COVID-19 infection, admission and death and the impact of corticosteroids among people with rare autoimmune rheumatic disease during the second wave of COVID-19 in England: results from the RECORDER Project.

OBJECTIVES: To calculate the rates of COVID-19 infection and COVID-19-related death among people with rare autoimmune rheumatic diseases (RAIRD) during the second wave of the COVID-19 pandemic in England, and describe the impact of corticosteroids on outcomes. METHODS: Hospital Episode Statistics data were used to identify people alive on 1 August 2020 with ICD-10 codes for RAIRD from the whole population of England. Linked national health records were used to calculate rates and rate ratios of COVID-19 infection and death up to 30 April 2021. Primary definition of COVID-19-related death was mention of COVID-19 on the death certificate. NHS Digital and Office for National Statistics general population data were used for comparison. The association between 30-day corticosteroid usage and COVID-19-related death, COVID-19-related hospital admissions and all-cause deaths was also described. RESULTS: Of 168 330 people with RAIRD, 9961 (5.92%) had a positive COVID-19 PCR test. The age-standardized infection rate ratio between RAIRD and the general population was 0.99 (95% CI: 0.97, 1.00). 1342 (0.80%) people with RAIRD died with COVID-19 on their death certificate and the age-sex-standardized mortality rate for COVID-19-related death was 2.76 (95% CI: 2.63, 2.89) times higher than in the general population. There was a dose-dependent relationship between 30-day corticosteroid usage and COVID-19-related death. There was no increase in deaths due to other causes. CONCLUSIONS: During the second wave of COVID-19 in England, people with RAIRD had the same risk of COVID-19 infection but a 2.76-fold increased risk of COVID-19-related death compared with the general population, with corticosteroids associated with increased risk.

The incidence of Kawasaki disease using hospital admissions data for England 2006-2021.

OBJECTIVE: To describe the incidence of Kawasaki Disease (kDa) between 2006 and 2021 in England. METHODS: We identified all cases in hospital episode statistics with an ICD-10 diagnostic code M303 (for kDa) between 1 April 2006 and 31 March 2021. We validated 83 diagnoses using hospital medical records and found >97% accuracy. We calculated incidence rate ratios (IRRs) using Poisson regression and assessed the influence of age, sex, ethnicity and index of multiple deprivation (IMD). We used Office for National Statistics population estimates for England as the denominator. RESULTS: We identified a total of 5908 cases of kDa in all children under the age of 16 (mean age 3.8, s.d.=3.2, 95% CI: 3.7, 3.9). Incidence in children aged <5 years was 8.9 (95% CI: 8.6, 9.2)/100 000 person-years; in children aged 5-9, 2.4 (95% CI: 2.3, 2.6)/100 000 person-years; and in children aged 10-15, 0.6 (95% CI: 0.6, 0.7). Male : female ratio was 1.5 : 1. Incidence was higher among non-White than White ethnicities [adjusted IRR 2.1 (2.0-2.2) for Asian, 3.0 (2.8-3.3) for Black and 4.5 (4.2-4.8) for other ethnicities]. The incidence increased with socioeconomic deprivation; the adjusted IRR of the least deprived IMD quintile compared with the most deprived quintile was 0.81 (0.77-0.84). CONCLUSIONS: Incidence rates of kDa derived from hospital admission data in England were higher than in studies relying on clinician reporting. We confirm previous findings on the influence of sex and ethnicity on kDa incidence and observe that there was a higher incidence of kDa within more deprived socioeconomic groups.

Humoral and cellular immunity in patients with rare autoimmune rheumatic diseases following SARS-CoV-2 vaccination.

OBJECTIVES: Coronavirus 2019 vaccine responses in rare autoimmune rheumatic diseases (RAIRDs) remain poorly understood; in particular there is little known about whether people develop effective T cell responses. We conducted an observational study to evaluate the short-term humoral and cell-mediated T cell response after the second severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in RAIRD patients compared with healthy controls (HCs). METHODS: Blood samples were collected after the second dose and anti-spike, anti-nucleocapsid antibody levels and SARS-CoV-2-specific T cell responses were measured and compared with those of HCs. Activation-induced marker and deep phenotyping assays were used to identify differences in T cells between high and no/low antibody groups, followed by multidimensional clustering. RESULTS: A total of 50 patients with RAIRDs were included (31 with AAV, 4 with other systemic vasculitis, 9 with SLE and 6 with myositis). The median anti-spike levels were significantly lower in RAIRD patients compared with HCs (P < 0.0001). Fifteen (33%) patients had undetectable levels and 26 (57%) had levels lower than the lowest HC. Rituximab in the last 12 months (P = 0.003) was associated with reduced immunogenicity compared with a longer pre-vaccination period. There was a significant difference in B cell percentages (P = 0.03) and spike-specific CD4+ T cells (P = 0.02) between no/low antibody vs high antibody groups. Patients in the no/low antibody group had a higher percentage of terminally differentiated (exhausted) T cells. CONCLUSIONS: Following two doses, most RAIRD patients have lower antibody levels than the lowest HC and lower anti-spike T cells. RAIRD patients with no/low antibodies have diminished numbers and poor quality of memory T cells that lack proliferative and functional capacities.

COVID-19 infection, admission and death among people with rare autoimmune rheumatic disease in England: results from the RECORDER project.

OBJECTIVES: To calculate the rates of COVID-19 infection and COVID-19-related death among people with rare autoimmune rheumatic diseases (RAIRD) during the first wave of the COVID-19 pandemic in England compared with the general population. METHODS: We used Hospital Episode Statistics to identify all people alive on 1 March 2020 with ICD-10 codes for RAIRD from the whole population of England. We used linked national health records (demographic, death certificate, admissions and PCR testing data) to calculate rates of COVID-19 infection and death up to 31 July 2020. Our primary definition of COVID-19-related death was mention of COVID-19 on the death certificate. General population data from Public Health England and the Office for National Statistics were used for comparison. We also describe COVID-19-related hospital admissions and all-cause deaths. RESULTS: We identified a cohort of 168 680 people with RAIRD, of whom 1874 (1.11%) had a positive COVID-19 PCR test. The age-standardized infection rate was 1.54 (95% CI: 1.50, 1.59) times higher than in the general population. A total of 713 (0.42%) people with RAIRD died with COVID-19 on their death certificate and the age-sex-standardized mortality rate for COVID-19-related death was 2.41 (2.30-2.53) times higher than in the general population. There was no evidence of an increase in deaths from other causes in the RAIRD population. CONCLUSIONS: During the first wave of COVID-19 in England, people with RAIRD had a 54% increased risk of COVID-19 infection and more than twice the risk of COVID-19-related death compared with the general population. These increases were seen despite shielding policies.

A systematic review and meta-analysis of the incidence rate of Takayasu arteritis.

OBJECTIVES: Takayasu arteritis (TAK) is a rare autoimmune rheumatic disease causing large-vessel vasculitis. Onset is typically between the ages of 20 and 30 years. It is associated with substantial morbidity and mortality, notably due to its effects on the cardiovascular system. It has a poorly understood global epidemiology. Our objective was to systematically review the available evidence in order to calculate the incidence rate of TAK. METHODS: Three databases (MEDLINE, PubMed and Embase) were searched in November 2019 and the results were screened by two reviewers. A random effects meta-analysis was then conducted in R to calculate the overall incidence rate. Heterogeneity was assessed using I2. The quality of the studies was assessed using an adapted Newcastle-Ottawa scale. Further subgroup analyses were performed by quality, sex, research setting and geographical location. Publication bias was assessed using a Begg's funnel plot. RESULTS: The incidence rate for TAK was 1.11 per million person-years (95% CI 0.70-1.76). The heterogeneity in the data was extremely high in all analyses, which suggests that there was considerable variation in incidence rates across the different populations studied. TAK was found to be more common in women (incidence rate 2.01 per million person-years, 95% CI 1.39-2.90). CONCLUSIONS: TAK is an extremely rare disease. It affects women more commonly than men. There is considerable variation in the incidence rate between populations. We suggest that future research should focus on discrete populations in order to better identify genetic and environmental risk factors.

Estimation of the burden of shielding among a cross-section of patients attending rheumatology clinics with SLE-data from the BSR audit of systemic lupus erythematosus.

OBJECTIVES: We aimed to estimate what proportion of people with SLE attending UK rheumatology clinics would be categorized as being at high risk from coronavirus disease 2019 (COVID-19) and therefore asked to shield, and explore what implications this has for rheumatology clinical practice. METHODS: We used data from the British Society for Rheumatology multicentre audit of SLE, which included a large, representative cross-sectional sample of patients attending UK Rheumatology clinics with SLE. We calculated who would receive shielding advice using the British Society for Rheumatology's risk stratification guidance and accompanying scoring grid, and assessed whether ethnicity and history of nephritis were over-represented in the shielding group. RESULTS: The audit included 1003 patients from 51 centres across all 4 nations of the UK. Overall 344 (34.3%) patients had a shielding score ≥3 and would have been advised to shield. People with previous or current LN were 2.6 (1.9-3.4) times more likely to be in the shielding group than people with no previous LN (P < 0.001). Ethnicity was not evenly distributed between the groups (chi-squared P < 0.001). Compared with White people, people of Black ethnicity were 1.9 (1.3-2.8) and Asian 1.9 (1.3-2.7) times more likely to be in the shielding group. Increased risk persisted after controlling for LN. CONCLUSION: Our study demonstrates the large number of people with SLE who are likely to be shielding. Implications for clinical practice include considering communication across language and cultural differences, and ways to conduct renal assessment including urinalysis, during telephone and video consultations for patients who are shielding.

BSR guideline on the management of adults with systemic lupus erythematosus (SLE) 2018: baseline multi-centre audit in the UK.

OBJECTIVES: To assess the baseline care provided to patients with SLE attending UK Rheumatology units, audited against standards derived from the recently published BSR guideline for the management of adults with SLE, the NICE technology appraisal for belimumab, and NHS England's clinical commissioning policy for rituximab. METHODS: SLE cases attending outpatient clinics during any 4-week period between February and June 2018 were retrospectively audited to assess care at the preceding visit. The effect of clinical environment (general vs dedicated CTD/vasculitis clinic and specialized vs non-specialized centre) were tested. Bonferroni's correction was applied to the significance level. RESULTS: Fifty-one units participated. We audited 1021 episodes of care in 1003 patients (median age 48 years, 74% diagnosed >5 years ago). Despite this disease duration, 286 (28.5%) patients had active disease. Overall in 497 (49%) clinic visits, it was recorded that the patient was receiving prednisolone, including in 28.5% of visits where disease was assessed as inactive. Low documented compliance (<60% clinic visits) was identified for audit standards relating to formal disease-activity assessment, reduction of drug-related toxicity and protection against comorbidities and damage. Compared with general clinics, dedicated clinics had higher compliance with standards for appropriate urine protein quantification (85.1% vs 78.1%, P ≤ 0.001). Specialized centres had higher compliance with BILAG Biologics Register recruitment (89.4% vs 44.4%, P ≤ 0.001) and blood pressure recording (95.3% vs 84.1%). CONCLUSIONS: This audit highlights significant unmet need for better disease control and reduction in corticosteroid toxicity and is an opportunity to improve compliance with national guidelines. Higher performance with nephritis screening in dedicated clinics supports wider adoption of this service-delivery model.

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren's syndrome: results of the TRACTISS randomised double-blind multicentre substudy.

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.

Novel insights into the aetiology of granulomatosis with polyangiitis-a case-control study using the Clinical Practice Research Datalink.

Objectives: We aimed to provide insights into the aetiology of granulomatosis with polyangiitis (GPA), by conducting a large case-control study using a general population-based, prospectively collected database of healthcare records. Methods: We compared all incident cases of GPA in the Clinical Practice Research Datalink 1990-2014, with up to 10 age-, sex- and general practice-matched controls. We identified potential risk factors, recorded numbers of cases and controls exposed to each, and calculated odds ratios (ORs) using conditional logistic regression. Our main analysis excluded data recorded during 1 year before diagnosis, to prevent early symptoms being mistaken for risk factors. Results: We identified 757 people with GPA and matched 7546 controls. People with GPA were five times more likely to have a previous diagnosis of bronchiectasis (OR = 5.1, 95% CI: 2.7, 9.4; P < 0.0001), and these effects remained stable in diagnoses recorded >5 years prior to diagnosis. People with GPA were two to three times more likely than controls to have previous diagnoses of autoimmune diseases or chronic renal impairment, and these effects also remained stable >5 years prior to diagnosis. People with GPA were more likely to have a diagnosis of pulmonary fibrosis (OR = 5.7, 95% CI: 1.7, 19.5; P = 0.01) and sinus infections (OR = 2.7, 95% CI: 1.8, 4.2; P < 0.0001) recorded in the 3 years before diagnosis, but not before this. We also found former smoking, some medications and higher socio-economic status significantly, but less strongly, associated. Conclusion: We found novel long-term associations between GPA and pre-existing bronchiectasis and autoimmune diseases.

The incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK Clinical Practice Research Datalink.

Objective: To estimate the incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (HES). We calculated incidence rate ratios, adjusted for age, gender and ethnicity, using Poisson regression. Results: We identified 462 cases diagnosed between 1997 and 2013. Our overall estimate of incidence was 11.8 (95% CI: 10.7, 12.9)/million person-years. The incidence was 0.88 (95% CI: 0.40, 1.96) in children (aged <16 years) and 14.0 (95% CI: 12.8, 15.4) in adults. The incidence was lower in females (adjusted incidence rate ratio = 0.68; 95% CI: 0.56, 0.81) and highest in the 55-69 year age group (adjusted incidence rate ratio = 6.8, 95% CI: 4.9, 9.6; reference group 16-39 years). The incidence was not significantly different in the Black/Minority Ethnic population from that in the White population (adjusted odds ratio = 0.78, 95% CI: 0.53, 1.13, P = 0.13). The prevalence in 2013 was 134.9 (95% CI: 121.3, 149.6)/million. Mortality was 13.6% at 1-year, and higher in the HES- than in the Clinical Practice Research Datalink-identified cases (hazard ratio = 3.16, 95% CI: 2.19, 4.56, P < 0.001). Conclusion: By combining primary and secondary care datasets, we have found the incidence and mortality of granulomatosis with polyangiitis to be higher than previously reported. We predict that at present each year in the UK there will be ∼700 new cases, of whom 95 will die within 12 months.

Incidence of ANCA-associated vasculitis in a UK mixed ethnicity population.

OBJECTIVES: We aimed to estimate the incidence of ANCA-associated vasculitis in the UK and how this varied by ethnic group. METHODS: We identified incident cases of ANCA-associated vasculitis between March 2007 and June 2013 in the Nottingham-Derby urban area from medical records using multiple sources. We derived the denominator population from the 2011 census, and we calculated incidence rate ratios using Poisson regression. RESULTS: Overall, we identified 107 cases of ANCA-associated vasculitis, giving an incidence of 23.1 per million person-years (95% CI: 18.9, 27.9). The incidence among the white population was 25.8 per million person-years (95% CI: 21.0, 31.3) and among the black and minority ethnic (BME) population 8.4 per million person-years (95% CI: 3.1, 18.3). After adjustment for age and sex, the difference between ethnic groups was not statistically significant (incidence rate ratio 0.7, 95% CI: 0.3, 1.5, P = 0.3). CONCLUSION: Overall, the incidence of ANCA-associated vasculitis was similar to other epidemiological studies. Crude incidence rates were lower in the BME than in the white population, but this was partly explained by the older age profile among the white compared with BME population.

Prevalence, incidence, and mortality of Raynaud's phenomenon, Sjögren's syndrome and scleroderma: an umbrella review of systematic reviews.

Objectives: To comprehensively review systematic reviews of prevalence, incidence, and mortality of Raynaud's, Sjögren's and Scleroderma, and to identify any research gaps. Methods: An umbrella review of English language systematic reviews was undertaken using PubMed and Embase (OVID) covering the period 2000-2023 (PROSPERO CRD42023434865). The estimate and its corresponding 95% confidence interval were reported when available from each systematic review. The quality of systematic reviews was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) tool. A narrative synthesis was undertaken. Results: Seventeen systematic reviews were identified, of which 1 was for RP, 5 for Sjögren's and 11 for Scleroderma. There were some high-quality systematic reviews for Sjögren's and mortality of Scleroderma. However, there were only low-quality systematic reviews of prevalence and incidence of RP and Scleroderma. Furthermore, there were no systematic reviews for the mortality of RP. For RP, the pooled prevalence was 4850 per 100 000; pooled annual incidence was 250 per 100 000. For Sjögren's, prevalence was 60-70 per 100 000; annual incidence was 6.92 per 100 000 and the pooled standardized mortality ratio ranged from 1.38 to 1.48. For Scleroderma, pooled prevalence ranged from 17.6 to 23 per 100 000; annual incidence was 1.4 per 100 000; and the pooled standardized mortality ratio ranged from 2.72 to 3.53. Conclusion: The outcomes of RP were less well described compared with Sjögren's and Scleroderma. There was a lack of high-quality systematic reviews for the prevalence and incidence of RP and Scleroderma. Therefore, further studies and systematic reviews with rigorous case definitions, assessing different ethnic groups are warranted in this area.

Identifying key health system components associated with improved outcomes to inform the re-configuration of services for adults with rare autoimmune rheumatic diseases: a mixed-methods study.

BACKGROUND: Adults with rare autoimmune rheumatic diseases face unique challenges and struggles to navigate health-care systems designed to manage common conditions. Evidence to inform an optimal service framework for their care is scarce. Using systemic vasculitis as an exemplar, we aimed to identify and explain the key service components underpinning effective care for rare diseases. METHODS: In this mixed-methods study, data were collected as part of a survey of vasculitis service providers across the UK and Ireland, interviews with patients, and from organisational case studies to identify key service components that enable good care. The association between these components and patient outcomes (eg, serious infections, mortality) and provider outcomes (eg, emergency hospital admissions) were examined in a population-based data linkage study using routine health-care data obtained from patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis from national health datasets in Scotland. We did univariable and multivariable analyses using Bayesian poisson and negative binomial regression to estimate incident rate ratios (IRRs), and Cox proportional hazards models to estimate hazard ratios (HRs). People with lived experiences were involved in the research and writing process. FINDINGS: Good care was characterised by service components that supported timely access to services, integrated care, and expertise. In 1420 patients with ANCA-associated vasculitis identified from national health datasets, service-reported average waiting times for new patients of less than 1 week were associated with fewer serious infections (IRR 0·70 [95% credibility interval 0·55-0·88]) and fewer emergency hospital admissions (0·78 [0·68-0·92]). Nurse-led advice lines were associated with fewer serious infections (0·76 [0·58-0·93]) and fewer emergency hospital admissions (0·85 [0·74-0·96]). Average waiting times for new patients of less than 1 week were also associated with reduced mortality (HR 0·59 [95% credibility interval 0·37-0·93]). Cohorted clinics, nurse-led clinics, and specialist vasculitis multi-disciplinary team meetings were associated with fewer serious infections (IRR 0·75 [0·59-0·96] for cohorted clinics; 0·65 [0·39-0·84] for nurse-led clinics; 0·72 [0·57-0·90] for specialist vasculitis multi-disciplinary team meetings) and emergency hospital admissions (0·81 [0·71-0·91]; 0·75 [0·65-0·94]; 0·86 [0·75-0·96]). Key components were characterised by their ability to overcome professional tensions between specialties. INTERPRETATION: Key service components associated with important health outcomes and underpinning factors were identified to inform initiatives to improve the design, delivery, and effectiveness of health-care models for rare autoimmune rheumatic diseases. FUNDING: Versus Arthritis.

Antibody response to four doses of SARS-CoV-2 vaccine in rare autoimmune rheumatic diseases: an observational study.

Objective: Antibody responses to coronavirus disease 2019 (COVID-19) vaccines are reduced among immunocompromised patients but are not well quantified among people with rare disease. We conducted an observational study to evaluate the antibody responses to the booster SARS-CoV-2 vaccine in people with rare autoimmune rheumatic diseases (RAIRD). Methods: Blood samples were collected after second, before third, after third and after fourth vaccine doses. Anti-spike and anti-nucleocapsid antibody levels were measured using an in-house ELISA. Logistic regression models were built to determine the predictors for non-response. Results were compared with age- and sex-matched healthy controls. Results: Forty-three people with RAIRD were included, with a median age of 56 years. Anti-spike seropositivity increased from 42.9% after second dose to 51.2% after third dose and 65.6% after fourth dose. Median anti-spike antibody levels increased from 33.6 (interquartile range 7.8-724.5) binding antibody units after second dose to 239.4 (interquartile range 35.8-1051.1) binding antibody units after the booster dose (third dose, or fourth dose if eligible). Of the participants who had sufficient antibody levels post-second dose, 22.2% had insufficient levels after the booster, and 34.9% of participants had lower antibodies after the booster than the lowest healthy control had after the second dose. Rituximab in the 6 months prior to booster (P = 0.02) and non-White ethnicity (P = 0.04) were associated with non-response. There was a dose-response relationship between the timing of rituximab and generation of sufficient antibodies (P = 0.03). Conclusion: Although the booster dose increased anti-spike IgG and seropositivity rates, some people with RAIRD, particularly those on rituximab, had insufficient antibody levels despite three or four doses.