Abstract
Objectives
This analysis set out to estimate the risk of opportunistic infection (OI) among patients with RA by biologic class.
Methods
The British Society for Rheumatology Biologics ...Register for Rheumatoid Arthritis is a prospective observational cohort study established to evaluate safety of biologic therapies. The population included adults commencing biologic therapy for RA. The primary outcome was any serious OI excluding tuberculosis (TB). Event rates were compared across biologic classes using Cox proportional hazards with adjustment for potential confounders identified a priori. Analysis of the incidence of TB was performed separately.
Results
In total, 19 282 patients with 106 347 years of follow-up were studied; 142 non-TB OI were identified at a rate of 134 cases/100 000 patient years (pyrs). The overall incidence of OI was not significantly different between the different drug classes; however, the rate of Pneumocystis infection was significantly higher with rituximab than with anti-TNF therapy (adjusted hazard ratio = 3.2, 95% CI: 1.4, 7.5). The rate of TB fell dramatically over the study period (783 cases/100 000 pyrs in 2002 to 38 cases/100 000 pyrs in 2015). The incidence of TB was significantly lower among rituximab users than anti-TNF users, with 12 cases/100 000 pyrs compared with 65 cases/100 000 pyrs.
Conclusions
The overall rate of OI was not significantly different between drug classes; however, a subtle difference in the pattern of OI was seen between the cohorts. Patient factors such as age, gender and comorbidity were the most important predictors of OI.
The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe ...Covid were different in the first and second waves.
The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone.
There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 adjSHR 0.49 (0.37, 0.65) p<0.001. Analysis of treatment impact did not show statistically different effects of remdesivir HR 0.84 (95%CI 0.65, 1.08), p = 0.17 or dexamethasone HR 0.97 (95%CI 0.70, 1.35) p = 0.87.
There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.
To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages.
Using data from the British Society for ...Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients.
A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy adjHR 1.8 (95% CI 1.3, 2.6). Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort odds ratio 0.5 (95% CI 0.3, 0.8).
These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.
A diverse collection of 14 metal−organic frameworks (MOFs) was screened for CO2 capture from flue gas using a combined experimental and modeling approach. Adsorption measurements are reported for the ...screened MOFs at room temperature up to 1 bar. These data are used to validate a generalized strategy for molecular modeling of CO2 and other small molecules in MOFs. MOFs possessing a high density of open metal sites are found to adsorb significant amounts of CO2 even at low pressure. An excellent correlation is found between the heat of adsorption and the amount of CO2 adsorbed below 1 bar. Molecular modeling can aid in selection of adsorbents for CO2 capture from flue gas by screening a large number of MOFs.
Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it ...harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization.
The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)-naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time.
There were 32 trials in total: anti-tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09-0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04-0.31, p = 0.01) that remained significant after controlling for potential confounders.
There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.
Myalgia is a widely publicised feature of Covid-19, but severe muscle injury can occur. This systematic review summarises relevant evidence for skeletal muscle involvement in Covid-19.
A systematic ...search of OVID and Medline databases was conducted on 16/3/2021 and updated on 28/10/2021 to identify case reports or observational studies relating to skeletal muscle manifestations of Covid-19 (PROSPERO: CRD42020198637). Data from rhabdomyolysis case reports were combined and summary descriptive statistics calculated. Data relating to other manifestations were analysed for narrative review.
1920 articles were identified. From these, 61 case reports/series met inclusion criteria, covering 86 rhabdomyolysis cases. Median age of rhabdomyolysis patients was 50 years, (range 6-89). 49% had either hypertension, diabetes mellitus or obesity. 77% were male. Symptoms included myalgia (74%), fever (69%), cough (59%), dyspnoea (68%). Median peak CK was 15,783U/L. 28% required intravenous haemofiltration and 36% underwent mechanical ventilation. 62% recovered to discharge and 30% died. Dyspnoea, elevated CRP and need for intravenous haemofiltration increased risk of fatal outcome. Additional articles relating to skeletal muscular pathologies include 6 possible concomitant diagnoses or relapses of idiopathic inflammatory myopathies and 10 reports of viral-induced muscle injuries without rhabdomyolysis. Localised myositis and rhabdomyolysis with SARS-CoV-2 vaccination have been reported.
Rhabdomyolysis is an infrequent but important complication of Covid-19. Increased mortality was associated with a high CRP, renal replacement therapy and dyspnoea. The idiopathic inflammatory myopathies (IIM) may have viral environmental triggers. However, to date the limited number of case reports do not confirm an association with Covid-19.
A standardised approach to assessing COVID-19 survivors has not been established, largely due to the paucity of data on medium- and long-term sequelae. Interval chest radiography is recommended ...following community-acquired pneumonia; however, its utility in monitoring recovery from COVID-19 pneumonia remains unclear.
This was a prospective single-centre observational cohort study. Patients hospitalised with severe COVID-19 pneumonia (admission duration ≥48 h and oxygen requirement ≥40% or critical care admission) underwent face-to-face assessment at 4-6 weeks post-discharge. The primary outcome was radiological resolution of COVID-19 pneumonitis (Radiographic Assessment of Lung Oedema score <5). Secondary outcomes included clinical outcomes, symptom questionnaires, mental health screening (Trauma Screening Questionnaire, seven-item Generalised Anxiety Disorder assessment and nine-item Patient Health Questionnaire) and physiological testing (4-m gait speed (4MGS) and 1-min Sit-to-Stand (STS) tests).
119 patients were assessed between June 3, 2020 and July 2, 2020 at median (interquartile range (IQR)) 61 (51-67) days post-discharge: mean±sd age 58.7±14.4 years, median (IQR) body mass index 30.0 (25.9-35.2) kg·m
, 62% male and 70% ethnic minority. Despite radiographic resolution of pulmonary infiltrates in 87%, modified Medical Research Council Dyspnoea (breathlessness) scale grades were above pre-COVID-19 baseline in 44%, and patients reported persistent fatigue (68%), sleep disturbance (57%) and breathlessness (32%). Screening thresholds were breached for post-traumatic stress disorder (25%), anxiety (22%) and depression (18%). 4MGS was slow (<0.8 m·s
) in 38% and 35% desaturated by ≥4% during the STS test. Of 56 thoracic computed tomography scans performed, 75% demonstrated COVID-19-related interstitial and/or airways disease.
Persistent symptoms, adverse mental health outcomes and physiological impairment are common 2 months after severe COVID-19 pneumonia. Follow-up chest radiography is a poor marker of recovery; therefore, holistic face-to-face assessment is recommended to facilitate early recognition and management of post-COVID-19 sequelae.
•Multiple RCTs of IL-6 inhibitors in the treatment of COVID-19 have been published, with conflicting conclusions.•Our meta-analysis of nine RCTs demonstrated improvements in 28-day mortality in ...favour of IL-6 inhibition over comparators.•Variability across study mortality rates were explained by individual and country-level predictors using meta-regression.•These findings support the use of IL-6 inhibitors for the treatment of severe, hospitalised COVID-19.•Long-term benefits of IL-6 inhibition and implications for differing standards of care are currently unknown.
Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results.
Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification.
Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence.
IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.
Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses ...to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose.
In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor TNF inhibitors, interleukin IL-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination.
Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 78%; 95% CI 67–87 of 77) than in controls (17 100%; 80–100 of 17), with the lowest rate in those receiving methotrexate (seven 47%; 21–73 of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 IQR 40–236) than in controls (317 213–487, p=0·0032), but was preserved in those receiving targeted biologics (269 141–418). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls.
Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness.
UK National Institute for Health Research.
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