Feasibility of methotrexate discontinuation following tocilizumab and methotrexate combination therapy in patients with long-standing and advanced rheumatoid arthritis: a 3-year observational cohort study

Objectives: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. Methods: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. Results: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). Conclusions: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression

Population Difference in Allele Frequency of HLA-C*05 and Its Correlation with COVID-19 Mortality

Background: coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19. Methods: data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor KIR2DS4fl, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed. Results: HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted p = 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (p = 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor KIR2DS4fl, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic. Conclusions: we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted

Influence of proton pump inhibitor use on clinical outcomes of patients with inflammatory bowel disease

AbstractObjective Proton pump inhibitor (PPI) use has been associated with reduced diversity of the gut microbiome and may lead to worse clinical outcomes in inflammatory bowel disease (IBD). We aimed to evaluate whether PPI use affects clinical outcomes in a real-world setting.Design Healthcare claims data of adult IBD patients were obtained from the IBM MarketScan Database. Multivariable analysis and propensity score-matched analysis were performed to assess associations between PPI use and new biologic start, and IBD-related hospitalizations and surgeries.Results A total of 46,234 IBD patients were identified (6,488 (14%) and 39,746 (86%) patients with and without PPI, respectively). Patients on PPI were more likely to be older, female, and smokers and less likely to be on immunomodulators. Multivariable analyses demonstrated that PPI use was associated with new biologic start (odds ratio (OR) 1.11, 95% confidence interval (CI) 1.04–1.18), and IBD-related admissions (OR 1.95, 95% CI 1.74–2.19) and surgeries (OR 1.46, 95% CI 1.26–1.71). Following propensity score matching, patients on PPI remained more likely to start a new biologic (23% vs 21%, p = 0.011), and have IBD-related admissions (8% vs 4%, p < 0.001) and surgeries (4% vs 2%, p < 0.001). Subgroup analyses stratified by age, smoking, and glucocorticoid use showed similar results. There was a dose-response relationship between the number of PPI prescriptions and the risk of new biologic use (p < 0.001) and IBD-related admissions (p < 0.001).Conclusion PPI use was associated with worse clinical outcomes in patients with IBD in the real-world setting. Further studies are warranted to validate these findings, but caution may be needed when prescribing a PPI to IBD patients.Study highlights WHAT IS KNOWNProton pump inhibitors (PPIs) are one of the most prescribed therapies in the United States (US).Reduction of gastric acid secretion by PPI use increases the risk of imbalance in gut microbiota composition and may increase the risk of enteric infections.Recent studies have reported that the use of PPI was associated with development of inflammatory bowel disease (IBD) and reduced rates of remission in patients on infliximab therapy, which may be due to alterations of intestinal microbiota.WHAT IS NEW HEREIn a large real-world US healthcare database study, IBD patients with PPI use were more likely to have a new biologic medication started, have an IBD-related surgery, and have an IBD-related hospitalization, which remained significant after adjusting for confounders by multivariable analysis, propensity-score matched analysis, and subgroup analysis.Appropriate clinical review of PPI necessity may need to be performed in patients with IBD when considering prescribing a PPI or who are already on PPI therapy

A Systematic Review and Meta-Analysis of Serologic Response following Coronavirus Disease 2019 (COVID-19) Vaccination in Solid Organ Transplant Recipients

Solid organ transplant (SOT) recipients are at greater risk of coronavirus disease 2019 (COVID-19) and have attenuated response to vaccinations. In the present meta-analysis, we aimed to evaluate the serologic response to the COVID-19 vaccine in SOT recipients. A search of electronic databases was conducted to identify SOT studies that reported the serologic response to COVID-19 vaccination. We analyzed 44 observational studies including 6158 SOT recipients. Most studies were on mRNA vaccination (mRNA-1273 or BNT162b2). After a single and two doses of vaccine, serologic response rates were 8.6% (95% CI 6.8&ndash;11.0) and 34.2% (95% CI 30.1&ndash;38.7), respectively. Compared to controls, response rates were lower after a single and two doses of vaccine (OR 0.0049 [95% CI 0.0021&ndash;0.012] and 0.0057 [95% CI 0.0030&ndash;0.011], respectively). A third dose improved the rate to 65.6% (95% CI 60.4&ndash;70.2), but in a subset of patients who had not achieved a response after two doses, it remained low at 35.7% (95% CI 21.2&ndash;53.3). In summary, only a small proportion of SOT recipients achieved serologic response to the COVID-19 mRNA vaccine, and that even the third dose had an insufficient response. Alternative strategies for prophylaxis in SOT patients need to be developed. Key Contribution: In this meta-analysis that included 6158 solid organ transplant recipients, the serologic response to the COVID-19 vaccine was extremely low after one (8.6%) and two doses (34.2%). The third dose of the vaccine improved the rate only to 66%, and in the subset of patients who had not achieved a response after two doses, it remained low at 36%. The results of our study suggest that a significant proportion of solid organ transplant recipients are unable to achieve a sufficient serologic response after completing not only the two series of vaccination but also the third booster dose. There is an urgent need to develop strategies for prophylaxis including modified vaccine schedules or the use of monoclonal antibodies in this vulnerable patient population

Worldwide association of lifestyle-related factors and COVID-19 mortality

AbstractBackground Several lifestyle-related factors, such as obesity and diabetes, have been identified as risk factors for Coronavirus disease 2019 (COVID-19) mortality. The objective of this study was to examine the global association between lifestyle-related factors and COVID-19 mortality using data from each individual country.Methods The association between prevalence of seven lifestyle-related factors (overweight, insufficient physical activity, smoking, type-2 diabetes, hypertension, hyperlipidaemia, and age over 65) and COVID-19 mortality was assessed by linear and multivariable regression among 186 countries. The cumulative effect of lifestyle-related factors on COVID-19 mortality was assessed by dividing countries into four categories according to the number of lifestyle-related factors in the upper half range and comparing the mean mortality between groups.Results In linear regression, COVID-19 mortality was significantly associated with overweight, insufficient physical activity, hyperlipidaemia, and age ≥65. In multivariable regression, overweight and age ≥65 demonstrated significant association with COVID-19 mortality (p = .0039, .0094). Countries with more risk factors demonstrated greater COVID-19 mortality (P for trend <.001).Conclusion Lifestyle-related factors, especially overweight and elderly population, were associated with increased COVID-19 mortality on a global scale. Global effort to reduce burden of lifestyle-related factors along with protection and vaccination of these susceptible groups may help reduce COVID-19 mortality