1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018.

Haemophagocytic lymphohistiocytosis (HLH) is a lethal syndrome of excessive immune activation. We undertook a nationwide study in England of all cases of HLH diagnosed between 2003 and 2018, using linked electronic health data from hospital admissions and death certification. We modelled interactions between demographics and comorbidities and estimated one-year survival by calendar year, age group, gender and comorbidity (haematological malignancy, auto-immune, other malignancy) using Cox regression. There were 1628 people with HLH identified. Overall, crude one-year survival was 50% (95% Confidence interval 48-53%) which varied substantially with age (0-4: 61%; 5-14: 76%; 15-54: 61%; > 55: 24% p < 0.01), sex (males, 46%, worse than females, 55% p < 0.01) and associated comorbidity (auto-immune, 69%, haematological malignancy 28%, any other malignancy, 37% p < 0.01). Those aged < 54 years had a threefold increased risk of death at 1-year amongst HLH associated with malignancy compared to auto-immune. However, predicted 1-year survival decreased markedly with age in those with auto-immune (age 0-14, 84%; 15-54, 73%; > 55, 27%) such that among those > 55 years, survival was as poor as for patients with haematological malignancy. One-year survival following a diagnosis of HLH varies considerably by age, gender and associated comorbidity. Survival was better in those with auto-immune diseases among the young and middle age groups compared to those with an underlying malignancy, whereas in older age groups survival was uniformly poor regardless of the underlying disease process.

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Quality standards for the care of people with giant cell arteritis in secondary care.

OBJECTIVE: GCA is the commonest primary systemic vasculitis in adults, with significant health economic costs and societal burden. There is wide variation in access to secondary care GCA services, with 34% of hospitals in England not having any formal clinical pathway. Quality standards provide levers for change to improve services. METHODS: The multidisciplinary steering committee were asked to anonymously put forward up to five aspects of service essential for best practice. Responses were qualitatively analysed to identify common themes, subsequently condensed into domain headings, and ranked in order of importance. Quality standards and metrics for each domain were drafted, requiring a minimum 75% agreement. RESULTS: 13 themes were identified from the initial suggestions. Nine quality standards with auditable metrics were developed from the top 10 themes. Patient Access, glucocorticoid use, pathways, ultrasonography, temporal artery biopsy, PET scan access, rheumatology/ophthalmology expertise, education, multidisciplinary working have all been covered in these quality standards. Access to care is a strand that has run through each of the developed standards. An audit tool was developed as part of this exercise. CONCLUSION: These are the first consensus auditable quality standards developed by clinicians from rheumatology and ophthalmology, nursing representatives and involvement of a patient charity. We hope that these standards will be adopted by commissioning bodies to provide levers for change from the improvement of patient care of individuals with GCA.

Antibody prevalence after three or more COVID-19 vaccine doses in individuals who are immunosuppressed in the UK: a cross-sectional study from MELODY.

BACKGROUND: In the UK, additional COVID-19 vaccine booster doses and treatments are offered to people who are immunosuppressed to protect against severe COVID-19, but how best to choose the individuals that receive these vaccine booster doses and treatments is unclear. We investigated the association between seropositivity to SARS-CoV-2 spike protein with demographic, disease, and treatment-related characteristics after at least three COVID-19 vaccines in three cohorts of people who are immunosuppressed. METHODS: In a cross-sectional study using UK national disease registries, we identified, contacted, and recruited recipients of solid organ transplants, participants with rare autoimmune rheumatic diseases, and participants with lymphoid malignancies who were 18 years or older, resident in the UK, and who had received at least three doses of a COVID-19 vaccine. The study was open to recruitment from Dec 7, 2021, to June 26, 2022. Participants received a lateral flow immunoassay test for SARS-CoV-2 spike antibodies to complete at home, and an online questionnaire. Multivariable logistic regression was used to estimate the mutually adjusted odds of seropositivity against each characteristic. FINDINGS: Between Feb 14 and June 26, 2022, we screened 101 972 people (98 725 invited, 3247 self-enrolled) and recruited 28 411 (27·9%) to the study. 23 036 (81·1%) recruited individuals provided serological data. Of these, 9927 (43·1%) were recipients of solid organ transplants, 6516 (28·3%) had rare autoimmune rheumatic diseases, and 6593 (28·6%) had lymphoid malignancies. 10 485 (45·5%) participants were men and 12 535 (54·4%) were women (gender was not reported for 16 [<0·1%] participants), and 21661 (94·0%) participants were of White ethnicity. The median age of participants with solid organ transplants was 60 years (SD 50-67), with rare autoimmune rheumatic diseases was 65 years (54-73), and with lymphoid malignancy was 69 years (61-75). Of the 23 036 participants with serological data, 6583 (28·6%) had received three vaccine doses, 14 234 (61·8%) had received four vaccine doses, and 2219 (9·6%) had received five or more vaccine doses. IgG anti-spike antibodies were undetectable in 2310 (23·3%) of 9927 patients with solid organ transplants, 922 (14·1%) of 6516 patients with rare autoimmune rheumatic diseases, and 1366 (20·7%) of 6593 patients with lymphoid malignancies. In all groups, seropositivity was associated with younger age, higher number of vaccine doses (ie, five vs three), and previous COVID-19. Immunosuppressive medication reduced the likelihood of seropositivity: the lowest odds of seropositivity were found in recipients of solid organ transplants receiving a combination of an anti-proliferative agent, a calcineurin inhibitor, and steroids, and those with rare autoimmune rheumatic diseases or lymphoid malignancies treated with anti-CD20 therapies. INTERPRETATION: Approximately one in five recipients of solid organ transplants, individuals with rare autoimmune rheumatic diseases, and individuals with lymphoid malignancies have no detectable IgG anti-spike antibodies despite three or more vaccine doses, but this proportion decreases with sequential booster doses. Choice of immunosuppressant and disease type is strongly associated with serological response. Antibody testing using lateral flow immunoassay tests could enable rapid identification of individuals who are most likely to benefit from additional COVID-19 interventions. FUNDING: UK Research and Innovation, Kidney Research UK, Blood Cancer UK, Vasculitis UK and the Cystic Fibrosis Trust.

Temporal Trends in the Incidence of Hemophagocytic Lymphohistiocytosis: A Nationwide Cohort Study From England 2003-2018.

Hemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality, and is increasingly being diagnosed. We aimed to quantify the incidence of diagnosed HLH and examine temporal trends in relation to age and associated diseases. Using national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between January 1, 2003, and December 31, 2018. We calculated incidence rates of diagnosed HLH per million population by calendar year, age group, sex, and associated comorbidity (hematological malignancy, inflammatory rheumatological or bowel diseases [IBD]). We modeled trends in incidence and the interactions between calendar year, age, and associated comorbidity using Poisson regression. There were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (incidence rate ratio [IRR] 2018 compared to 2003: 3.88, 95% confidence interval [CI] 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11, 95% CI 1.09 to 1.12). There was a transition across age groups with greater increases in those aged 5-14 years of HLH associated with rheumatological disease/IBD compared with hematological malignancy, with similar increases in HLH associated with both comorbidities for those 15-54, and greater increases in HLH associated with hematological malignancies for those 55 years and older. The incidence of HLH in England has quadrupled between 2003 and 2018. Substantial variation in the incidence occurred with inflammatory rheumatological diseases/IBD-associated HLH increasing more among the younger age groups, whereas in older age groups, the largest increase was seen with hematological malignancy-associated HLH.

Incidence, prevalence and survival in patients with Langerhans cell histiocytosis: A national registry study from England, 2013-2019.

This analysis is the largest population-based study to date to provide contemporary and comprehensive epidemiological estimates of all third edition of the International Classification of Diseases for Oncology (ICD-O-3) coded Langerhans cell histiocytosis (LCH) from England. People of all ages were identified from the National Cancer Registration Dataset using ICD-O-3 morphologies 9751-9754 for neoplasms diagnosed in 2013-2019. A total of 658 patients were identified, of whom 324 (49%) were children aged <15 years. The age-standardised incidence rate was 4.46 (95% confidence interval [CI] 3.99-4.98) per million children and 1.06 (95% CI 0.94-1.18) per million adults aged ≥15 years. Prevalence of LCH was 9.95 (95% CI 9.14-10.81) per million persons at the end of 2019. The 1-year overall survival (OS) was 99% (95% CI 97%-100%) for children and 90% (95% CI 87%-93%) for adults. Those aged ≥60 years had poorer OS than those aged <15 years (hazard ratio [HR] 22.12, 95% CI 7.10-68.94; p < 0.001). People in deprived areas had lower OS than those in the least deprived areas (HR 5.36, 95% CI 1.16-24.87; p = 0.03). There will inevitably be other environmental factors and associations yet to be identified, and the continued standardised data collection will allow further evaluation of data over time. This will be increasingly important with developments in LCH management following the large collaborative international trials such as LCH IV.

Incidence and survival of haemophagocytic lymphohistiocytosis: A population-based cohort study from England.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. OBJECTIVES: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. METHODS: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan-Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. RESULTS: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15-44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%-86%) in those <15 years to 30% (95% CI 14%-49%) in those ≥75. In patients with haematological cancer, the adjusted HR for death was 2.60 (95% CI 1.45-4.66) compared to patients with no malignant or rheumatological disease. CONCLUSION: The incidence of HLH diagnosis in England has increased between 2000 and 2016 and occurs in all ages with varying underlying diseases. One-year survival varies substantially, being particularly poor in those aged over 75 years and those with haematological malignancy.

A validation study of the identification of haemophagocytic lymphohistiocytosis in England using population-based health data.

We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Rising Incidence of Acute Hospital Admissions due to Gout.

OBJECTIVE: To describe trends in acute hospital admissions due to gout in England, with rheumatoid arthritis (RA) as a comparator, alongside prescribing trends for common gout medications. METHODS: An ecological study was performed using UK National Health Service (NHS) Digital Hospital Episode Statistics data to calculate the incidence of unplanned admissions with primary diagnoses of gout or RA in adults in England between April 2006 and March 2017. NHS Digital Community Prescription data for allopurinol, febuxostat, and colchicine were considered over a similar period. RESULTS: The incidence of unplanned gout admissions increased by 58.4% over the study period, from 7.9 admissions per 100,000 population in 2006/07 to 12.5 admissions per 100,000 population in 2016/17 (p < 0.0001). Gout admissions increased as a proportion of all hospital admissions, and accounted for 349,768 bed-days cumulatively. Unplanned RA admissions halved over the study period, from 8.6 admissions per 100,000 population in 2006/07 to 4.3 admissions per 100,000 population in 2016/17 (p < 0.0001). Community prescriptions dispensed for allopurinol and colchicine have increased by 71.4% and 165.6%, respectively, since 2006 (p < 0.0001). Febuxostat prescriptions have increased 20-fold since 2010 (p < 0.0001), when prescription data became available. CONCLUSION: Acute gout admissions in England increased between 2006 and 2017, accompanied by increasing prescription of gout therapies. Acute admissions due to RA halved over the same time period. These data call for aggressive target-driven therapy for this highly treatable disease.

Increased fasting small-bowel water content in untreated coeliac disease and scleroderma as assessed by magnetic resonance imaging.

Background and aims: The regular overnight migrating motor complex (MMC) ensures that the normal fasting small-bowel water content (SBWC) is minimised. We have applied our recently validated non-invasive magnetic resonance technique to assess SBWC in newly diagnosed coeliac disease (CD), scleroderma (SCD) and irritable bowel syndrome (IBS), conditions possibly associated with small intestinal bacterial overgrowth (SIBO). Methods: A total of 20 CD and 15 SCD patients with gastrointestinal symptoms were compared to 20 healthy volunteers (HV) and 26 IBS with diarrhoea (IBS-D) patients, as previously reported. All underwent a fasting magnetic resonance imaging (MRI) scan on a 1.5 T Philips Achieva MRI scanner to assess fasting SBWC and colonic volumes. Stool and symptom diaries were completed for one week. Results: Compared to HV, all patients had significantly increased stool frequency and Bristol stool form score. SBWC was significantly increased in CD (median 109 mL; interquartile range (IQR) 53-224 mL) compared to HV (median 53 mL; IQR 31-98 mL; p < 0.01) and IBS-D (median 42 mL; IQR 28-67 mL; p < 0.01). A variable increase in SBWC was also found in SCD (median 77 mL; IQR 39-158 mL), but this was not significant (p = 0.2). Colonic volumes were similar for all groups, being a median of 547 mL (IQR 442-786 mL) for CD, 511 mL (453-789 mL) for SCD, 612 mL (445-746 mL) for HV and 521 mL (428-757 mL) for IBS-D. When CD patients were subdivided according to the Marsh classification, the higher grades had larger colonic volumes. Conclusion: Fasting SBWC as assessed by MRI is significantly increased in newly diagnosed CD and SCD but decreased in IBS-D. Future studies should test whether increased resting fluid predisposes to SIBO.

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

Temporal relationships between systemic lupus erythematosus and comorbidities.

OBJECTIVE: To examine the burden of comorbidities prior to and after the diagnosis of SLE and its impact on mortality. METHODS: We identified 1605 incident cases of SLE and 6284 matched controls from the UK primary care. The risks of comorbidities before (prevalence; odds ratios) and after SLE diagnosis (incidence; hazard ratios) and the impact of comorbidities at diagnosis on all-cause mortality were estimated. RESULTS: At diagnosis, SLE was associated with adjusted odds ratios (95% CI) of 2.25 (1.97-2.56), 3.37 (2.49-4.57) and 3.54 (1.89-6.63) for a Charlson comorbidity index of 1-2, 3-4 and ≥5, respectively. Following diagnosis, SLE also associated with increased risk of developing any comorbidity with an adjusted hazard ratio (95% CI) of 1.30 (95% CI, 1.13-1.49). At diagnosis, SLE was associated with a greater risk of cancer, cardiovascular, renal, liver, rheumatological and neurological diseases as well as depression, anaemia and psoriasis. Risks of developing incident comorbidity in the categories of neoplasm, cardiovascular, genitourinary, metabolic/endocrine, gastrointestinal and hepatic diseases, chronic pulmonary diseases, musculoskeletal/connective tissue and neurological diseases were higher in SLE patients. People with SLE had higher mortality risk compared with controls, with adjusted hazard ratio of 1.91 (95% CI, 1.62-2.26); after further adjusting for comorbidities this reduced to 1.64 (1.37-1.97). Comorbidities at SLE diagnosis accounted for 27.6% of the apparent difference in mortality between SLE patients and matched controls. CONCLUSION: People with SLE have increased risks of multiple comorbidities both prior to and after diagnosis and this contributes significantly to all-cause mortality.

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.

Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines.

OBJECTIVES: This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). METHODS: Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. RESULTS: 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines-interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)-were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. CONCLUSIONS: Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions. Instead, we hypothesise that mechanisms regulating inflammatory responses may be important.

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.