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Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease of unknown aetiology, characterised by the production of auto-antibodies and formation of immune complexes against self-antigens and complement activation. This inflammatory response can lead to tissue infiltration and eventually, to organ damage.Patients with SLE invariably have periods of relapse and remission. Flares can occur even when the patient is on seemingly adequate treatment, which suggests that more effective therapies are necessary for the management of SLE. Thus, trials with many drugs against different targets, such as CD22, IL-12 and IL-23 or tyrosine kinases, have been carried out in recent years.A frustrating feature of some of the biologic drugs used to treat SLE has been the reporting of successful phase II trials followed by failures of the phase III trials.In this review, we will focus on phase II and III trials carried out with epratuzumab (anti CD22), baricitinib (Janus kinases inhibitor), rigerimod (P140 peptide) and ustekinumab (IL-12 and IL-23 inhibitor) and consider the reasons for their ultimate failure to ‘make the grade’. Likewise, we will try to explain the possible reasons that can influence why good results may be obtained in phase II trials and lead to undue optimism.

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.

Background/Aims The BEAT-lupus double-blind randomised trial demonstrated that belimumab (anti-BAFF antibody) reduced the number of severe-flares (compared to placebo) after B-cell depletion (rituximab) in patients with systemic lupus erythematosus (SLE)(1). We longitudinally immune profiled patients recruited to the trial to identify which patients would benefit most from belimumab after rituximab combination therapy. Methods We constructed two models (because the number of patients who provided serum/blood RNA samples and peripheral blood mononuclear cells differed) using baseline data to predict a major clinical response (MCR)(2) to belimumab after rituximab at 52-weeks utilising conventional and machine learning approaches: A) Model 1: serum autoantibodies and cytokines, peripheral blood RNA expression, clinical data, and routinely collected laboratory-markers (10 responders, 11 non-responders). B) Model 2: B-cell flow-cytometry (8 responders, 8 non-responders). The emerging key variables were then used as effect modifiers comparing response to belimumab and placebo after rituximab. Results Baseline serum IgA2 anti-dsDNA antibody levels emerged from model 1 as the key predictor of MCR with an AUROC (area under the curve of the receiver operator characteristic) of 0.81 (95% CI: 0.70-0.96) in predicting an MCR by 52-weeks in the belimumab arm. An optimal cut point of serum IgA2 anti-dsDNA antibody (10.7 AU/arbitrary unit), derived from AUROC, was applied as an effect modifier which improved the delta between response to belimumab vs placebo from 13% (without the effect modifier) to 48% (95% CI: 10-70; p = 0.021) (Belimumab - 64% [9 responders, 5 non-responders], placebo - 16% [2 responders, 10 non-responders]). Belimumab significantly reduced serum IgA2 anti-dsDNA antibody levels compared to placebo at 52-weeks (difference: 20 AU; 95% CI: 13-27; p Conclusion High baseline serum IgA2 anti-dsDNA antibody and peripheral blood T-bet+CD11c+DNM-2 B-cell frequency could guide patient selection for belimumab after rituximab combination therapy thereby improving outcomes and access to targeted therapies for patients with SLE. Exploration of the underlying mechanisms and confirmation of these results including combining the two prediction models in a larger clinical trial are required. Reference 1. Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57. 2. McDonald S, et al. Lupus Sci Med. 2022;9:e000584. Disclosure M. Shipa: Grants/research support; Versus arthritis, LUPUS-UK. M. Parvaz: None. D. Nguyen: None. L. Santos: None. D.A. Isenberg: Consultancies; Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB. C. Gordon: Consultancies; Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB. M.R. Ehrenstein: Consultancies; GSK. Grants/research support; Versus arthritis.

Background/Aims Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of immune-mediated systemic diseases, characterized by muscle inflammation and multiple systemic manifestations. We aimed to characterize clinical manifestations, course, treatment, and mortality of IIM patients. We have also attempted to assess predictors of mortality in IIM. Methods Retrospective single center study IIM patients followed between 1980 and June 2022, including IIM patients fulfilling three or four of the Bohan and Peter criteria. Patients were divided in 6 groups: adult-onset polymyositis (APM), adult-onset dermatomyositis (ADM), juvenile-onset dermatomyositis (JDM), ‘overlap’ myositis (OM), cancer-associated myositis (CAM), and antisynthetase syndrome (ASyS). Sociodemographic, clinical and immunological features and treatment were collected. Additionally, disease complications and causes of death were recorded. The log rank test was used to compare survival curves between subgroups. The Cox proportional hazards regression was used to assess predictors of mortality. Results A total of 158 patients were included with a mean age at diagnosis of 40.81±15.63 years. Most patients were female (77.2%) and Caucasian (63.9%). The most frequent diagnoses were ADM (35.4%), OM (20.9%) and APM (24.7%), respectively. The majority of patients presented with both upper and lower limb involvement (89.2%), with a mean creatinine kinase level of 4423 ± 7633 U/L. Electromyography, muscle biopsy and magnetic resonance were positive for active myositis in 81.3% (104/128), 77.7% (101/130) and 40.9% (54/132), respectively. Antinuclear antibodies were positive in 62.4% of the patients. Remitting and relapsing (RR) was the most common disease course (35.4%). Most patients were treated with a combination of steroids and one-to-three immunosuppressive drugs (74.1%). Interstitial lung disease, gastrointestinal and cardiac involvement were frequent, affecting 38.5%, 36.5% and 23.4% of the patients, respectively. The survival rates at 5, 10, 15, 20 and 25 years of follow-up were 89%, 74%, 67%, 62% and 43%, respectively. During a median follow up of 13.61 ± 10.24 years, 46 (29.1%) have died, mainly due to infection (28.3%), followed by malignancy (19.6%) and cardiovascular events (10.9%). Positive biopsy (p = 0.044), Jo-1 (p = 0.039), malignancy (p = 0.026), cardiac involvement (p = 0.011) and infections (p = 0.016) were associated with mortality. Older age at diagnosis (HR:1.058, 95CI 1.031-1.085), cardiac involvement (HR: 3.23, 95CI 1.60-6.53), and malignancy (HR 2.20, 95CI 1.09-4.44) were independent predictors of mortality. Conclusion IIM is a rare disease with important systemic complications. Older age at diagnosis, cardiac involvement, and malignancy are independent predictors on mortality. Early diagnosis and aggressive treatment of cardiac involvement could improve survival of these patients. Disclosure F. Guimarães: None. R. Yildirim: None. D.A. Isenberg: None.

Background/Aims Previous research into B cell biomarkers of poor response to the anti-CD20 drug rituximab in autoimmune disease relates to insufficient B cell depletion. Expansion of memory B cell (MBC) subsets were also associated with poorer response. We investigated whether the relative expression of the target antigen CD20 on B cell subpopulations could also contribute to drug resistance. Methods Peripheral blood samples from 6 rituximab naïve (RTX-N) patients with autoimmune rheumatic diseases (active systemic lupus erythematosus and rheumatoid arthritis), 6 patients previously treated with rituximab (RTX-T), and 6 healthy controls (HC) were obtained. B cell subpopulations were defined using the relative expression of IgD and CD27 using flow cytometry. Results Patients in the RTX-N group had significantly higher frequency of CD19+CD20- B cells (median=25.9% of total B cells, compared to 1.26% in HC), p = 0.0022. CD19+CD20-B cells were predominantly switched MBC (IgD-CD27+) and double negative (IgDCD27-) MBC cells. All patients in the RTX-T group (median 22 months post-rituximab) had detectable CD19+CD20- B cells (median=52.25% of total B cells), of which the majority were switched MBC (median=4.54%, range 0.23-74%) and DN B cells (median=53.5%, range 11.6-98.1%). Collectively, we noted that the frequency of CD19+CD20- B cells in peripheral circulation was higher in RTX-T>RTX-N>HC. Conclusion Our preliminary results have identified greater frequency of CD19+CD20- population of B cells in peripheral blood of patients with autoimmune disease, particularly after treatment with rituximab, suggesting that they evade rituximab. These are predominantly of the switched MBC and DN B cell subpopulations. Given the potential of these cells to contribute to disease activity in autoimmune disease, alternative strategies targeting CD19 may help overcome rituximab resistance. Disclosure K. Shah: Grants/research support; Roche Glycart. C. Klein: Corporate appointments; Roche Glycart. Shareholder/stock ownership; Roche. G. Cambridge: None. D. Sen: None. M. Castelino: None. A. Akbar: None. D.A. Isenberg: None. M. Leandro: None. V.R. Reddy: Grants/research support; Roche Glycart, BRC UCLH.

Objective Patients with SLE have increased prevalence of clinical cardiovascular disease (CVD) and subclinical atherosclerosis. Although 30–40% of patients with SLE have vascular plaque on ultrasound scanning, this study is the first to consider the relationship between total burden of plaque and subsequent CVD risk. Methods One hundred patients with SLE and without any previous clinical CVD underwent vascular ultrasound scans of both carotid and both common femoral bifurcations between 2011 and 2013. Clinical, serological, demographic and treatment data were collected at baseline. Patients were followed till 2020 to identify those who developed new onset coronary disease or stroke. Statistical analysis to identify factors associated with increased risk of developing CVD events was carried out. Results Thirty-six patients had plaque at baseline. During follow-up five patients (all had baseline plaque) developed coronary disease and two, without baseline plaque, developed lacunar strokes. Mean (s.d.) age of these patients was 46.5 (4.5) years. Patients with three or more baseline bifurcations with plaque were 10 times more likely to develop CVD than those with 0–2 bifurcations with plaques (OR 9.9, P = 0.009). TPA > 16mm2 was associated with six-fold increased risk of CVD (OR = 6.44, P = 0.028). Patients with disease duration > 14 years were more likely than those with disease duration < 14 years to develop CVD (OR 8.3 P = 0.043) Conclusions The number of bifurcations with plaque and TPA in patients with SLE may be valuable in assessing risk of CVD and deciding on clinical measures to reduce this risk.

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.

Clinical heterogeneity in systemic lupus erythematosus (SLE) is a challenge to effective treatment. This Review describes advances in our understanding of genetic and epigenetic variations in SLE and the roles of immune profiling and biomarker identification in the progress towards precision medicine.Systemic lupus erythematosus (SLE) is an autoimmune disease that has diverse clinical manifestations, ranging from restricted cutaneous involvement to life-threatening systemic organ involvement. The heterogeneity of pathomechanisms that lead to SLE contributes to between-patient variation in clinical phenotype and treatment response. Ongoing efforts to dissect cellular and molecular heterogeneity in SLE could facilitate the future development of stratified treatment recommendations and precision medicine, which is a considerable challenge for SLE. In particular, some genes involved in the clinical heterogeneity of SLE and some phenotype-related loci (STAT4, IRF5, PDGF genes, HAS2, ITGAM and SLC5A11) have an association with clinical features of the disease. An important part is also played by epigenetic varation (in DNA methylation, histone modifications and microRNAs) that influences gene expression and affects cell function without modifying the genome sequence. Immune profiling can help to identify an individual's specific response to a therapy and can potentially predict outcomes, using techniques such as flow cytometry, mass cytometry, transcriptomics, microarray analysis and single-cell RNA sequencing. Furthermore, the identification of novel serum and urinary biomarkers would enable the stratification of patients according to predictions of long-term outcomes and assessments of potential response to therapy.

BACKGROUND B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING England. PARTICIPANTS Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS Small sample size; biomarker primary end point. CONCLUSION Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE Versus Arthritis.

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.

Objectives To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. Methods We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. Results In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. Conclusions BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

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.

Objective aPL are found in the blood of 20–30% of patients with SLE. Although aPL cause vascular thrombosis in the antiphospholipid syndrome, it is not clear whether positive aPL levels in early SLE increase risk of subsequent vascular events (VE). In a previous analysis of 276 patients with SLE, we found that early positivity for ≥2 of IgG anti-cardiolipin (anti-CL), IgG anti-β2-glycoprotein I (anti-β2GPI) and anti-domain I of β2-glycoprotein I (anti-DI) showed a possible association with VE. Here we have extended that analysis. Methods Serum samples taken from 501 patients with SLE early in their disease had been tested for IgG anti-CL, anti-β2GPI and anti-DI by ELISA. Complete VE history was available for 423 patients of whom 23 were excluded because VE occurred before the diagnosis of SLE. For the remaining 400 patients we carried out Kaplan–Meier survival analysis to define groups at higher risk of VE. Results Of 400 patients, 154 (38.5%) were positive for one or more aPL, 27 (6.8%) were double/triple-positive and 127 (31.8%) were single-positive. There were 91 VE in 77 patients, of whom 42 were aPL-positive in early disease. VE were significantly increased in aPL-positive vs aPL-negative patients (P = 0.041) and in double/triple-positive vs single-positive vs aPL-negative patients (P = 0.0057). Omission of the IgG anti-DI assay would have missed 14 double/triple-positive patients of whom six had VE. Conclusion Double/triple-positivity for IgG anti-CL, anti-β2GPI and anti-DI in early SLE identifies a population at higher risk of subsequent VE.

Objective Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study. Methods Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48. Results Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. Conclusion While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition.

ObjectiveTo identify clinical and serological features that distinguish patients with SLE who require single as opposed to repeated rituximab (RTX) cycles.MethodsAll 175 SLE patients followed up at University College Hospital from 2000 onwards were retrospectively reviewed. They were divided into a one-RTX-cycle group and a multiple-cycle group (2 or more cycles). Patients included had a follow-up of at least 3 years after their first RTX cycle, unless they needed a second infusion sooner.ResultsA total of 131 patients were included; 44 (33.6%) received one cycle of RTX and 87 (66.4%) received two or more. The former were older at diagnosis (31.4 vs 21 years, P ConclusionsRTX is an effective option for SLE patients with severe flares. Patients who received more immunosuppressive drugs were more likely to receive more than one set of RTX infusions. This suggests that RTX is best used for SLE patients with no history of refractory disease.

Objectives High rates of anti-drug antibodies (ADA) to rituximab have been demonstrated in patients undergoing treatment for SLE. However, little is known with regard to their long-term dynamics, impact on drug kinetics and subsequent implications for treatment response. In this study, we aimed to evaluate ADA persistence over time, impact on circulating drug levels, assess clinical outcomes and whether they are capable of neutralizing rituximab. Methods Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected across a follow-up period of 36 months following treatment (n = 114). Clinical and laboratory data were collected pre-treatment and throughout follow-up. ADA were detected via electrochemiluminescent immunoassays. A complement dependent cytotoxicity assay was used to determine neutralizing capacity of ADA in a sub-cohort of positive samples (n = 38). Results ADA persisted over the 36-month study period in 64.3% of patients undergoing treatment and titres peaked earlier and remained higher in those who had previously been treated with rituximab when compared with than those who were previously treatment naive. ADA-positive samples had a significantly lower median drug level until six months post rituximab infusion (P = 0.0018). Patients with persistent ADA positivity showed a significant early improvement in disease activity followed by increased rates of relapse. In vitro analysis confirmed the neutralizing capacity of ADA to rituximab. Conclusions ADA to rituximab were common and persisted over the 36-month period of this study. They associated with earlier drug elimination, an increased rate of relapse and demonstrated neutralizing capacity in vitro.

We aimed to characterise the frequency of thrombocytopenia in systemic lupus erythematosus (SLE) and determine its time of onset during the course of the disease, and its severity and impact on mortality.This was a single-centre cohort analysis of 707 patients with SLE followed for up to 40 years. We reviewed the patients' clinical notes identifying the presence of thrombocytopenia, its time of onset and ascertained other clinical and serological features of the disease. Thrombocytopenia was classified as mild (100-149x109/L), moderate (31-99x109/L) or severe (≤30x109/L platelets). It was also classified as asymptomatic, with minor bleeding or with major bleeding.22.9% of patients (n=162) had thrombocytopenia prior to or during the course of SLE. Twenty-three patients (14.2%) had isolated immune thrombocytopenia (ITP) before the diagnosis of SLE. Median follow-up time was 19 years (IQR=13). Most patients (n=67, 41.4%) had mild thrombocytopenia. More than half the patients (n=98, 60.5%) developed asymptomatic thrombocytopenia and only 6 patients (3.7%) had major bleeding events in the context of thrombocytopenia. The development of severe thrombocytopenia any time during the course of SLE was associated with an increased risk of death (HR=3.57, p=0.025). Anti-phospholipid syndrome was over twice as common in patients with thrombocytopenia in the cohort. There is an increased risk of death for male patients (HR=3.41, p=0.036) who develop thrombocytopenia and for those who present with concomitant haemolytic anaemia (HR=3.07, p=0.027).The presence of severe thrombocytopenia (platelets ≤30x109) in patients with SLE is associated with an increased risk of death, regardless of bleeding events. Male patients with SLE and thrombocytopenia have an increased mortality risk, as have those who develop concomitant thrombocytopenia and haemolytic anaemia.

For many years, the failure of randomized controlled trials (RCTs) has prevented patients with systemic lupus erythematosus (SLE) from benefiting from biological drugs that have proved to be effective in other rheumatological diseases. Only two biologics are approved for SLE, however they can only be administered to a restricted proportion of patients. Recently, several phase II RCTs have evaluated the efficacy and safety of new biologics in extra-renal SLE and lupus nephritis. Six drug trials have reported encouraging results, with an improvement in multiple clinical and serological outcome measures. The possibility of combining B-cell depletion and anti-BLyS treatment has also been successfully explored.

ObjectivesA novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes.MethodsDemographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset.ResultsCluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2.ConclusionFour discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.

Objectives The long-term outcome of psychosis in association with systemic lupus erythematosus (SLE) has been insufficiently characterised. We used a specialist centre cohort of patients with SLE and psychosis to investigate their clinical outcome and phenotypic and laboratory characteristics. Methods Retrospective cohort study of 709 SLE patients seen at a specialist centre between January 1978 and November 2018. Clinical, biochemical and immunological characteristics (Bonferroni corrected), and serum neuronal surface antibody profile using novel cell-based assays, were compared between patients with and without psychosis. Results Eighteen (18/709, 2.5%) patients developed lupus psychosis over a mean ± SD of 17.5 ± 11.0 years follow-up. Psychosis fully remitted in 66.7% (12/18) with a combination of antipsychotic (in 38.9%) and immunosuppressive therapy (methylprednisolone 72.2%, cyclophosphamide 55.6%, rituximab 16.7%, plasma exchange 27.8%, prednisolone 50%). Patients who developed lupus psychosis may be more likely to have anti-RNP antibodies (50.0% vs 26.5%) and less likely to have anti-cardiolipin antibodies (5.6% vs 30.0%), but this was not significant in our small sample. Neuronal surface autoantibody tests found GABABR autoantibodies in 3/10 (30.0%) lupus psychosis patients compared with only 3/27 (11.1%) in age- and sex-matched SLE controls using fixed cell-based assays (P =0.114). However, GABABR antibodies were not replicated using a live cell-based assay. NMDAR-antibodies were not detected with fixed or live cell assays in any samples. Conclusion Lupus psychosis is rare but treatable. In this rare sample of eighteen patients from a 40-year cohort, no significant biomarker was found, but some preliminary associations warrant further exploration in a larger multicentre analysis.

It is now two decades since Rituximab was first used in the treatment of patients with systemic lupus erythematosus. There have been many challenges but in spite of failing to meet its primary endpoints in two clinical trials it is widely used for many aspects of lupus, its side-effects and the possibility that combining it with Benlysta may be of value. We also consider the proposal that it may provide a useful initial therapy. In this review, we consider the place of Rituximab in the treatment of lupus and anticipate how developments in fully-humanized anti-CD20 monoclonals may well extend the “therapeutic life” of B-cell depletion as a viable treatment option.

Objectives Patients with SLE have an increased risk of developing cardiovascular disease (CVD). Multiple studies have shown that these patients have increased numbers of carotid plaques and greater intima-media thickness (IMT) than healthy controls. Measures such as total plaque area (TPA) and plaque echogenicity may be more sensitive and more relevant to cardiovascular risk than presence of plaque and IMT alone. Our objective was to produce the first report of TPA and echogenicity in a population of patients with SLE. Methods One hundred patients with SLE and no history of clinical CVD were recruited. Clinical, serological and treatment variables were recorded and serum was tested for antibodies to apolipoprotein A-1 and high-density lipoprotein. Both carotid and both femoral artery bifurcations of each patient were scanned to determine IMT, TPA and echogenicity of plaques. Univariable and multivariable statistical analyses were carried out to define factors associated with each of these outcomes. Results Thirty-six patients had carotid and/or femoral plaque. Increasing age was associated with presence of plaque and increased IMT. Triglyceride levels were associated with presence of plaque. Mean (s.d.) TPA was 60.8 (41.6) mm2. Patients taking prednisolone had higher TPA. Most plaques were echolucent, but increased echogenicity was associated with prednisolone therapy and persistent disease activity. Conclusion TPA and plaque echogenicity in patients with SLE are associated with different factors than those associated with presence of plaque and IMT. Longitudinal studies may show whether these outcome measures add value in the management of cardiovascular risk in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by multiple pathologies in which sustained inflammatory activity leads to progressive tissue destruction and organ damage. One of the main proinflammatory cytokines playing a key role in autoimmune diseases such as rheumatoid arthritis (RA) or SLE, is tumor necrosis factor (TNF) alpha.The introduction of TNF-alpha inhibitors revolutionized the treatment of RA and other conditions including psoriatic arthritis and ankylosing spodylitis. We review here the efficacy and safety of TNF-alpha blockers in SLE focussing on why it has not been more widely used since TNF-alpha was reported to be increased in SLE patients and to correlate with disease activity.We summarize the reported SLE cases that have received TNF-alpha blockers and the main results to date. We reflect on whether there is a case to reconsider the use of TNF-alpha blockade in SLE.

Background/Aims Patients with systemic lupus erythematosus (SLE) have increased mortality compared to age- and sex-matched controls. Lupus nephritis (LN) is a severe manifestation of SLE and an important cause of death. Our objective was to carry out a retrospective survival analysis to investigate factors that could influence risk of mortality and LN in a large multi-ethnic cohort of patients with SLE. Methods By careful review of medical records, we identified 496 patients with SLE for whom we had complete information regarding period of observation and occurrence of death and nephritis. Patients were stratified into groups according to sex, ethnicity (Caucasian, African/Caribbean, South Asian, East Asian, Other), age at start of follow-up (above and below median) and time-period of diagnosis (1978-89, 1990-99, 2000-5, 2006-11). Kaplan-Meier analysis was used to investigate differences between the groups in survival and LN. Results Overall, there were 454 women and 42 men. 91 patients died and 165 developed LN. Mean follow-up was 15.8 ± 8.75 years with a maximum of 40 years. Median age at start of follow-up was 28.0 ± 12.13 years. Results are shown in Table 1 There were no differences between men and women in mortality or LN. Caucasian patients were significantly less likely to develop LN (P < 0.0001) than other groups but there was no mortality difference between ethnic groups. Patients diagnosed below age 28 were more likely to develop LN (P < 0.0001) but less likely to die (P = 0.0039) than those diagnosed above age 28. Patients diagnosed between 2006 and 2011 were significantly less likely to die than those diagnosed between 1978 and1989 by Cox proportional hazards analysis of survival curves. (P = 0.019) Conclusion In this long-term survival analysis of 496 patients, non-Caucasian patients and those diagnosed below the age of 28 years were more likely to develop LN. The latter group were less likely to die than those diagnosed at older ages. Survival curves for groups of patients diagnosed in successive time periods suggested improved survival over time. Disclosure W. Luo: None. F. Farinha: None. D.A. Isenberg: None. A. Rahman: 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.

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 Chronic glucocorticoid use is complicated by osteoporosis and increases the risk of fragility fractures. EULAR guidelines on SLE management recommend reducing chronic glucocorticoid dosage to ≤7.5 mg/day to minimize this risk. We examined the relationship of glucocorticoid dose to fragility fracture risk in a cohort of SLE patients. Methods Retrospective analysis of SLE patients attending University College Hospital over 28 years was undertaken. Collected data included consecutive steroid dose, dual-energy X-ray absorptiometry scans and fragility fractures. Results We collected data on 250 patients with a median of 17 years’ follow-up. Fragility fractures were diagnosed in 28 (11.2%) patients and the mean ± s.d. age of first fracture was 51 ± 16 years. A total of 94% received glucocorticoids, the average dose being 6.20 mg/day. Patients with fragility fractures had a lower average daily dose (5.36 vs 6.23 mg/day) but a higher median cumulative dose (25.19 vs 20.96 g). These differences were not significant (P = 0.127 and 0.229, respectively). Some 93% of patients received vitamin D, and 85% received calcium. Cox regression analysis showed older age at SLE diagnosis, osteoporosis and secondary hyperparathyroidism were associated with fragility fractures. Glucocorticoid dose was not significantly associated with the occurrence of fragility fractures. Twenty-two patients with fractures were treated with bisphosphonates, two with denosumab and two with teriparatide. Conclusions We found no significant association between glucocorticoid treatment and fragility fractures in our group of patients; however, a prospective study including more patients not treated with CS would be necessary to confirm these results.

Objective To compare the ability of the American College of Rheumatology (ACR), Systemic Lupus International Collaborating Clinics (SLICC), and European League Against Rheumatism (EULAR)/ACR systemic lupus erythematosus (SLE) classification criteria sets to provide information regarding organ damage and mortality, over a 10-year follow-up period. Methods Using data from 100 patients, we completed each classification set at the time of diagnosis and recorded the SLICC/ACR Damage Index (SDI) score, renal damage, major cardiovascular events, and death, 10 years later. We reviewed the presence of other autoantibodies, linked to SLE but not included in the classification criteria sets, and assessed whether they impacted the predictive capacity of the classification sets. Results We found a statistically significant association between the EULAR/ACR set and renal damage and SDI score, the latter after adjustment for age and sex. In the patients negative for other autoantibodies, higher EULAR/ACR scores were associated with higher rates of organ damage. Conclusion These data suggest that the EULAR/ACR set may offer useful prognostic information, because higher scores were associated with higher rates of organ damage. These findings were clearer in patients negative for nondiagnostic SLE autoantibodies, who may benefit more from the predictive capacity of the EULAR/ACR set.

Objectives To characterize a LN cohort over 40 years, assessing its evolution, analysing two major outcomes: the development of end-stage renal disease and mortality rates in the first 5 years after LN diagnosis. Methods An observational retrospective study of patients with LN, followed up from 1975 at University College Hospital. Patients were divided into four groups, depending on the decade of LN diagnosis: 1975–1985 (D1), 1986–1995 (D2), 1996–2005 (D3) and 2006–2015 (D4). Comparison between groups was performed with respect to demographic, clinical, serological and histological characteristics and outcome. Results Two hundred and nineteen patients with LN were studied. There was a change in ethnic distribution, with a decreasing proportion of Caucasians (58.6% in D1 to 31.3% in D4, P = 0.018) and increase in African-ancestry (17.2% in D1 to 39.6% in D4, P = 0.040). Serological and histological patterns changed throughout time, with a reduction in class IV nephritis (51.7% in D1 to 27.1% in D4, P = 0.035), and increase in class II nephritis (10% in D2 to 18.8% in D4, P = 0.01) and anti-extractable nuclear antigen antibody positivity (17.2% in D1 to 83.3% in D4, P = 0.0001). The 5-year mortality rates decreased from D1 (24.1%) to D2 (4%), stabilizing for the next 30 years. The 5-year progression to end-stage renal disease remained stable over the decades. Conclusion Despite the changes in treatment of LN in the past 20 years, we have reached a plateau in 5-year mortality and progression to end-stage renal disease rates, suggesting that new therapeutic and management approaches, and strategies to enhance adherence, are needed to improve outcomes further in LN patients.

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.

Objectives Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. Methods In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. Results Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P Conclusion Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE.

Clarity and guidance is required with regard to the use of direct oral anticoagulants in antiphospholipid syndrome (APS) patients, within the confines of the recent European Medicines Agency recommendations, discrepant recommendations in other international guidelines and the limited evidence base. To address this, the Lupus Anticoagulant/Antiphospholipid Antibodies Scientific and Standardization Committee (SSC) chair and co-chairs together with SSC Control of Anticoagulation members propose guidance for healthcare professionals to help them manage APS patients. Uncertainty in this field will be addressed. This guidance will also serve as a call and focus for research.

Objective To characterize the systemic phenotype of primary Sjögren’s syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores. Methods The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren’s syndrome from the five continents. Results The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available. At diagnosis, the mean total ESSDAI score was 6.1; 81.8% of patients had systemic activity (ESSDAI score ≥1). Males had a higher mean ESSDAI (8.1 vs 6.0, P 65 years, P Conclusion The systemic phenotype of primary Sjögren’s syndrome is strongly influenced by personal determinants such as age, gender, ethnicity and place of residence, which are key geoepidemiological players in driving the expression of systemic disease at diagnosis.

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis, which presents a great variability in its presentation and can affect almost all organs and systems. Multiple therapeutic targets have been discovered recently, but there also have been failed attempts to treat SLE using biologic agents. Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in several types of cells of hematopoietic origin which participate in both innate and adaptive immunity. Ibrutinib, a BTK inhibitor, is approved for the treatment of several B cell malignancies, including some types of lymphoma and leukemia. As BTK is expressed on several immune cell types, the mechanism of action of BTK also suggests the use of BTK inhibitors in the treatment of autoimmune diseases. In this review, we will summarize what is known and what has been published so far about the treatment of mouse models of SLE and the human disease, using BTK inhibitors.

Objectives To compare membranous lupus nephritis (MLN) and proliferative lupus nephritis (PLN) with respect to survival, demographic, clinical and laboratory characteristics; and to investigate predictors of renal and patient survival. Methods Single-centre retrospective observational study. Patients with biopsy-proven PLN, MLN and mixed lupus nephritis were included. Groups were compared using appropriate statistical tests and survival was analysed through the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of renal and patient survival. Results A total of 187 patients with biopsy-proven lupus nephritis (135 with PLN, 38 with MLN and 14 with mixed LN) were followed for up to 42 years (median 12 years). There was a higher proportion of MLN amongst Afro-Caribbeans than amongst Caucasians (31% vs 15%, P = 0.010). Patients with MLN had significantly lower anti-dsDNA antibodies (P = 0.001) and higher C3 levels (P = 0.018) at diagnosis. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75 and 66% for PLN and 100, 97, 92 and 84% for MLN, respectively (P = 0.028). Cumulative patient survival at 5, 10, 15 and 20 years was 94, 86, 80 and 76%, with no difference between PLN and MLN. Urinary protein-creatinine ratio above 42 mg/mmol and eGFR below 76 ml/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to end-stage renal disease. eGFR below 77 ml/min/1.73 m2, at one year, development of end-stage renal disease and Afro-Caribbean ethnicity were associated with higher mortality. Conclusion Patients with MLN and PLN differ significantly regarding serological profiles and renal survival, suggesting different pathogenesis. Renal function at year one predicts renal and patient survival.

Mixed connective tissue disease was first described as a new autoimmune rheumatic disease in 1972 based on the claim of a distinct clinical picture associated with anti-RNP antibody positivity. Subsequently, this new entity has divided opinions in the rheumatology community. We have reviewed recent cohort studies with more than 100 patients, comparing the clinical and immunological features, treatment, prognosis and evolution to well-defined autoimmune rheumatic diseases. We also reviewed clinical features of undifferentiated autoimmune rheumatic diseases based on the most recent studies. After gathering and reviewing these data, we discuss whether the designation “mixed connective tissue disease” should be maintained.

Summary Background Primary Sjogren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjogren's syndrome have shown efficacy. CD40–CD154-mediated T cell–B cell interactions in primary Sjogren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjogren's syndrome. Methods This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18–75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjogren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjogren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov , NCT02291029 . Findings Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96–9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. Interpretation To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjogren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40–CD154 interactions in primary Sjogren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. Funding Novartis Pharma.

Systemic lupus erythematosus (SLE) is a remarkable condition characterised by diversity amongst its clinical features and immunological abnormalities. In this review, we attempt to capture the major immunological changes linked to the pathophysiology of lupus and discuss the challenge it presents in moving towards the concept of precision medicine. Currently broadly similar types of drugs, e.g., steroids, immunosuppressives, hydroxychloroquine are used to treat many of the diverse clinical features of SLE. We suspect that, as the precise immunopathological abnormalities differ between the various organs/systems in lupus patients, it will be some time before precision medicine can be fully applied to SLE.

Objective Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Methods Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment Results Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. Conclusion At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

To determine whether early damage and its kinetics measured by the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality.We carried out a single-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria), using the DIAPS for damage assessment. Early damage was considered to be at six months after disease onset; early damage increase (delta-DIAPS) was deemed to be at least a one-point rise in DIAPS within the first five years of illness. Groups were compared using appropriate statistical tests. Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality.A total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) were followed for up to 43 years (median 10). Damage developed in 143 (73.6%) patients. Twenty-three patients (12%) died. Secondary APS (HR 3.07, 95%CI 1.32-7.12, p=0.009), male sex (HR 3.14, 95%CI 1.35-7.33, p=0.008) and age at APS onset ≥40 years (HR 5.34, 95%CI 1.96-14.53, p=0.001) were risk factors for death. Early damage (n=69, 35.0%) was not associated with death (p=0.231). Having a first arterial event was associated with early damage (p0.001), but not with delta-DIAPS (p=0.539) nor with the risk of death (p=0.151). Delta-DIAPS (n=53/181, 29.3%) predicted mortality (HR 5.40, 95%CI 2.33-12.52, p0.001), even after adjusting individually for APS category (secondary), sex (male), early damage and age at APS onset (≥40 years) (all p0.005).Evolving damage in the first five years of illness, but not early damage, predicted mortality regardless of the nature of the first thrombotic event, sex, APS category and age.

Objectives Patients with SLE have increased mortality compared with age- and sex-matched controls. LN is a severe manifestation of SLE and an important cause of death. We carried out a retrospective survival analysis to investigate factors that could influence the risk of mortality and LN in a large multi-ethnic cohort of patients with SLE. Methods By careful review of medical records, we identified 496 patients with SLE for whom we had complete information regarding the period of observation and occurrence of death and nephritis. Patients were stratified into groups according to sex, ethnicity, age at start of follow-up and time period of diagnosis. Kaplan–Meier analysis was used to investigate differences between the groups. Results Of the 496 patients in the study, 91 (18.3%) died, 165 (33.3%) developed LN and 33 (6.7%) developed end-stage renal failure. There was no difference between men and women in either mortality or development of LN. Caucasian patients were significantly less likely to develop LN than other ethnic groups (P Conclusion In our cohort, non-Caucasian ethnicity and younger age at diagnosis are associated with the risk of developing LN. There is evidence of improvement in survival of patients with SLE over time.