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Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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Background: A highly controversial question is whether or not corticosteroids should be prescribed for patients with early diffuse cutaneous systemic sclerosis (dcSSc). Although the painful and disabling features of early dcSSc (including tight itchy skin, contractures, fatigue) have an infammatory basis and are likely to respond to corticosteroids, corticosteroids are a risk factor for potentially life-threatening scleroderma renal crisis. Objectives: Our aim was to examine safety and efficacy of moderate dose prednisolone in patients with early dcSSc. Specific objectives were to evaluate whether moderate dose prednisolone reduced pain and disability, and improved skin score, and whether prednisolone was safe with particular reference to renal function Methods: PRedSS set out as a Phase II, multicentre, double-blind randomised controlled trial, converted to open-label because of the Covid-19 pandemic. Patients were randomised to receive either moderate dose prednisolone (approximately 0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. The co-primary endpoints were the Health Assessment Questionnaire Disability Index (HAQ-DI) and modifed Rodnan skin core (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures refecting pain, itch, anxiety and depression, fatigue and helplessness. 72 participants randomised 1:1 were planned and anticipated to yield 60 evaluable, giving over 80% power for each co-primary outcome in ANCOVA analyses [assumptions;HAQ-DI (a = 0.025, ô =-0.6, o = 0.9, p = 0.6), mRSS (a = 0.025, ô =-5.5, a = 8.2, p = 0.6)]. Mixed Models for Repeated Measures (week 6, month 3, month 6) were ftted with covariates trial arm, baseline score, anti-Scl-70 and their interactions with time point. An unstructured covariance matrix was assumed with the primary focus being the trial arm effect at 3 months. Results: The study terminated early due to the Covid-19 pandemic and consequently did not meet the recruitment target of 72 patients. Thirty-five patients (Table 1) were randomised (17 to prednisolone and 18 to placebo/control, 25 during the double-blind phase), of whom 34 completed the 3 month assessment. The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was-0.10 (97.5% CI-0.29 to 0.10), p=0.25, and in mRSS-3.90 (97.5% CI-8.83 to 1.03), p=0.070, both favouring prednisolone but not signifcantly. Patients in the prednisolone group experienced less pain, helplessness and anxiety than control patients at 3 months: mean difference in pain scores-0.49, 95%CI (-0.93 to-0.06), p=0.027, in Hospital Anxiety and Depression (HADS) anxiety scores-2.05, 95%CI (-3.73 to-0.37), p=0.018, and in helplessness scores-1.54, 95%CI (-3.01 to-0.07), p=0.040. There were no renal crises. Conclusion: PRedSS exemplifed the challenges of running a clinical trial of an investigational medicinal product potentially associated with increased infection risk during the Covid-19 pandemic. Because PRedSS was terminated prior to target recruitment, it was underpowered, and any conclusions have to be extremely cautious. Although PRedSS suggested some beneft from moderate dose predni-solone, the small sample indicates the need for a further randomised trial.
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Background/Aims People with ANCA-associated vasculitis (AAV) have high rates of hospital admissions. They may have emergency admissions at the time of diagnosis, or day case admissions to receive immunosuppressive treatment. We describe the trends in emergency and day case admissions over the past 9 years, and the effect of the COVID-19 pandemic. Methods We extracted hospital episode statistics available publicly from NHS Digital for 2012/13 to 2019/20 and added provisional data from the National Congenital Anomaly and Rare Disease Registration Service for 2020/21 under their legal permissions (CAG 10-02(d)/2015) because the publicly available data had not yet been released. We extracted all emergency and day-case admission rates with ICD codes for each AAV subtype (M301, M313 and M317, in the primary position denoting main admission diagnosis). We used England population estimates from the Office for National Statistics as the denominator for rates. We calculated Poisson confidence intervals to quantify the difference in rates between 2019/20 and 2020/21 financial years. Results Rates of day case admissions per 1,000,000 for AAV increased from 49.1 (47.2 - 50.9) in 2012/13 to 63.3 (61.2 - 65.4) in 2019/20, then decreased by 26.4% to 48.6 (46.7 - 50.4) in 2020/21 (Table). The trends in emergency admissions were relatively unchanged between 2012/13 and 2019/20 (mean 6.7 per 1,000,000), and there was no significant decrease in emergency admissions during the COVID-19 pandemic. Conclusion Day case admission rates increased between 2012/13 and 2019/20 but decreased during the COVID-19 pandemic. Emergency admission rates for patients with AAV remained relatively unchanged, despite the context of the significant disruption and reconfiguration of healthcare services. Further work on patient-level data is needed to establish whether the day case reduction is due to fewer new patients or relapsing patients being diagnosed (and therefore fewer remission induction infusions) during this period or altered clinical practice leading to postponement of planned remission maintenance treatment that would have usually been given. Alternatively, this change may reflect a change in clinical practice to preferentially use oral rather than IV agents. All of this may have future consequences both for clinical practice and individual patient care and outcomes post-pandemic.
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Background/AimsTo quantify the risk of death among people with rare autoimmunerheumatic diseases (RAIRD) during the UK 2020 COVID-19 epidemiccompared with baseline risk and the risk of death in the generalpopulation during COVID-19.MethodsA cohort study was performed using data from the National CongenitalAnomaly and Rare Disease Registration Service (NCARDRS). Codeddiagnoses for RAIRD were identified from Hospital Episode Statisticsfrom 2003 onwards. Previous coding validation work demonstratedour case ascertainment methods had a positive predictive value>85%. ONS published data were used for general population mortalityrates. The main outcome measure was age-standardised mortalityrates (ASMRs) for all-cause death. Secondary outcome measureswere age-sex standardised mortality rates, and age-stratified mortalityrates.Results168, 691 people with RAIRD were alive on 1 March 2020. Their medianage was 61.7 (IQR 41.5-75.4) years, and 118, 379 (70.2%) were female.1, 815 (1.1%) people with RAIRD died during March and April 2020.The ASMR among people with RAIRD was 3669.3 (95% CI 3500.4-3838.1) per 100, 000 person-years, which was 1.44 (95% CI 1.42-1.45)times higher than the average ASMR during the same months of theprevious 5 years. In the whole population of England, the ASMR duringMarch and April 2020 was 1361.1 (1353.6- 1368.7) per 100, 000people, which was 1.38 times higher than the average ASMR duringthe same months of the previous 5 years (see related abstract aboutinfluenza seasons). Unlike in the general population, sex-specific ratesin RAIRD were similar in males and females. When comparing risk ofdeath during COVID-19 to pre-COVID-19, people with RAIRD had anincreased risk of death from age 35 upwards, compared to around age55 upwards in the general population. As the protective effect of beingfemale was not seen in RAIRD, the group at the largest increased riskcompared to their pre-COVID-19 risk were women aged 35 upwards.The absolute risk of all-cause death for someone aged 20-29 withRAIRD was similar to someone in the general population aged >20years older, someone aged 40-49 years with RAIRD similar tosomeone in the general population 20 years older, and someoneaged 60-69 with RAIRD similar to someone in the general populationaged >10 years older.ConclusionThe excess risk of all-cause death during COVID-19 occurs at ayounger age among people with RAIRD than among the generalpopulation, and particularly affects females. . We urgently need toquantify how much risk is due to COVID-19 infection and how muchdue to disruption to healthcare services to inform better guidanceabout shielding, access to healthcare and vaccine priorities for peoplewith rare diseases.
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Background/AimsTo quantify the risk of death among people with vasculitis during theUK 2020 COVID-19 epidemic compared with baseline risk, risk duringannual influenza seasons and risk of death in the general populationduring COVID-19.MethodsWe performed a cohort study using data from the National CongenitalAnomaly and Rare Disease Registration Service (NCARDRS) undertheir legal permissions (CAG 10-02(d)/2015). Coded diagnoses forvasculitis (ANCA-associated vasculitis, Takayasu arteritis, Behç et'sdisease, and giant cell arteritis) were identified from Hospital EpisodeStatistics from 2003 onwards. Previous coding validation workdemonstrated a positive predictive value >85%. The main outcomemeasure was age-standardised mortality rates (ASMRs) for all-causedeath. ONS published data were used for general population mortalityrates.ResultsWe identified 55, 110 people with vasculitis (median age 74.9 (IQR64.1-82.7) years, 68.0% female) alive 01 March 2020. During MarchApril 2020, 892 (1.6%) died of any cause. The crude mortality rate was9773.0 (95% CI 9152.3-10, 435.9) per 100, 000 person-years. TheASMR was 2567.5 per 100, 000 person-years, compared to 1361.1(1353.6-1368.7) in the general population (see table).The ASMR in March-April 2020 was 1.4 times higher than the meanASMR for March-April 2015-2019 (1965.6). The increase in deathsduring March-April 2020 occurred at a younger age than in the generalpopulation.We went on to investige the effect of previous influenza seasons. The2014/15 season saw the greatest excess all-cause mortality nationallyin recent years, and there were 624 deaths in 38, 888 people (6472.5person-years) with vasculitis in our data (crude mortality rate 9640.8(8913.3-10427.7);The ASMR was 2657.6, which was marginally higher than the ASMR among people with vasculitis recorded during MarchApril 2020 during the COVID-19 pandemic.ConclusionPeople with vasculitis are at increased risk of death during circulatingCOVID-19 and influenza epidemics. The ASMR among people withvasculitis was high both during the 2014/15 influenza season andduring the first wave of the COVID-19 epidemic. COVID-19 vaccinationand annual influenza vaccination for people with vasculitis are bothimportant, regardless of patient age.