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The Systemic Lupus International Collaborating Clinics (SLICC), American College of Rheumatology (ACR), and the Lupus Foundation of America are developing a revised systemic lupus erythematosus (SLE) damage index (the SLICC/ACR Damage Index [SDI]). Shifts in the concept of damage in SLE have occurred with new insights into disease manifestations, diagnostics, and therapy. We evaluated contemporary constructs in SLE damage to inform development of the revised SDI.We conducted a 3-part qualitative study of international SLE experts. Facilitated small groups evaluated the construct underlying the concept of damage in SLE. A consensus meeting using nominal group technique was conducted to achieve agreement on aspects of the conceptual framework and scope of the revised damage index. The framework was finally reviewed and agreed upon by the entire group.Fifty participants from 13 countries were included. The 8 thematic clusters underlying the construct of SLE damage were purpose, items, weighting, reversibility, impact, time frame, attribution, and perspective. The revised SDI will be a discriminative index to measure morbidity in SLE, independent of activity or impact on the patient, and should be related to mortality. The SDI is primarily intended for research purposes and should take a life-course approach. Damage can occur before a diagnosis of SLE but should be attributable to SLE. Damage to an organ is irreversible, but the functional consequences on that organ may improve over time through physiological adaptation or treatment.We identified shifts in the paradigm of SLE damage and developed a unifying conceptual framework. These data form the groundwork for the next phases of SDI development.

Organ damage is a key determinant of poor long-term prognosis and early death in patients with systemic lupus erythematosus (SLE). Prevention of damage is a key treatment goal of the 2019 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for SLE management. Belimumab is a monoclonal antibody that inhibits B lymphocyte stimulator (BLyS) and is the only therapy approved for both SLE and lupus nephritis. Here, we review the clinical trial and real-world data on the effects of belimumab on organ damage in adult patients with SLE. Across 4 phase III studies, belimumab in combination with background SLE therapy demonstrated consistent reductions in key drivers of organ damage including disease activity, risk of new severe flares, and glucocorticoid exposure compared to background therapy alone. Long-term belimumab use in SLE also reduced organ damage progression measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, as reported in open-label extension studies, and propensity score–matched comparative analyses to background therapy alone. Results from a clinical trial showed that in patients with active lupus nephritis, belimumab treatment improved renal response, reduced the risk of renal-related events, and impacted features related to kidney damage progression compared to background therapy alone. The decrease of organ damage accumulation observed with belimumab treatment in SLE, including lupus nephritis, suggest a disease-modifying effect.

Objectives HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding. Methods Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models. Results We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049]. Conclusions There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study.

OBJECTIVE: To compare the responsiveness of the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity indices and to determine whether there was any added value in combining BILAG-2004, BILAG-2004 system tally (BST), or simplified BST (sBST) with SLEDAI-2K. METHODS: This was a multicenter longitudinal study of SLE patients. Data were collected on BILAG-2004, SLEDAI-2K, and therapy on consecutive assessments in routine practice. The external responsiveness of the indices was assessed by determining the relationship between change in disease activity and change in therapy between 2 consecutive visits. Comparison of indices and their derivatives was performed by assessing the main effects of the indices using logistic regression. Receiver operating characteristic curves analysis was used to describe the performance of these indices individually and in various combinations, and comparisons of area under the curve were performed. RESULTS: There were 1,414 observations from 347 patients. Both BILAG-2004 and SLEDAI-2K maintained an independent relationship with change in therapy when compared. There was some improvement in responsiveness when continuous SLEDAI-2K variables (change in score and score of previous visit) were combined with BILAG-2004 system scores. Dichotomization of BILAG-2004 or SLEDAI-2K resulted in poorer performance. BST and sBST had similar responsiveness as the combination of SLEDAI-2K variables and BILAG-2004 system scores. There was little benefit in combining SLEDAI-2K with BST or sBST. CONCLUSION: The BILAG-2004 index had comparable responsiveness to SLEDAI-2K. There was some benefit in combining both indices. Dichotomization of BILAG-2004 and SLEDAI-2K leads to suboptimal performance. BST and sBST performed well on their own; sBST is recommended for its simplicity and clinical meaningfulness.

Objectives Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. Material and methods This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. Results Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. Conclusions Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. Study Registration ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.

Background/Aims Patients with systemic lupus erythematosus (SLE) are known to have an increased risk of certain cancers, such as lymphoma, compared to the general population. We aimed to characterise the incidence of cancers in patients with moderate-severe SLE receiving biologic and standard of care (SoC) therapies. Methods The BILAG Biologics Registry (BILAG-BR) is a large prospective observational register of patients with SLE. Participants receiving rituximab, belimumab and SoC therapies from 2010-2021 were included. Data relating to malignancy were collected from study centres and the UK national cancer register. Overall cancer risk was assessed using a Cox proportional hazards model in Stata V14. Results There were 114 previous cancer diagnoses in 108 patients recorded. The most common cancer sites were cervical (43/114), non-melanoma skin cancer (20), breast (15) and lymphoma (13). All cervical neoplasms were carcinoma in situ. Five patients had more than one cancer diagnosis recorded; three had >1 non-melanoma skin cancer and two individuals had unrelated malignancies. During follow-up, (1437 patients with 5,738 person years [pys]), 33 incident cancers occurred in 32 individuals at a median of 477 (IQR 218-1265) days after registration. Incidence rates were 5.9 (95% CI 3.9-8.8) in rituximab, 7.8 (2.5-24.2) in belimumab and 4.16 (1.7-10.0) per 1,000 pys in the SoC group. Using rituximab as the comparator, the age and gender adjusted hazard ratio (HR) was 1.62 (0.48-5.52) for belimumab and 0.63 (0.24-1.65) for the SoC group. Patients who developed an incident cancer were older at registration (HR 1.07 [1.04-1.09] per year) and more likely to be of male sex (HR 2.95 [1.31-6.57]). Caucasian ethnicity was associated with increased risk in univariate analysis (HR 4.25 [1.46-12.32]), but not after adjusting for age and sex (HR 2.60 [0.86-7.83]). There were 6 cancer-related deaths which all occurred in the rituximab group a median of 2.3 (IQR 1.4-3.2) years from registration. Conclusion Although overall cancer numbers are low, the findings of this study are reassuring. The incidence of cancer in this cohort of SLE patients with moderate-to-severe disease appears to be broadly similar between those on biologic and standard of care therapies. Disclosure M. Rodziewicz: Grants/research support; North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics. Award Ref. MR/N025989/1, UCB. S. Dyball: Grants/research support; North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics. Award Ref. MR/N025989/1, UCB, Eli Lilly. E. Sutton: None. B. Parker: Honoraria; Fresenius-Kabi, AbbVie. Member of speakers’ bureau; Eli Lilly, Roche. Grants/research support; Genzyme/Sanofi, GSK. I.N. Bruce: Consultancies; AstraZeneca, Eli Lilly, ILTOO, GSK, Aurinia. Member of speakers’ bureau; GSK, UCB, AstraZeneca. Grants/research support; GSK, Roche, Janssen.

ObjectivesTo evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance.MethodsWe analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999–2019). We evaluated person-time contributed while on the initial HCQ dose (‘maintenance’), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare.ResultsWe studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts.ConclusionsSLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.

ObjectiveTo determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE).MethodsUpon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician-determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time-to-event analysis using a multistate modeling structure.ResultsNP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE-associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P=0.028), concurrent non-SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non-SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non-SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001).ConclusionIn a large and long-term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.

Objective To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined. Methods This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving fourth ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1 January 2005 to 31 December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage. Results A total of 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilizing at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI: 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states [BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA] were inversely associated with development of damage. Conclusions BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets.

Objective: The British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials. To understand the relevance of BICLA in clinical practice, we investigated relationships between BICLA response and routine SLE assessments, patient-reported outcomes (PROs), and medical resource utilization. Methods: This was a post hoc analysis of pooled data from the phase III, randomized, placebo-controlled, 52-week TULIP-1 (ClinicalTrials.gov identifier: NCT02446912; n = 457) and TULIP-2 (ClinicalTrials.gov identifier: NCT02446899; n = 362) trials of intravenous anifrolumab (150/300 mg once every 4 weeks) in patients with moderate-to-severe SLE. Changes from baseline to week 52 in clinical assessments, PROs, and medical resource use were compared in BICLA responders versus nonresponders, regardless of treatment assignment. Results: BICLA responders (n = 318) achieved significantly improved outcomes compared with nonresponders (n = 501), including lower flare rates, higher rates of attainment of sustained oral glucocorticoid taper to ≤7.5 mg/day, greater improvements in PROs (Functional Assessment of Chronic Illness Therapy–Fatigue, Short Form 36 Health Survey), and fewer SLE-related hospitalizations/emergency department visits (all nominal P < 0.001). Compared with nonresponders, BICLA responders had greater improvements in global and organ-specific disease activity (Physician’s Global Assessment, SLE Disease Activity Index 2000, Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity, and joint counts; all nominal P < 0.001). BICLA responders had fewer lupus-related serious adverse events than nonresponders. Conclusion: BICLA response is associated with clinical benefit in SLE assessments, PROs, and medical resource utilization, confirming its value as a clinical trial end point that is associated with measures important to patient care.

To explore long-term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo-controlled 3-year long-term extension (LTE) study (ClinicalTrials.gov identifier: NCT02794285).In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re-randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure-adjusted incidence rates (EAIRs) per 100 patient-years were calculated.In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non-opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure-adjusted event rates of COVID-related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID-related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo.This LTE study represents the longest placebo-controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit-risk profile of anifrolumab for patients with moderate-to-severe SLE receiving standard therapy.

Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.

Gene expression profiles are associated with the clinical heterogeneity of SLE but are not well studied as biomarkers for therapy. Many clinical and demographic features influence treatment responses. We studied gene expression and response to rituximab in a multi-ethnic UK cohort refractory to standard therapy.Baseline expression of transcripts known to associate with clinical features of SLE was evaluated in whole blood by 96-probe Taqman® array in patients (n=213) with active SLE, prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Registry. Autoantibodies were measured using immunoprecipitation and ELISA. Response to first cycle rituximab (n=110) was determined by BILAG-2004 criteria at 6 months.Interferon scores were lower in European ancestry patients than all other groups. The relationship between blood interferon scores and plasmablast, neutrophil, myeloid, inflammation and erythropoiesis-annotated scores differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified response to rituximab which was not explained by sociodemographic and clinical variables. Response was lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression across all signatures (p0.001). Clusters within European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters associated with U1RNP-Sm antibodies.Ancestry appears central to the immunological and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity and transcriptional signatures could each assist predict the effectiveness of B-cell depletion. This article is protected by copyright. All rights reserved.

Undifferentiated connective tissue disease (UCTD) encapsulates a broad range of conditions including incomplete forms of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), some of whom progress to a formal clinical diagnosis over time. This systematic review (SR) and meta-analysis aimed to identify clinical and laboratory features and biomarkers that can predict progression of UCTD.A systematic literature search was carried out on MEDLINE, EMBASE and the Cochrane Central Register of Randomized Controlled Trials. Abstracts and full-text manuscripts were screened by two reviewers. Publications were included if they included at least 20 UCTD patients, a minimum of six months of follow up, and provided data on at least one risk factor for developing a defined CTD. The QUIPS tool was used to assess risk of bias (RoB) and GRADE for grading the quality of the evidence. The study is registered with PROSPERO (ID: CRD42021237725).Fifty-nine studies were included in the SR, and forty-one in the meta-analysis. The predictors for progression to SLE with the highest certainty of evidence included those with younger age (MD -5.96 [-11.05-0.87 years]), serositis (RR 2.69 [1.61-4.51]), or the presence of anti-dsDNA antibodies (RR 4.27 [1.92-9.51]). For SSc, the highest certainty of evidence included puffy fingers (RR [3.09 [1.48-6.43]), abnormal nailfold changes (NFC) (avascular areas [RR 5.71 (3.03-10.8)] or active or late SSc pattern [RR 2.24 (1.25-4.01)] and anti-topoisomerase-I (RR 1.83 [1.45-2.30]). No novel biomarkers were included in the meta-analysis; however HLA molecules, regulatory T cell shift, pro-inflammatory cytokines and complement activation products were identified as potential predictors for evolution of disease.Clinical and immunological parameters may predict which patients with UCTD progress to definitive disease; however, the heterogeneous nature and RoB in most studies limits the ability to apply these results in routine clinical practice. Limited data suggest that some novel biomarkers may provide additional predictive value but these will need larger well designed studies to fully delineate their clinical utility.

ObjectivesA perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians’ approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years.MethodsDemographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively.ResultsAt enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640–1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640–1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU–203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2.ConclusionIn recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing.

Objective To phenotype SLE based on symptom burden (disease damage, system involvement and patient reported outcomes), with a specific focus on objective and subjective cognitive function. Methods SLE patients ages 18–65 years underwent objective cognitive assessment using the ACR Neuropsychological Battery (ACR-NB) and data were collected on demographic and clinical variables, disease burden/activity, health-related quality of life (HRQoL), depression, anxiety, fatigue and perceived cognitive deficits. Similarity network fusion (SNF) was used to identify patient subtypes. Differences between the subtypes were evaluated using Kruskal–Wallis and χ2 tests. Results Of the 238 patients, 90% were female, with a mean age of 41 years (s.d. 12) and a disease duration of 14 years (s.d. 10) at the study visit. The SNF analysis defined two subtypes (A and B) with distinct patterns in objective and subjective cognitive function, disease burden/damage, HRQoL, anxiety and depression. Subtype A performed worst on all significantly different tests of objective cognitive function (P Conclusion This study demonstrates the complexity of cognitive impairment (CI) in SLE and that individual, multifactorial phenotypes exist. Those with greater disease burden, from SLE-specific factors or other factors associated with chronic conditions, report poorer cognitive functioning and perform worse on objective cognitive measures. By exploring different ways of phenotyping SLE we may better define CI in SLE. Ultimately this will aid our understanding of personalized CI trajectories and identification of appropriate treatments.

ObjectiveTo develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).MethodsFollowing European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion.ResultsFour overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target ConclusionThese recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.

Summary Background 300 mg of intravenous anifrolumab every 4 weeks added to standard-of-care treatment for patients with systemic lupus erythematosus (SLE) reduced disease activity and glucocorticoid requirement in a previous phase 3 trial. Because patients might find subcutaneous administration more convenient than intravenous delivery, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous anifrolumab in patients with SLE, active skin disease, and a high type I interferon gene signature. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 2 study was done at 12 hospitals and outpatient clinics in Hungary, South Korea, Poland, and the USA. Eligible patients were aged 18–70 years, and had SLE with high type I interferon gene signature and an activity score on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) of at least 10. Enrolled participants were randomly assigned (3:1:3:1) by use of a voice-web response system to receive either 150 mg of subcutaneous anifrolumab or corresponding placebo, or 300 mg of subcutaneous anifrolumab or corresponding placebo in addition to stable standard-of-care treatment. The study was double-blinded with respect to intervention but not dose, until 12 weeks. Doses of oral glucocorticoids were tapered after week 12. The primary pharmacokinetic endpoint was the serum concentration of anifrolumab based on the maximum concentration after the first dose and the minimum (trough) concentration before subsequent doses and was measured in all patients who received anifrolumab and had at least one quantifiable serum pharmacokinetics observation following the first dose. The primary pharmacodynamic endpoint was neutralisation of the type I interferon pharmacodynamic signature at week 12 and was assessed in all patients with a high type I interferon pharmacodynamics signature at baseline based on a 21-gene test. Safety was evaluated in the full analysis set, which included all patients who received at least one dose of anifrolumab. This trial is completed and is registered at ClinicalTrials.gov , NCT02962960 . Findings Between March 14, 2017, and Oct 26, 2017, 36 patients were randomly assigned to receive 150 mg of anifrolumab (n=14), 300 mg of anifrolumab (n=13), or placebo (n=9). Two patients in the anifrolumab 150 mg group were excluded from the pharmacodynamic analysis set (n=34). Ten (71%) of 14 patients in the anifrolumab 150 mg group, ten (77%) of 13 patients in the anifrolumab 300 mg group, and nine (100%) of the nine patients in the placebo group completed 52 weeks of treatment. At week 12, pre-dose mean trough serum concentrations of anifrolumab were more than dose proportional between the anifrolumab 150 mg group (19·82 μg/mL [SD 15·01]) and the anifrolumab 300 mg group (60·28 μg/mL [43·66]), and the pharmacokinetics were non-linear. At week 12, the median percentage neutralisation of the type I interferon gene signature was higher with 150 mg (88·0% [median absolute deviation 7·4]) and 300 mg (90·7% [3·3]) of anifrolumab than with placebo (18·5% [8·1]), and more patients in the anifrolumab 150 mg group and the anifrolumab 300 mg group than in the placebo group had neutralisation of 75% or more (eight [67%] of 12 vs ten [77%] of 13 vs one [11%] of nine). At least one adverse event was reported by 23 (85%) of 27 patients in the anifrolumab groups and by seven (78%) of nine patients in the placebo group; most adverse events were of mild-to-moderate severity. Serious adverse events were reported in six (22%) of 27 patients in the anifrolumab groups (four patients in the 150 mg group and two in the 300 mg group). No serious adverse events were reported in the placebo group. Herpes zoster infection was reported by three (11%) of 27 patients in the anifrolumab groups and by one (11%) of nine patients in the placebo group. There were no treatment-related deaths. Interpretation Anifrolumab, administered subcutaneously every 2 weeks to patients with SLE and moderate-to-severe skin manifestations, had non-linear pharmacokinetics that were more than dose proportional, and neutralised the type I interferon gene signature in a dose-dependent manner. The safety profile was consistent with previous studies of intravenous anifrolumab, supporting the continued development of anifrolumab as a subcutaneously administered therapy for patients with SLE. Funding AstraZeneca.

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6–18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.

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 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.

OBJECTIVE This study assessed prevalence of connective tissue disease (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) in women with previous adverse pregnancy outcome compared with uncomplicated livebirths. DESIGN Retrospective case-control study. SETTING UK Primary Care. POPULATION OR SAMPLE Records of women, 18 years and older, within the Clinical Practice Research Datalink (CPRD) (1 January 2000-31 December 2013). METHODS Clinical Practice Research Datalink was searched for pregnancy terms to identify adverse pregnancy outcome. Each identified case was matched to five livebirths. MAIN OUTCOME MEASURES Diagnosis of SLE, CTD, APS or autoimmune antibodies. Poisson regression was performed to calculate relative risk ratios (RR), comparing adverse pregnancy outcome with livebirth cohorts. RESULTS Clinical Practice Research Datalink identified 20 123 adverse pregnancy outcomes matched to 97 323 livebirths, with a total of 875 590 person-years follow up. Median follow up from study entry was 7.29 years (SD 4.39). Compared with women with an uncomplicated livebirth, women with adverse pregnancy outcome had an increased risk of developing CTD or autoimmune antibodies (RR 3.20, 95% CI 2.90-3.51). Risk was greatest following a stillbirth (RR 5.82, 95% CI 4.97-6.81). For CTD and SLE, the risk was greatest within the first 5 years of adverse pregnancy outcome. Risk for aPL and APS diagnosis was highest ≥5 years from adverse pregnancy outcome. CONCLUSIONS Adverse pregnancy outcome is associated with increased risk of developing maternal CTD, including SLE. Either immunological factors predispose women to adverse pregnancy outcome and subsequent CTD diagnosis or, alternatively, adverse pregnancy outcome initiates autoimmune events which culminate in CTD in later life. TWEETABLE ABSTRACT Stillbirth is associated with increased maternal risk of developing systemic lupus erythematosus (SLE).

To compare imaging biomarkers from hyperpolarisedProspective longitudinal.Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), five connective tissue disease related-ILD (CTD-ILD)) patients and ten healthy volunteers imaged at visit 1. Thirty-four ILD patients completed visit 2 (eleven IPF, eight HP, ten DIILD, five CTD-ILD) after 6 or 26 weeks.MRI was performed at 1.5 T, including inversion recovery TFiveTo evaluate differences at visit 1 among subgroups: ANOVA or Kruskal-Wallis rank tests with correction for multiple comparisons. To assess the relationships between imaging biomarkers, PFT, age and gender, at visit 1 and for the change between visit 1 and 2: Pearson correlations and multilinear regression models.The global PFT tests could not distinguish ILD subtypes. Percentage ventilated volumes were lower in ILD patients than in HVs when measured withNeither

Background/Aims Current British Society for Rheumatology guidance suggests 3-monthly blood monitoring for patients prescribed methotrexate whose disease, drug dosage and blood results are stable, although evidence for this recommendation is limited. Anecdotal reports suggest monitoring may have reduced during the pandemic. The study aims were, in patients with rheumatoid arthritis (RA) prescribed methotrexate, to determine: 1) interval length between blood tests during the pandemic, and 2) whether prolonged intervals were associated with abnormal blood test results. Methods Data came from the Greater Manchester Care Record, a database containing electronic health records from both primary and secondary care for people across Greater Manchester. Inclusion criteria were: a diagnosis of RA; regular blood monitoring ( < =91 days between blood tests) and regular methotrexate prescriptions in the year prior to the pandemic (01/03/2019-01/03/2020). Blood test intervals during the pandemic were determined, a prolonged interval was defined as > 91 days. Cytopenia and transaminitis events were identified between March-December 2020 and March-December 2019 (as a comparator). Proportions of events are presented for each time-period and stratified by whether the interval was prolonged. Results 1011 patients met the inclusion criteria, with a median of 5 blood tests (interquartile range (IQR): 3-7) during the pandemic and a median interval of 57 days (IQR: 34-84). 612 (61%) patients had at least one prolonged interval, with 241 (23.8%) having multiple. Prolonged intervals had a median length of 112 days (IQR: 99-135). 115 (11.4%) people had a prolonged interval but no subsequent blood test before the study end date (median 120 days [IQR: 104-150]). The proportion of cytopenia and transaminitis events was low and similar across time-periods and when stratified by interval length (Table 1). Conclusion Nearly two-thirds of patients on stable methotrexate had at least one prolonged interval and 1 in 10 had a prolonged interval with no subsequent blood test. Initial analyses of test results do not indicate increased occurrence of methotrexate blood toxicity in those with prolonged blood test intervals during the pandemic. Further work is required to determine whether those with prolonged intervals represent a group at lower risk where less frequent blood tests would be appropriate. Disclosure R.E. Costello: None. R. Williams: None. I.N. Bruce: None. K. Hyrich: None. W.G. Dixon: Consultancies; Consultancy fees from Abbvie and Google unrelated to this work. J.H. Humphreys: None.

Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

Background/Aims Anti-CD20 monoclonal antibodies (MAb) are used to deplete B cells in autoimmune and haematological disease. Rituximab (RTX) failed to meet its primary endpoint in two Phase III trials for systemic lupus erythematosus (SLE) but is commonly used for the treatment of patients with severe or refractory disease. outcomes including clinical response and adverse effects are highly variable. Alternative anti-CD20 MAbs such as Ofatumumab, have been suggested as a potentially effective alternative treatment for those patients who fail treatment with RTX. We aimed to provide an update of a systematic review of predictive and prognostic factors of anti-CD20 MAb treatment in SLE patients. Methods A systematic literature search was undertaken and included adult and paediatric randomised controlled trials (RCTs) and cohort studies. Articles included in the previous systematic review were excluded. Methodological quality was assessed for RCTs using the Cochrane Collaboration Risk of Bias (RoB2) tool for RCTs and the Quality In Prognosis Studies Tool (QUIPS) for cohort studies. The quality of evidence (QoE) was assessed as high, moderate, low or very low using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for RCTs and the 2013 adaptation for prognostic factor research. The quality of subgroup analysis for predictors of differential treatment response was also evaluated. A narrative synthesis of the evidence from included studies was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Sixteen studies from an initial 849 results were included. There were two post-hoc analyses of RCTs of RTX, one RCT of ocrelizumab in lupus nephritis and 13 cohort studies examining RTX treatment. Outcomes assessed included global clinical, cutaneous, haematological and renal response, treatment failure, relapse and adverse effects. The overall QoE was assessed as low and very-low for all studies and was limited by significant heterogeneity of inclusion criteria, assessment tools, outcomes assessed and definitions of response and failure. Studies also often included small numbers of participants and failed to account for confounders and multiple subgroup analyses of differing outcomes. Novel biomarkers, such as S100 proteins, anti-vimentin and anti-drug antibodies showed some evidence of prognostic value but QoE was limited due to moderate to high risk of bias, early phase of investigation and imprecision of results. Conclusion Since 2015, there has been little progress in the identification and confirmation of prognostic or predictive factors to guide outcome in lupus patients treated with anti-CD20 therapy. Further work is required to support those factors which appear to demonstrate prognostic potential. PROSPERO registration number: CRD42020220339 Disclosure M. Rodziewicz: Grants/research support; M.R. is supported by the NW England MRC Fellowship in Clinical Pharmacology and Therapeutics, which is funded by the MRC, Riche, Eli Lily UCB, Novartis and the Universities of Manchester and Liverpool. S. Dyball: Grants/research support; S.D. is supported by the NW England MRC Fellowship in Clinical Pharmacology and Therapeutics, which is funded by the MRC, Roche, Eli Lily UCB, Novartis and the Universities of Manchester and Liverpool. C. Mendoza-Pinto: None. P. Munguia-Realpozo: None. I.N. Bruce: Grants/research support; I.N.B. has received grants from GlaxoSmithKline and Sanofi Genzyme. Other; I.N.B. has received consultancy and speaker fees to his institution from GlaxoSmithKline, UCB, BMS, Eli Lily, Aurinia, AstraZeneca and Merck Serono. B. Parker: None.

ObjectiveThe Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in systemic lupus erythematosus (SLE), but its association with hospitalizations has not been described. Our objective was to estimate the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort.MethodsBaseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in the hospital. Multivariable models were adjusted for relevant baseline characteristics.ResultsThe 1,549 patients with SLE eligible for this analysis were mostly female (88.7%), with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5) at baseline. Mean ± SD baseline SLICC-FI was 0.17 ± 0.08. During mean ± SD follow-up of 7.2 ± 3.7 years, 614 patients (39.6%) experienced 1,570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up, with an incidence rate ratio of 1.21 (95% confidence interval [95% CI] 1.13-1.30) after adjustment for baseline age, sex, glucocorticoid use, immunosuppressive use, ethnicity/location, SLE Disease Activity Index 2000 score, SLICC/American College of Rheumatology Damage Index score, and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (relative rate 1.09 [95% CI 1.02-1.16]).ConclusionThe SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.

ObjectiveTo determine the independent impact of different definitions of remission and low disease activity (LDA) on damage accrual.MethodsPatients with ≥2 annual assessments from a longitudinal multinational inception lupus cohort were studied. Five mutually exclusive disease activity states were defined: remission off-treatment: clinical Systemic Lupus Erythematosus Disease Activity Index (cSLEDAI)-2K=0, without prednisone or immunosuppressants; remission on-treatment: cSLEDAI-2K score=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; low disease activity Toronto cohort (LDA-TC): cSLEDAI-2K score of ≤2, without prednisone or immunosuppressants; modified lupus low disease activity (mLLDAS): Systemic Lupus Erythematosus Disease Activity Index-2K score of 4 with no activity in major organ/systems, no new disease activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants; active: all remaining visits. Only the most stringent definition was used per visit. Antimalarials were allowed in all. The proportion of time that patients were in a specific state at each visit since cohort entry was determined. Damage accrual was ascertained with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Univariable and multivariable generalised estimated equation negative binomial regression models were used. Time-dependent covariates were determined at the same annual visit as the disease activity state but the SDI at the subsequent visit.ResultsThere were 1652 patients, 1464 (88.6%) female, mean age at diagnosis 34.2 (SD 13.4) years and mean follow-up time of 7.7 (SD 4.8) years. Being in remission off-treatment, remission on-treatment, LDA-TC and mLLDAS (per 25% increase) were each associated with a lower probability of damage accrual (remission off-treatment: incidence rate ratio (IRR)=0.75, 95% CI 0.70 to 0.81; remission on-treatment: IRR=0.68, 95% CI 0.62 to 0.75; LDA: IRR=0.79, 95% CI 0.68 to 0.92; and mLLDAS: IRR=0.76, 95% CI 0.65 to 0.89)).ConclusionsRemission on-treatment and off-treatment, LDA-TC and mLLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers.