Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics.

OBJECTIVES: To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics. METHODS: The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16-250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models. RESULTS: Participants (n = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P-value for interaction >0.1). CONCLUSION: An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA.

A Model to Predict Future Biologic or Targeted Synthetic DMARD Switch at a Subsequent Clinic Visit in Rheumatoid Arthritis.

INTRODUCTION: To understand factors leading to biologic switches and to develop a readily usable model with data collected in clinical care at preceding visits, with the overall aim to predict the probability of switching biologic at a subsequent clinic visit in patients with rheumatoid arthritis (RA). METHODS: Participants were adults with RA participating in the CorEvitas RA registry. The study matched patients who switched biologics or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) with control patients who had not switched biologics/tsDMARDs; the cohort was divided into a training and test set for prediction model development and validation. Using the training set, the best subset regression, lasso, and elastic net methods were used to determine the best potential models. Area under the ROC curve (AUC) was used for the final selection of the best model, and estimated coefficients of this model were applied to the test dataset to predict switching. RESULTS: A total of 5050 patients were included, of whom 3016 were in the training set and 2034 were in the test dataset. The average age was 59.6 years, the majority were female (3998, 79.2%), and the average duration of RA at the time of switch or control visit was 12.8 years. The final model included prior Clinical Disease Activity Index (CDAI) by category, prior patient pain measurement, change in CDAI from baseline, age group, and number of prior biologics, all of which were significantly associated with switching biologics. The AUC was 0.690 for this model with the training dataset. The model was then applied to the test data with similar performance; the AUC was 0.687. CONCLUSION: We have developed a simple model to determine the probability of switching biologics for RA at the following clinic visit. This model could be used in practice to provide clinicians with more information about their patient's trajectory and likelihood of switching to a new biologic.

Does the Type of Failure and the Choice of the Second Biologic Influence Response and Persistence on Medication in Rheumatoid Arthritis?

BACKGROUND: The type of failure may predict response to a second biologic. We evaluated the response to a second tumor necrosis factor inhibitor (TNFi) or non-TNFi in patients failing their initial TNFi, either primarily or secondarily. METHODS: Patients with rheumatoid arthritis who were biologic-naive and had a Clinical Disease Activity Index (CDAI) >10, who started their first TNFi for ≥3 months and then switched to a second biologic, were included in the study. Secondary failure was defined as 2 consecutive low-CDAI visits and then switching to a second biologic while they had moderate/severe CDAI. Primary failure was defined if it did not meet the definition of secondary failure, or if they had at least 1 moderate/severe CDAI after 3 months on treatment. We used multivariable logistic regression comparing primary versus secondary failure for achievement of CDAI ≤10 (primary outcome) and minimal clinically important differences (secondary outcome) at 6 months after switch. RESULTS: Of the 462 patients included, 64.3% and 35.7% stopped the first TNFi because of a primary and secondary failure, respectively. Patients with primary failure had a more severe disease (CDAI mean, 26.39 vs. 21.61; p < 0.001). The likelihood of achieving CDAI ≤10 (odds ratio, 4.367; 95% confidence interval, 2.428-7.856) and minimal clinically important difference (odds ratio, 2.851; 95% confidence interval, 1.619-5.020) was significantly higher for secondary than primary failure regardless of choice of a second agent. CONCLUSION: Patients with rheumatoid arthritis with secondary failure to a first TNFi responded better to a second biologic agent, regardless of the choice of biologic.

SARS-CoV-2 Serosurveys: How Antigen, Isotype and Threshold Choices Affect the Outcome.

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 PCRconfirmed 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 antiSARS-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.

Neisseria gonorrhoeae Infection in Women Increases With Rising Gonococcal Burdens in Partners: Chlamydia Coinfection in Women Increases Gonococcal Burden.

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.

Obesity and Response to Advanced Therapies in Rheumatoid Arthritis.

OBJECTIVE: We performed a study of tumor necrosis factor inhibitors (TNFi) compared to non-TNFi biologic therapies in rheumatoid arthritis to test whether body mass index (BMI) modified the effect of each therapy. METHODS: We utilized data from CorEvitas. We studied 3 clinical outcomes based on the Clinical Disease Activity Index (CDAI) at 6 months from therapy initiation: 1) achievement of low disease activity (LDA); 2) a change as large as the minimum clinically important difference (MCID); and 3) the absolute change. We categorized BMI and utilized restricted cubic splines to consider nonlinear associations. We used linear and logistic regression to evaluate associations with response, adjusting for confounders. To determine if comparative effectiveness of therapy varied by BMI, we tested for interactions between BMI and class of therapy. RESULTS: The sample included 2,891 TNFi and 3,010 non-TNFi initiators. Among all initiators, those with severe obesity experienced lower odds of achieving LDA or MCID and less improvement in CDAI score, although associations were attenuated with adjustment. Low BMI was associated with reduced response rates in adjusted models including lower odds of LDA (odds ratio 0.32 [95% confidence interval (95% CI) 0.15, 0.71], P = 0.005). Analyses stratified by TNFi and non-TNFi therapies demonstrated no differences in clinical response rates for TNFi versus non-TNFi across BMI categories (all P for interaction >0.05). Estimates for non-TNFi biologics fit within the 95% CI for TNFi. CONCLUSION: This study observed lower response rates among obese and underweight patients and no evidence of a superior effect of non-TNFi therapy over TNFi therapy in particular BMI categories.

TNFi Cycling Versus Changing Mechanism of Action in TNFi-Experienced Patients: Result of the Corrona CERTAIN Comparative Effectiveness Study.

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] <2.67). Propensity score modeling probability of treatment with nTNFi versus TNFi adjusted for imbalanced factors. The response rate was modeled using mixed-effect logistic regression models, adjusting for a priori and imbalanced baseline factors and accounting for the practice-related treatment patterns. RESULTS: After applying inclusion criteria, 939 biologic initiations were analyzed, 505 (53.7%) nTNFis and 434 (46.3%) TNFis. Patients who started nTNFis were significantly more likely to have longer disease duration, more prior TNFi use, and higher patient fatigue scores and were more likely to have government insurance. At 12 months, 28% of nTNFi and 24% of TNFi initiators were in LDA by CDAI, and 22% of nTNFi and 19% of TNFi initiators were in LDA by DAS28-CRP. After multivariable adjustment and controlling for the influence of site-related confounding, there were no significant differences in the likelihood to reach LDA by CDAI (adjusted odds ratio [aOR] = 1.12; 95% confidence interval [CI], 0.78-1.62) or DAS28-CRP (aOR = 1.16; 95% CI, 0.77-1.75). CONCLUSION: In this large, real-world study enrolling patients with RA with prior TNFi exposure, switching to an nTNFi biologic was comparable in its clinical effectiveness with switching to another TNFi.

Weight Fluctuation and the Risk of Cardiovascular Events in Patients With Rheumatoid Arthritis.

OBJECTIVE: Fluctuations in weight have been linked to cardiovascular (CV) outcomes in the general population. The present study was undertaken to evaluate 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 hazards 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 who lost or gained 10% of their weight had greater disease activity and worse physical function, and they were more likely to smoke, have diabetes mellitus, receive corticosteroids, and be disabled. In adjusted models, a greater risk of CV events was observed in those who experienced 10% weight loss (hazard ratio [HR] 1.18 [95% confidence interval (95% CI) 1.03-1.36], P = 0.02) or weight gain (HR 1.20 [95% CI 1.04-1.38], P = 0.01). The association between weight change and CV events was stronger among participants with body mass index <25 kg/m2 for 10% weight loss (HR 1.34 [95% CI 1.08-1.66], P = 0.001] and 10% weight gain (HR 1.74 [95% CI 1.41-2.24], P < 0.001). Patients with greater variability in weight had a higher risk of CV events. CONCLUSION: Recent changes and high variability in weight predict CV events in RA, particularly among thin patients. Further study is necessary to determine if weight fluctuation has adverse cardiometabolic consequences that are independent of other risk factors.

Short-term dose and duration-dependent glucocorticoid risk for cardiovascular events in glucocorticoid-naive patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid 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. METHODS: Patients 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. RESULTS: 19 902 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. CONCLUSIONS: Over 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.

Assessment of Video Capsule Endoscopy in the Management of Acute Gastrointestinal Bleeding During the COVID-19 Pandemic.

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.

Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection.

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.IMPORTANCENeisseria gonorrhoeae has become resistant to most antibiotics in clinical use. Currently, there is no safe and effective vaccine against gonorrhea. Measures to prevent the spread of gonorrhea are a global health priority. A monoclonal antibody (MAb) called 2C7, directed against a lipooligosaccharide glycan epitope expressed by most clinical isolates, displays complement-dependent bactericidal activity and hastens clearance of gonococcal vaginal colonization in mice. Fc mutations in a human IgG1 chimeric version of MAb 2C7 further enhance complement activation, and the resulting MAb displays greater activity than wild-type MAb 2C7 in vivo Here, we utilized a DNA-encoded MAb (DMAb) construct designed to launch production and assembly of "complement-enhanced" chimeric MAb 2C7 in vivo The ensuing rapid and sustained MAb 2C7 expression attenuated gonococcal colonization in mice at 8 days as well as 65 days postadministration. The DMAb system may provide an effective, economical platform to deliver MAbs for durable protection against gonorrhea.

The Clinical Disease Activity Index and the Routine Assessment of Patient Index Data 3 for Achievement of Treatment Strategies.

OBJECTIVE: To compare the Clinical Disease Activity Index (CDAI) with the Routine Assessment of Patient Index Data 3 (RAPID3) from 2 large United States registries. METHODS: Using a cross section of clinic visits within 2 registries, we determined whether the outcome of each metric would place the patient in remission (REM), low (LDA), moderate (MDA), or high disease activity (HDA) using the CDAI, with the assumption that a patient in MDA or HDA would be a candidate for acceleration of treatment. RESULTS: We identified significant disparities between the 2 indices in final disease categorization using each index system. For patients identified in LDA by CDAI, RAPID3 identified 20.4% and 28.3% as LDA in Corrona and the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS), respectively. For patients identified as MDA by CDAI, RAPID3 identified 36.2% and 31.1% as MDA in Corrona and BRASS, respectively, with the greatest disparities within each system identified for LDA and MDA activity by the CDAI (20.4% and 36.2% agreement of RAPID3 with CDAI, respectively, in Corrona and 28.3% and 31.1% agreement in BRASS). Overall comparison between CDAI and RAPID3 in the 4 disease categories resulted in estimated κ = 0.285 in both. The RAPID3 scores indicated the potential for treat-to-target acceleration in 34.4% of patients in REM or LDA based on CDAI in Corrona and 27.7% in BRASS, respectively. CONCLUSION: The RAPID3, based on patient-reported outcomes, shows differences with CDAI categories of disease activity. The components of CDAI are not highly correlated with RAPID3, except for patient global assessment. These differences could significantly affect the decision to advance treatment when using a treat-to-target regimen.

Real-World Outcomes Associated With Methotrexate, Sulfasalazine, and Hydroxychloroquine Triple Therapy Versus Tumor Necrosis Factor Inhibitor/Methotrexate Combination Therapy in Patients With Rheumatoid Arthritis.

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.

Hydroxychloroquine and the risk of respiratory infections among RA patients.

OBJECTIVES: To 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). METHODS: We 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. RESULTS: No 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. CONCLUSIONS: In patients with RA, the risk for respiratory infections was similar among patients using HCQ as compared to other non-biologic DMARDs.

Mycoplasma genitalium in Symptomatic Male Urethritis: Macrolide Use Is Associated With Increased Resistance.

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.

Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal 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.IMPORTANCENeisseria 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.

Real-World Comparative Effectiveness of Tofacitinib and Tumor Necrosis Factor Inhibitors as Monotherapy and Combination Therapy for Treatment of Rheumatoid Arthritis.

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.