were 0.34 (95% confidence interval [95% CI] 0.22–0.52), 0.30 (95% CI 0.17–0.52), and 0.41 (95% CI 0.22–0.77), respectively. After adjustment, time to switch to a subsequent biologic agent was not associated with infection, which remained unchanged when number and rate of rituximab retreatments were included in the models. Conclusion In this real-world cohort of patients with RA, infection rates ranged from 0.30 to 0.41 per patient-year, with no significant difference in the rate between patients who initiated a subsequent biologic agent earlier versus later after rituximab treatment.

Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18–20 (FH18–20). We explored the use of fusing FH18–20 with IgG Fc (FH18–20/Fc) to create a novel anti-infective immunotherapeutic. FH18–20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18–20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18–20/Fc but, unlike FH18–20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition (≥10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae.

Background We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality. Methods Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ. Results The combined registry cohorts included 57 251 patients with RA (234 089 person-years)—24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates. Conclusions This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.

ObjectiveInflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA).MethodsThe study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, 30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes.ResultsWe identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed ≥7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI >30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI ≤25.ConclusionDMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups.

Novel therapeutics against multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococcal lipooligosaccharide often expresses lacto-N-neotetraose (LNnT), which becomes sialylated in vivo, enhancing factor H (FH) binding and contributing to the organism’s ability to resist killing by complement. We previously showed that FH domains 18–20 (with a D-to-G mutation at position 1119 in domain 19) fused to Fc (FHD1119G/Fc) displayed complement-dependent bactericidal activity in vitro and attenuated gonococcal vaginal colonization of mice. Gonococcal lipooligosaccharide phase variation can result in loss of LNnT expression. Loss of sialylated LNnT, although associated with a considerable fitness cost, could decrease efficacy of FHD1119G/Fc. Similar to N. meningitidis, gonococci also bind FH domains 6 and 7 through Neisserial surface protein A (NspA). In this study, we show that a fusion protein comprising FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/Fc) bound to 15 wild-type antimicrobial resistant isolates of N. gonorrhoeae and to each of six lgtA gonococcal deletion mutants. FH6,7/Fc mediated complement-dependent killing of 8 of the 15 wild-type gonococcal isolates and effectively reduced the duration and burden of vaginal colonization of three gonococcal strains tested in wild-type mice, including two strains that resisted complement-dependent killing but on which FH6,7/Fc enhanced C3 deposition. FH/Fc lost efficacy when Fc was mutated to abrogate C1q binding and in C1q−/− mice, highlighting the requirement of the classical pathway for its activity. Targeting gonococci with FH6,7/Fc provides an additional immunotherapeutic approach against multidrug-resistant gonorrhea.

Sialylation of lacto-W-neotetraose (LNnT) extending from heptose I (HepI) of gonococcal lipooligosaccharide (LOS) contributes to pathogenesis. Previously, gonococcal LOS sialyltransterase (Lst) was shown to sialylate LOS in Triton X-100 extracts of strain 15253, which expresses lactose from both HepI and HepII, the minimal structure required for mAb 2C7 binding. Ongoing work has shown that growth of 15253 in cytidine monophospho-W-acetylneuraminic acid (CMP-Neu5Ac)-containing media enables binding to CD33/Siglec-3, a cell surface receptor that binds sialic acid, suggesting that lactose termini on LOS of intact gonococci can be sialylated. Neu5Ac was detected on LOSs of strains 15253 and a MS11 mutant with only lactose from HepI and HepII by mass spectrometry; deleting HepII lactose rendered Neu5Ac undetectable. Resistance of HepII lactose Neu5Ac to desialylation by α2-3-specific neuraminidase suggested an α2-6-linkage. Although not associated with increased factor H binding, HepII lactose sialylation inhibited complement C3 deposition on gonococci. 15253 mutants that lacked Lst or HepII lactose were significantly attenuated in mice, confirming the importance of HepII Neu5Ac in virulence. All 75 minimally passaged clinical isolates from Nanjing, China, expressed HepII lactose, evidenced by reactivity with mAb 2C7; mAb 2C7 was bactericidal against the first 62 (of 75) isolates that had been collected sequentially and were sialylated before testing. mAb 2C7 effectively attenuated 15253 vaginal colonization in mice. In conclusion, this novel sialylation site could explain the ubiquity of gonococcal HepII lactosein vivo. Our findings reiterate the candidacy of the 2C7 epitope as a vaccine antigen and mAb 2C7 as an immunotherapeutic antibody.

Background The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. Methods Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). Results There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. Conclusion In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.

OBJECTIVE: Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries. METHODS: Using predefined definitions, 2 subsets of patients (main cohort and sub-cohort) from 5 international observational registries (CORRONA, SRR, NOAR, IORRA, and CORRONA International) were evaluated and compared. Patients with RA aged >18 years, and present in or recruited to the registry from January 1, 2000, were included in the main cohort. Patients from the main cohort with positive rheumatoid factor and/or erosive RA who had received ?1 sDMARD, and switched to or added another DMARD, were included in the sub-cohort at time of treatment switch. RESULTS: Age and gender distributions were fairly similar across the registries. The percentage of patients with high DAS28 score varied between main cohorts (17.5% IORRA, 18.9% CORRONA, 24.7% NOAR, 27.7% CORRONA International, and 36.8% SRR), with IORRA, CORRONA, and CORRONA International including more prevalent cases of RA; the differences were smaller for the sub-cohort. Prevalence of comorbidities varied across registries (e.g., coronary artery disease ranging from 1.5% in IORRA to 7.9% in SRR), partly due to the way comorbidity data was captured and general cultural differences; the pattern was similar for the sub-cohorts. CONCLUSION: Despite different inclusion criteria for the individual RA registries, it is possible to improve the comparability and interpretability of differences across RA registries by applying well-defined cohort definitions. This article is protected by copyright. All rights reserved.

Objective To identify the rheumatoid arthritis (RA) characteristics associated with increased herpes zoster (HZ) risk in the Corrona registry RA patients, and to evaluate the risk in initiators of tumor necrosis factor inhibitors (TNFi) or non-TNFi biologic agents or (among those who were currently on or had been previously treated with methotrexate [MTX]) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) other than MTX. Methods Cox regression modeling estimated the association between first HZ incidence and selected RA characteristics, including disease activity. Medication-related risk for HZ in RA patients taking current or past MTX (to exclude milder RA disease) were categorized by treatment initiation (TNFi versus non-TNFi versus csDMARD). Hazard ratios (HRs) estimated HZ risk of each treatment initiation category after stratification on trimmed propensity score (PS) quintiles to control for potential confounders. Results A total of 28,852 patients contributed 95,287 person-years. Seven hundred twenty-nine observed HZ cases yielded a 7.7 (95% confidence interval [95% CI] 7.1–8.2) per 1,000 patient-years crude incidence rate, lower than found in prior RA cohorts. However, consistent with prior studies, increasing age (HR 1.14, 95% CI 1.09–1.19 per 5 years) and prednisone therapy ≥7.5 mg/day (HR 1.81, 95% CI 1.23–2.67) were associated with a higher HZ risk. Referent to TNFi exposure, PS-stratified analysis showed an HR for csDMARDs of 1.36 (95% CI 0.82–2.25) and for non-TNFi of 0.83 (95% CI 0.51–1.38). Conclusion In the Corrona registry, the HZ risk in RA patients taking prior or current MTX increased with older age and higher prednisone dose. The HZ risk among these patients with RA was comparable after initiation of TNFi versus non-TNFi versus csDMARDs.

PURPOSE: Observational studies can provide context for adverse events observed in clinical trials, especially for infrequent events or long-term risks. We developed methods to improve safety contextualization for a rheumatoid arthritis drug development program through coordinated analyses of multiple registries. METHODS: We identified and characterized differences and similarities across five registries (Swedish Rheumatology Quality of Care Register, Consortium of Rheumatology Researchers of North America [CORRONA], Norfolk Arthritis Register, Institute of Rheumatology Rheumatoid Arthritis, and the new CORRONA International), harmonized outcome definitions, and investigated whether restricted subcohorts improved comparability with trial populations. To address confounding, we identified risk predictors for outcomes of interest (mortality, cardiovascular disease, infection, and malignancy). We used patient-level analyses at each registry and central analysis of standardized group-level data. RESULTS: Despite data differences, the coordinated approach enabled consistent variable definitions for key baseline characteristics and outcomes. Selection of restricted subcohorts (e.g., using active joint count criteria) improved baseline comparability with trial patients for some rheumatoid arthritis disease activity measures, but less for other characteristics (e.g., age and comorbidity); however, such selection decreased sample size considerably. For most outcomes, age was the most important risk predictor, emphasizing the importance of age/sex standardization to address confounding. The prospective approach enabled use of recent relevant data; the distributed analysis safeguarded confidentiality of registry data. CONCLUSIONS: Compared with reliance on published data alone, a forward-looking coordinated approach across multiple observational data sources can improve comparability and consistency and better support sensitivity analyses and data interpretation, in contextualizing safety data from clinical trials. This approach may have utility to support safety assessments across diverse diseases and drug development programs and satisfy future regulatory requirements. Copyright � 2015 John Wiley & Sons, Ltd.

Background Use of several immunomodulatory agents has been associated with reduced cardiovascular (CV) events in epidemiologic studies of rheumatoid arthritis (RA). However, it is unknown whether time-averaged disease activity in RA correlates with CV events.

Objective.To characterize the real-world effectiveness of rituximab (RTX) in patients with rheumatoid arthritis.Methods.Clinical effectiveness at 12 months was assessed in patients who were prescribed RTX based on the Clinical Disease Activity Index (CDAI). Change in CDAI was calculated (CDAI at 12 mos minus at initiation). Achievement of remission or low disease activity (LDA; CDAI ≤ 10) among those with moderate/high disease activity at the time of RTX initiation was compared based on prior anti-tumor necrosis factor agent (anti-TNF) use (1 vs ≥ 2) using logistic regression models.Results.Patients (n = 265) were followed for 12 months with a mean change in CDAI of −8.1 (95% CI −9.8 – −6.4). Of the 218 patients with moderate/high disease activity at baseline, patients with 1 prior anti-TNF (baseline CDAI 25.0) demonstrated a mean change in CDAI of −10.1 (95% CI −13.2 – −7.0); patients with ≥ 2 prior anti-TNF (baseline CDAI 30.0) demonstrated a mean change of −10.5 (95% CI −12.9 – −8.0). The unadjusted OR for achieving LDA/remission in patients with moderate/high disease activity at baseline exposed to ≥ 2 versus 1 prior anti-TNF was 0.40 (95% CI 0.22–0.73), which was robust to 4 different adjusted models (OR range 0.38–0.44).Conclusion.A good clinical response was observed in all patients; however, patients previously treated with 1 anti-TNF, who had lower baseline CDAI and a greater opportunity for clinical improvement compared with patients previously treated with ≥ 2 anti-TNF, were more likely to achieve LDA/remission.

Objective Depression is common in the rheumatoid arthritis (RA) population, yet little is known of its effect on the course of disease activity. The aim of our study was to determine if prevalent and incident depressive symptoms influenced longitudinal changes in RA disease activity. Methods RA patients with and without depressive symptoms were identified using single-item questions from an existing registry sample. Mixed-effects models were used to examine changes in disease activity over 2 years in those with and without prevalent and incident depressive symptoms. Outcome variables included composite disease activity, joint counts, global assessments, pain, function, and acute-phase reactants. Model-based outcome estimations at the index dates and corresponding 1- and 2-year changes were calculated. Results Rates of disease activity change were significantly different in patients with a lifetime prevalence of symptomology, but not incident depressive symptoms, when compared to controls. Prior symptoms were associated with slower rates of disease activity decline, evidenced by the estimated 1-year Clinical Disease Activity Index changes: −3.0 (−3.3, −2.6) and −4.0 (−4.3, −3.6) in patients with and without lifetime prevalence, respectively. Analogous results were obtained for most of the other disease activity outcomes; although, there was no temporal effect of prevalent symptoms of depression on swollen joints and acute-phase reactants. Conclusion Depressive symptoms temporally influence the evolution of RA disease activity, and the magnitude is dependent on the time of symptomatic onset. However, the effect is limited to patient-reported pain, global assessment, and function, as well as physician-reported global assessment and tender joints.

Malarial infection in naive individuals induces a robust innate immune response. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed training) or hyporespond (tolerance) to subsequent immune challenge. Previous work in both mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with Plasmodium falciparum–infected RBCs or the malaria crystal hemozoin induced human adherent PBMCs to hyperrespond to subsequent ligation of TLR2. This hyperresponsiveness correlated with increased H3K4me3 at important immunometabolic promoters, and these epigenetic modifications were also seen in Kenyan children naturally infected with malaria. However, the use of epigenetic and metabolic inhibitors indicated that the induction of trained immunity by malaria and its ligands may occur via a previously unrecognized mechanism(s).

Antibodies against reduction modifiable protein (anti-Rmp Abs) can block complement-dependent killing of Neisseria gonorrhoeae by otherwise bactericidal Abs. An anti-lipooligosaccharide bactericidal monoclonal Ab (mAb) 2C7, a gonococcal vaccine candidate Ab, attenuates vaginal colonization by gonococci in BALB/c mice. Here we show that anti-Rmp Abs block the efficacy of mAb 2C7 in mice in a dose-dependent manner. Anti-Rmp Abs also counteract 2C7-mediated enhancement of C3 deposition on gonococci in vivo. The mouse model will prove useful to study how blocking Abs influence the efficacy of gonococcal vaccines. Preexisting anti-Rmp Abs will be an important consideration in evaluating the efficacy of gonococcal vaccine candidates.

Summary The Plasmodium cell cycle, wherein millions of parasites differentiate and proliferate, occurs in synchrony with the vertebrate host's circadian cycle. The underlying mechanisms are unknown. Here we addressed this question in a mouse model of Plasmodium chabaudi infection. Inflammatory gene expression and carbohydrate metabolism are both enhanced in interferon-γ (IFNγ)-primed leukocytes and liver cells from P. chabaudi-infected mice. Tumor necrosis factor α (TNFα) expression oscillates across the host circadian cycle, and increased TNFα correlates with hypoglycemia and a higher frequency of non-replicative ring forms of trophozoites. Conversely, parasites proliferate and acquire biomass during food intake by the host. Importantly, cyclic hypoglycemia is attenuated and synchronization of P. chabaudi stages is disrupted in IFNγ−/−, TNF receptor−/−, or diabetic mice. Hence, the daily rhythm of systemic TNFα production and host food intake set the pace for Plasmodium synchronization with the host's circadian cycle. This mechanism indicates that Plasmodium parasites take advantage of the host's feeding habits.

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.

Objective Patients with rheumatoid arthritis (RA) have an increased risk of serious infections. Comparing infection rates across RA populations is complicated by differences in background infection risk, population composition and study methodology. We measured infection rates from five RA registries globally, with the aim to contextualise infection rates from an RA clinical trials population. Methods We used data from Consortium of Rheumatology Research of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (Sweden), Norfolk Arthritis Register (UK), CORRONA International (multiple countries) and Institute of Rheumatology Rheumatoid Arthritis (Japan) and an RA clinical trial programme (fostamatinib). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data. Infection definitions were harmonised across registries. Sensitivity analyses to address potential confounding explored subcohorts defined by disease activity, treatment change and/or prior comorbidities and restriction by calendar time or follow-up. Rates of infections were estimated and standardised to the trial population for age/sex and, in one sensitivity analysis also, for Health Assessment Questionnaire (HAQ) score. Results Overall, age/sex-standardised rates of hospitalised infection were quite consistent across registries (range 1.14-1.62 per 100 patient-years). Higher and more consistent rates across registries and with the trial programme overall were seen when adding standardisation for HAQ score (registry range 1.86-2.18, trials rate 2.92) or restricting to a treatment initiation subcohort followed for 18 months (registry range 0.99-2.84, trials rate 2.74). Conclusion This prospective, coordinated analysis of RA registries provided incidence rate estimates for infection events to contextualise infection rates from an RA clinical trial programme and demonstrated relative comparability of hospitalised infection rates across registries.

Malarial infection in naïve individuals induces a robust innate immune response. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed “training”) or hyporespond (“tolerance”) to subsequent immune challenge. Previous work in both mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with Plasmodium falciparum infected red blood cells (iRBCs) or the malaria crystal hemozoin (Hz) induced human adherent PBMCs to hyperrespond to subsequent ligation of TLR2. This hyperresponsiveness correlated with increased H3K4me3 at important immunometabolic promoters, and these epigenetic modifications were also seen in Kenyan children naturally infected with malaria. However, the use of epigenetic and metabolic inhibitors indicated that the induction of trained immunity by malaria and its ligands may occur via previously unrecognized mechanism(s).

Background Clinical studies have shown that the efficacy of TCZ monotherapy (TCZ mono) is superior to that of TNFi monotherapy and comparable to that of TCZ in combination with MTX. Objectives To compare the effectiveness of TCZ mono vs TNFi plus varying doses of MTX in patients with rheumatoid arthritis (RA) and prior exposure to TNFi in routine clinical practice. Methods Eligible participants were TCZ-naive patients from the Corrona RA registry who had prior exposure to ≥1 TNFi, initiated TCZ mono or a TNFi + MTX between 2010 and 2016 and had a 6-month follow-up visit. The primary outcome was mean change from baseline in Clinical Disease Activity Index (CDAI) at 6 months. Secondary outcomes included achievement of low disease activity (LDA; CDAI ≤10) at 6 months. Patients initiating a TNFi + MTX were grouped by MTX dose (≤10 mg; >10 to ≤15 mg; >15 to ≤20 mg; >20 mg); outcomes in each group were compared with those initiating TCZ mono using trimmed populations, excluding patients outside the propensity score (PS) distribution overlap (not on common support). The PS included age, sex, race, body mass index, smoking status, work status, disease duration, concomitant prednisone use/dose, prior biologic use, American College of Rheumatology functional class and baseline modified Health Assessment Questionnaire, CDAI and patient pain scores. As a sensitivity analysis, stratified-matched populations were created (stratified by 1 vs ≥2 prior biologics, then matched on PS). Linear and logistic regression models were estimated in the trimmed populations, adjusting for the same covariates as in the PS. Results Baseline demographics were generally comparable between the TNFi + MTX groups and their matched TCZ mono groups. Overall, the mean age was 54 to 59 years, and the mean disease duration was 10.5 to 15 years. A higher proportion of patients initiating TCZ mono had received ≥3 prior biologics compared with those initiating TNFi + MTX. Patients initiating TCZ mono had significantly longer mean disease duration than those initiating TNFi + MTX >15 to ≤20 mg (13.0 vs 10.5 years) or TNFi + MTX >20 mg (12.3 vs 9.3 years) and a higher mean baseline CDAI than those initiating TNFi + MTX ≤10 mg (28.1 vs 25.4). Patients in all groups had improvement in CDAI scores at 6 months. In adjusted models, improvement in CDAI and the likelihood of achieving LDA were similar between the TCZ mono group and all TNFi + MTX groups (Table). Similar results were observed in the PS-matched cohorts. Conclusions TCZ mono was as effective as TNFi + MTX, regardless of MTX dose, for improving disease activity in patients with prior TNFi exposure. These data suggest that TCZ mono is an effective treatment option for patients with RA who cannot tolerate or prefer not to use MTX. Acknowledgements This study is sponsored by Corrona, LLC. Corrona, LLC, has been supported through contracted subscriptions in the past 2 years by AbbVie, Amgen, BMS, Crescendo, Eli Lilly and Company, Genentech, GSK, Horizon Pharma USA, Janssen, Momenta Pharmaceuticals, Novartis, Pfizer, Roche and UCB. Disclosure of Interest L. Harrold Shareholder of: Corrona, LLC, Grant/research support from: Pfizer, Consultant for: Roche, Employee of: University of Massachusetts Medical School; Corrona, LLC, G. Reed Shareholder of: Corrona, LLC, Employee of: Corrona, LLC, J. Best Employee of: Genentech, Inc, S. Zlotnick Employee of: Genentech, Inc, G. Persuitte Employee of: Corrona, LLC, J. Kremer Shareholder of: Corrona, LLC, Consultant for: AbbVie; Amgen; Bristol-Meyers Squibb; Genentec, Inc; GlaxoSmithKline; Lilly; Pfizer; Regeron; Sanofi, Employee of: Corrona, LLC

Background Extended observations in clinical trials have not demonstrated an increased risk of serious infection events (SIE) in patients with rheumatoid arthritis (RA) treated with rituximab.1 However, continuous surveillance using large-scale observational data is of importance. Objectives To evaluate the rate of SIEs among patients with RA who received only an initial rituximab infusion vs those retreated with ≥1 rituximab infusion during the first year of therapy, and also to describe characteristics of rituximab-treated patients who experienced an SIE vs those who did not. Methods Patients with RA enrolled in the Corrona registry and treated with rituximab were followed until their most recent Corrona registry visit, first SIE, switch to another biologic or targeted synthetic disease-modifying antirheumatic drug, or 12 months after the most recent infusion with no further retreatment – whichever occurred first. The rate of SIEs was estimated in the overall population as well as in patients retreated with ≥1 infusion every 12 months after rituximab initiation and in those who did not receive a repeat infusion in the first 12 months. Patient characteristics were compared between those who experienced an SIE and those who did not. Results A total of 1361 patients with 1821 patient-years (PY) of follow-up were included; there were 59 SIEs for a rate of 3.24 SIE/100 PYs. 637 patients (46.8%) received ≥1 rituximab retreatment during the first 12 months and 724 (53.2%) received only the initial infusion. In the retreatment population there were 40 SIEs per 1312.8 PY for a rate (95% CI) of 3.05/100 PY (2.18–4.15), and in the no retreatment population there were 19 SIEs per 508.71 PY for a rate (95% CI) of 3.73/100 PY (2.25–5.83). The Kaplan-Meier curve depicting the occurrence of SIEs in the 2 cohorts during the first year of follow-up is shown (Figure). In the 59 patients (4.3%) who experienced an SIE, the mean (SD) number of rituximab infusions was 1.88 (1.18), compared with 2.07 (1.70) in the 1302 patients (95.7%) who did not experience an SIE. Patients who experienced an SIE vs those who did not were older (mean age [SD]: 62.9 [9.9] vs 58.1 [12.55] years), had longer disease duration (19.1 [13.1] vs 13.6 [10.4] years), were more frequently diabetic (16.9% vs 8.3%) and more frequently had cardiovascular disease (25.4% vs 12.8%), prior history of SIEs (18.6% vs 5.8%) and pulmonary disease (10.2% vs 4.8%). There were no differences in other clinical, demographic and medication history characteristics; steroid therapy was similar between the groups. Conclusions Retreatment with rituximab infusions was not associated with a higher rate of SIEs in this study. Patients who experienced an SIE had a higher prevalence of risk factors for infections. References Van Vollenhoven RF et al. J Rheumatol. 2015;42:1791–6. Acknowledgements This study is sponsored by Corrona, LLC. Corrona, LLC has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, BMS, Crescendo, Eli Lilly, Genentech, GSK, Horizon Pharma USA, Janssen, Momenta Pharmaceuticals, Novartis, Pfizer, Roche and UCB. Disclosure of Interest D. Pappas Grant/research support from: AbbVie, Consultant for: AbbVie, Employee of: Corrona, LLC, G. Reed Shareholder of: Corrona, LLC, Employee of: Corrona, LLC, S. Zlotnick Employee of: Genentech, Inc., J. Best Employee of: Genentech, Inc., R. Magner: None declared, G. Persuitte Employee of: Corrona, LLC, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: Genentech; Janssen; Novartis; Pfizer; Eli Lilly, Employee of: Corrona, LLC

Background Rheumatoid arthritis (RA) is a systemic, inflammatory disease and its burden extends beyond joint disease. In recent years, there has been significant advances in treating joint disease but we need a greater understanding of physical and especially psychosocial comorbities to improve quality of life in RA patients. In particular, patients often report “brain fog” meaning a diminished ability to think, learn, remember and perform other mental tasks. Doctors have long recognized that patients with certain physical conditions can experience cognitive dysfunction. Limited information is available in the literature with regard to the prevalence of cognitive dysfunction and factors associated with the condtion in RA. Objectives To characterize the association of disease activity with patient reported cognitive dysfunction in patients with RA overall and stratified by age. Methods We identified patients with RA aged ≥18 years who were enrolled in the Corrona registry who were biologic naive at their last follow-up visit (October 2010–June 2016). We compared those who reported cognitive dysfunction (responded “yes” to the question asking if they had “problems with thinking”) to those who did not with respect to disease activity based on the Clinical Disease Activity Index (CDAI). Unadjusted and adjusted logistic regression models controlling for demographic (age, gender, race, education), comorbidity/lifestyle (diabetes, fibromyalgia, body mass index, smoking) and RA disease characteristics (disease duration, disability and prednisone dose) were conducted. We further examined whether the relationship between disease activity and cognitive dysfunction varied based on patients age ( 55 years) testing the moderating effect using a likelihood ratio test. Results There were 10,401 patients who met inclusion criteria of whom 863 (8%) reported cognitive dysfunction. Those who reported cognitive dysfunction were more likely to be women (83% vs. 73%, p Conclusions Increasing disease activity is associated with a higher likelihood of reporting cognitive disfunction. The effect was more pronounced in younger as opposed to older RA patients. Disclosure of Interest G. Reed Shareholder of: Corrona, LLC, Employee of: Corrona, LLC, L. Harrold Shareholder of: Corrona, LLC, Grant/research support from: Pfizer, Inc., Consultant for: Roche, Employee of: Corrona, LLC, O. Pala: None declared, J. Kremer Shareholder of: Corrona, LLC, Grant/research support from: AbbVie, Genentech, Lilly, Novartis, Pfizer, Consultant for: AbbVie, Amgen, BMS, Genentech, Lilly, Regeneron, Sanofi, Pfizer, Employee of: Corrona, LLC

BackgroundThere is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit.MethodsWe assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan–Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit.ResultsWe identified 717 eligible patients with RA from 35 656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit.ConclusionsDiscontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.