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Objective In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting. Methods Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0–34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3–151.2). Results We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7–22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046). Conclusion Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.

Objectives In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. Methods Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3–26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. Results Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8–178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. Conclusion Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

ObjectivePatients with SLE have increased risk of myocardial infarction (MI). Few studies have investigated the characteristics of SLE-related MIs. We compared characteristics of and risk factors for MI between SLE patients with MI (MI-SLE), MI patients without SLE (MI-non-SLE) and SLE patients without MI (non-MI-SLE) to understand underlying mechanisms.MethodsWe identified patients with a first-time MI in the Karolinska SLE cohort. These patients were individually matched for age and gender with MI-non-SLE and non-MI-SLE controls in a ratio of 1:1:1. Retrospective medical file review was performed. Paired statistics were used as appropriate.ResultsThirty-four MI-SLE patients (88% females) with a median age of 61 years were included. These patients had increased number of coronary arteries involved (p=0.04), and ≥50% coronary atherosclerosis/occlusion was numerically more common compared with MI-non-SLE controls (88% vs 66%; p=0.07). The left anterior descending artery was most commonly involved (73% vs 59%; p=0.11) and decreased (ConclusionIn the great majority of cases, MIs in SLE are associated with coronary atherosclerosis. Furthermore, MIs in SLE are commonly preceded by symptomatic vascular disease, calling for attentive surveillance of cardiovascular disease and its risk factors and early atheroprotective treatment.

Background Febrile neutropenia is generally recognised as a complication of myelosuppressive chemotherapy. Recombinant human granulocyte colony stimulating factor (G-CSF) is commonly used as a primary or secondary prophylaxis to reduce the degree and duration of neutropenia in patients at risk of developing chemotherapy-induced neutropenic fever and infectious complications. G-CSF is known to decrease mortality and increase the possibility of maintaining adequate chemotherapy dose intensity and density, which is essential in curable malignancies. Common side effects are generally mild. However, potentially fatal adverse events have also been reported. Case presentation Herein, we summarise previously reported and report two new independent cases of G-CSF-induced aortitis, both in patients treated with chemotherapy for breast cancer. The two cases, identified only a few months apart, share several common characteristics including type of cancer, gender, age, chemotherapy, G-CSF treatment regimen, and time span from G-CSF initiation to aortitis manifestation. The two cases were both diagnosed by CT scan and successfully treated with corticosteroids along with discontinuation of G-CSF. Conclusion This case report highlights that although aortitis is a rare adverse event of G-CSF treatment, it should be considered in cases of unexplained fever and/or clinical and laboratory findings that do not respond to antibiotics.

Objective: Accumulating evidence supports an impaired health-related quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE). We investigated the effects of 2 biologic treatments on HRQoL of patients with SLE. Methods: Patients with SLE from the Karolinska University Hospital treated with belimumab (n = 34) or rituximab (n = 35) were included; normative values derived from Swedish population-based controls matched for age and sex were used for the purpose of comparisons. Data were collected prospectively at treatment initiation and at months 3, 6, 12, and 24, using the Short Form 36 (SF-36) health questionnaire, the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) scale, the EuroQol 5-dimension (EQ-5D) instrument, and the Stanford Health Assessment Questionnaire disability index (HAQ DI). Results: Substantial decrements from Swedish norms were observed across all SF-36 domains at baseline. Patients treated with belimumab reported gradual improvements in the SF-36 physical component summary (significant from month 12; P = 0.023) and FACIT-Fatigue (significant by month 24; P = 0.001), no changes in EQ-5D scores, and improvements in HAQ DI by month 6 (P = 0.014). Patients treated with rituximab showed rapid improvements in the SF-36 mental component summary and FACIT-Fatigue by month 3 (P = 0.031 and P = 0.007, respectively), as well as improvements in EQ-5D at month 6 (P = 0.016) and HAQ DI at month 3 (P = 0.033). Based on baseline evaluations, patients receiving antimalarial agents (n = 33) performed better in the SF-36 social functioning (P = 0.022) and mental health (P = 0.023) domains compared to patients who did not receive antimalarial agents (n = 36). Conclusion: Our results corroborated previous findings of considerable HRQoL impairments in patients with SLE. Patients' perceptions of HRQoL showed discrepant patterns over time in the 2 treatment groups and could provide additional information along with the clinical evaluation of biologic therapy in SLE. Further survey on the effects of antimalarial agents on the HRQoL of patients with SLE in larger cohorts is merited.

Summary Background The Definitions Of Remission In Systemic Lupus Erythematosus (DORIS) international task force has proposed remission definitions that are amenable to scientific testing. In this study, we aimed to evaluate their suitability as outcome measures in studies of systemic lupus erythematosus. Methods In this post-hoc study, we applied remission definitions as specified by DORIS criteria at multiple timepoints in the BLISS-52 (n=865) and BLISS-76 (n=819) clinical trials. All definitions required physician's global assessment scores less than 0·5 (possible range 0–3). The DORIS 1 definitions required clinical systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K)=0 (with serological items excluded). The DORIS 2 definitions required a score of D or E in all British Isles Lupus Assessment Group (BILAG) domains. The definitions were assessed in the trial populations both with (on therapy) and without (off therapy) treatment allowance—ie, low-dose glucocorticoids (prednisone ≤5 mg/day) and maintenance immunosuppressive and biological agents. Antimalarial agents were allowed in all definitions. The definitions were applied irrespective of serological activity (anti-double stranded DNA positivity, or low C3 or C4) and with normal serology. Finally, we applied modifications similar to DORIS on therapy but allowing higher prednisone doses (≤10 mg/day). Findings In the pooled dataset, the remission definition most frequently attained was the modified (prednisone ≤10 mg/day) DORIS 1a on therapy definition, which required a SLEDAI-2K score of 0 and permitted serological activity (237 [17·8%] of 1333 participants at week 52), followed by the unmodified (predisone ≤5 mg/day) DORIS 1 on therapy definition (140 [10·5%] of 1336 participants at week 52) based on these two definitions. We detected no significant difference between the placebo and belimumab groups. Proportions of patients achieving off therapy and BILAG-based definitions were low (≤0·9% at all timepoints). Sustained attainment of certain on therapy definitions showed an ability to discriminate between patients who received belimumab 10 mg/kg and patients who received placebo. Interpretation Attainment of DORIS remission definitions was infrequent overall. Use of clinical SLEDAI-2K=0 in the definitions yielded higher proportions of attainment than did use of BILAG D or E. Attainment was also higher using definitions that allowed for serological activity and maintenance treatment. Addition of the durability aspect to on therapy definitions led to an ability to discriminate between belimumab and placebo. Funding Swedish Rheumatism Association, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and Karolinska Institutet Foundations.

The coronavirus disease-2019 (COVID-19) pandemic continues to be a cause of unprecedented global morbidity and mortality. Whilst COVID-19 vaccination has emerged as the only tangible solution to reducing poor clinical outcomes, vaccine hesitancy continues to be an obstacle to achieving high levels of vaccine uptake. This represents particular risk to patients with autoimmune diseases, a group already at increased risk of hospitalization and poor clinical outcomes related to COVID-19 infection. Whilst there is a paucity of long-term safety and efficacy data of COVID-19 vaccination in patients with autoimmune diseases, the current evidence strongly suggests that the benefits of vaccination outweigh the risks of adverse effects and disease flares. Herein, we report the protocol of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study, an ongoing international collaborative study involving 29 countries and over 110 investigators. Supplementary Information The online version contains supplementary material available at 10.1007/s00296-021-05046-4.

Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum B-cell activating factor (BAFF) with immunogenicity after 6 months of TNFi treatment. A total of 127 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association. At 6 months, 31 patients (24%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value = 5.30; p = 0.02); therefore, subsequent results were stratified according to mean age (≤ / > 55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR = 1.51; 95% CI 1.03–2.21). Baseline serum BAFF ≥ 1034 pg/mL predicted the presence of ADA at 6 months (AUC = 0.81; 95% confidence interval (CI) 0.69–0.93; p = 0.001; positive likelihood ratio = 3.7). In conclusion, our results suggest that the association of BAFF concentration and immunogenicity depends on the patient’s age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.

Objectives The objectives of this study were to investigate the discriminative ability of EQ-5D-3L full health state (FHS) in clinical trials of SLE, and to identify factors associated with FHS after treatment. Methods Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials of belimumab (N = 1684) were utilized. FHS was defined as a response of no problems in all five EQ-5D-3L dimensions, yielding an index score of 1. The Pearson’s χ2 or Fisher’s exact test was employed for comparisons, and logistic regression for adjustments and assessment of independence. Results We demonstrated higher EQ-5D-3L FHS frequencies among patients given standard therapy (ST) plus the licensed belimumab dose vs ST alone (26.1% vs 19.4%; P = 0.001; week 52), and within SRI-4 responders vs non-responders (27.0% vs 19.8%; P < 0.001; week 52) from weeks 36 to 52. In multivariable regression analysis, SLEDAI-2K (OR: 0.90; 95% CI: 0.87, 0.94; P < 0.001) and SLICC/ACR Damage Index (OR: 0.79; 95% CI: 0.69, 0.91; P = 0.001) scores were independently associated with lower FHS frequencies at week 52, while adding monthly infusions of belimumab 10 mg/kg to ST favoured FHS perception (OR: 1.60; 95% CI: 1.15, 2.24; P = 0.006). Add-on belimumab 10 mg/kg yielded higher FHS frequencies in antimalarial users vs non-users (29.9% vs 20.1%; P = 0.011), and in anti-dsDNA- and anti-Sm- positive vs negative patients (31.4% vs 13.4%; P < 0.001 and 33.0% vs 22.6%; P = 0.010, respectively), whereas no significant differences were observed in patients given ST alone. Conclusion EQ-5D-3L FHS distinguished belimumab from placebo and responders from non-responders, and exhibited known-group validity in subgroup analysis. FHS may prove a useful patient-reported outcome in SLE studies.

Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, Objective: To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria 1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Objectives Associations between BMI and health-related quality of life (HRQoL) in SLE have been implied, but data are scarce. We determined the impact of overweight and obesity on HRQoL in a large SLE population. Methods We pooled cross-sectional baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N = 1684). HRQoL was evaluated using the 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and the European Quality of Life 5-dimension questionnaire (EQ-5D). Comparisons between BMI groups were conducted using the Mann–Whitney U test and adjustments using linear regression. Clinical relevance was determined by minimal clinically important differences (MCIDs). Results In total, 43.2% of the patients had BMI above normal and 17.4% were obese. Overweight and obese patients reported worse SF-36 physical component summary (PCS), physical functioning, role physical, bodily pain and FACIT-Fatigue scores than normal weight patients. Divergences were greater than corresponding MCIDs and more prominent with increasing BMI. Despite no clinically important difference in SF-36 mental component summary scores across BMI categories, patients experienced progressively diminished vitality and social functioning with increasing BMI. In linear regression analysis, BMI above normal and obesity were associated with worse PCS (standardized coefficient β = −0.10, P Conclusion Patients with SLE and BMI above normal experienced clinically important HRQoL diminutions in physical aspects, fatigue and social functioning. A survey of potential causality underlying this association is warranted.

Background Patients with Systemic Lupus Erythematosus (SLE) suffer an impaired health-related quality of life (HRQoL), and the majority of them experience fatigue as a major problem. Traditionally, treatment of SLE has been symptomatic, and antimalarial agents (AMA) are considered a cornerstone of SLE treatment. In previous literature, results regarding the effect of AMA on HRQoL have been conflicting. In this study, we aimed at investigating the potential influence of AMA on SLE patients’ self-perception of HRQoL aspects. Methods We utilised pooled baseline data from the BLISS-52 and BLISS-76 clinical trials of belimumab (N=1684). Access to data was granted by GlaxoSmithKline. The patients’ HRQoL and fatigue were self-reported using the Medical Outcomes Study short form 36 (SF-36) health survey, the functional assessment of chronic illness therapy (FACIT)-Fatigue scale and the three-level EuroQol 5 Dimension (EQ-5D) questionnaire. Minimal clinically important difference (MCID) was set to ≥5.0 points for SF-36 subscales, ≥2.5 points for SF-36 component summary scores, and ≥4 points for FACIT-Fatigue scores. The Mann-Whitney U test was used for comparisons. Linear regression models were next used to adjust for possible confounding factors; these included age, sex, ethnic origin, disease activity and duration, organ damage, corticosteroid use and use of immunosuppressants. Results Patients receiving AMA (N=1098) performed better than patients who did not receive AMA (N=586) with regard to SF-36 physical component summary score, physical functioning, role physical, bodily pain, FACIT-Fatigue scores, EQ-5D score and EQ-5D visual analogue scale score. The difference in SF-36 physical functioning was the greatest one among the SF-36 parameters, exceeding the corresponding MCID. The association between AMA use and better physical functioning was still significant after adjustment for potential confounding factors (β=0.08; P=0.001). In this analysis, Asian patients performed better in physical functioning (β=0.07; P=0.004) while African/African American patients performed worse (β=-0.07; P=0.003). High disease activity (β=-0.09; P Conclusions AMA use is associated with favourable physical functioning in patients with SLE, independently of other factors.

Background Belimumab is approved for the treatment of systemic lupus erythematosus (SLE) since 2011. We investigated whether belimumab treatment impacts on levels of cytokines and autoantibodies of interest in SLE, as well as circulating immune complexes (ICs). Methods Longitudinally collected serum samples from 78 belimumab-treated SLE patients from the Karolinska, Skane and Linkoping University Hospitals were analysed. Serum cytokine levels and nuclear antigen autoantibody specificities were determined using addressable laser bead immunoassay, and circulating C1q-binding ICs were measured using enzyme-linked immunosorbent assay. Results In patients with detectable levels at baseline, serum IFN-α2 levels were lower at month 6 (median: 8.9; IQR: 1.5–54.9 pg/mL) versus baseline (median: 28.4; IQR: 20.9–100.3 pg/mL; P=0.043). IL-6 levels decreased from baseline (median: 7.1; IQR: 2.9–16.1 pg/mL) to month 6 (median: 0.5; IQR: 0.5–6.3 pg/mL; P=0.018) and throughout the 24-month follow-up. Levels of IL-10 (baseline median: 12.6; IQR: 2.8–29.7 pg/mL) showed more rapid decreases from month 3 (median: 1.8; IQR: 0.6–9.1 pg/mL; P=0.003). Levels of anti-dsDNA (P Conclusions In our cohort, belimumab treatment lowered IFN-α2, IL-6, IL-10 and circulating IC levels, as well as levels of multiple autoantibodies against nuclear components. Interestingly, anti-Sm antibody positivity was associated with favourable treatment response.

Background Patients with Systemic Lupus Erythematosus (SLE) are at increased risk of premature mortality due to myocardial infarction (MI). The underlying mechanisms are not fully understood. This study aims to generate new hypothesizes on these mechanisms through description of MI subtypes and locations and by identifying risk factors for MI. Methods We identified 35 SLE patients with and a first-time non-procedural MI (MI-SLE). We matched these 35 MI-SLE patients to 35 patients with MI but not SLE (MI-nonSLE) and 35 patients with SLE but not MI (nonMI-SLE) for gender, age and geographical location. Patients and controls were matched individually (1:1:1). Detailed retrospective medical file review was performed. Results Median age was 62 years and 89% were female in all groups. Prevalence of ST-elevation MI was similar in MI-SLE patients and MI-nonSLE patients (27% vs 36%; p=0.80). The left ventricle was the most commonly infarcted in both MI-SLE and MI-nonSLE - 77% vs 59% according to coronary angiography and 42% vs 55% according to echocardiography. The left ventricular ejection fraction was similar in MI-SLE and MI-nonSLE patients (p=0.62). MI with coronary atherosclerosis was trends wise more common in MI-SLE patients compared to MI-nonSLE patients (88% vs 66%; p=0.065). Previous cardiovascular disease (43%, 5.7%, 14%; p Conclusion Coronary atherosclerosis was present in a large majority of MI-SLE patients at the event of MI. In addition, coronary artery disease preceding MI was more prevalent in SLE patients than in the general population, indicating accelerated coronary atherosclerosis as a cause of increased MI prevalence in SLE. Among SLE patients, low albumin levels were a risk factor for MI.

Background In patients with Lupus Nephritis (LN), clinical response to treatment and renal histopathology have been shown to be discordant. We investigated whether per-protocol repeat renal biopsies are predictive of LN relapses and long-term impairment of renal function. Methods Forty-two patients with an incident biopsy-proven active proliferative (class III/IV ± V) LN from the LN database of the Universite catholique de Louvain were included in the present retrospective study. Per-protocol repeat kidney biopsies were performed in all patients after a median time of 24.3 (IQR: 21.3–26.2) months. The NIH activity index (AI) and chronicity index (CI) scores were assessed in both baseline and repeat biopsies. Results Despite a moderate correlation between urinary protein/creatinine (U-P/C) ratios and AI scores at repeat biopsy (r=0.48; P=0.001), ten patients (23.8%) with U-P/C ratios 3; figure 1). High AI scores in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (N=11) following the repeat biopsy (HR: 1.2; 95% CI: 1.1–1.3; P=0.007), independently of proteinuria levels. High NIH CI scores in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR: 1.8; 95% CI: 1.1–2.9; P=0.016) through a median follow-up time of 131.5 (IQR: 73.8–178.2) months. Baseline AI/CI scores were not predictive of these outcomes. Conclusions Our results highlight the usefulness of per-protocol repeat biopsies as an integral part of the treatment evaluation, also in patients who have shown adequate clinical response.

Background Standard-of-care (SoC) for systemic lupus erythematosus (SLE) includes use of glucocorticoids, antimalarials, immunosuppressive agents and biologics. Selection of drug(s) for each unique patient is mainly based on the severity of afflicted organ system(s), the global disease activity, and serological status (i.e. anti-dsDNA and complement levels). Development of lupus nephritis (LN) during treatment with belimumab, an inhibitor of soluble B cell activating factor (BAFF), has previously been reported.1,2 This observational follow-up study, utilising data from several university centers, aimed to evaluate the real-life frequency of LN during belimumab treatment. Methods At the Swedish university centers in Linkoping, Lund, Stockholm and Uppsala, as well as in Leeds, UK, all patients who received belimumab from 2011 until 2018 (N=95; 52% anti-dsDNA positive, 60% low complement) were followed longitudinally in regional observational study programmes (median follow up: 13 months). In cases of a suspected incident LN or LN relapse/worsening, renal biopsy was performed. As a comparator, non-renal SLE cases not exposed to belimumab (N=107; 40% anti-dsDNA positive, 47% low complement) were encompassed; these patients were followed for a median time of 132 months and incident LN cases were registered. Total follow-up and time to LN was calculated for each group and was utilised in Cox regression analysis. Results We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 were class III or IV) in the non-renal SLE belimumab-treated group after a median follow-up time of 7.4 (IQR: 2.7–22.2) months, and 2/29 cases (6.9%) of LN relapse after 1 and 9 months in the belimumab-treated group with historical but quiescent LN at treatment initiation. In the comparator group, 2/107 cases (1.9%) of de novo LN (1 class III, 1 class IV) were observed after 21 and 50 months. Cox regression analysis revealed increased risk and/or shorter time to de novo LN in non-renal patients who received belimumab compared with non-renal SLE comparators (HR: 17.4; 95% CI: 2.7–110.8; P=0.002). A Kaplan-Meier graph is attached. Conclusions This observational study indicates that addition of belimumab to SoC may not prevent LN among patients with ongoing non-renal SLE disease activity. Selection of cases suitable for belimumab based on serological activity could be troublesome as these patients may be at high risk of developing LN.3 The effects of BAFF inhibition on different lymphocyte subsets which may contribute to LN susceptibility have yet to be explored. Identification of predictors of LN development among belimumab-treated patients is merited. References Sjowall C, Coster L. Belimumab may not prevent lupus nephritis in serologically active patients with ongoing non-renal disease activity. Scand J Rheumatol 2014;43:428–30. Staveri C, Karokis D, Liossis SC. New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab. Semin Arthritis Rheum 2017;46:788–790. van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012;71:1343–49.

Background:Patients with systemic lupus erythematosus (SLE) experience a considerably impaired health-related quality of life (HRQoL) compared with the general population. Previous literature has implied an association between high body mass index (BMI) and HRQoL diminutions. However, data are scarce and further exploration in large study populations and, importantly, with regard to the clinical significance of this association is needed.Objectives:The aim of this study was to determine whether overweight and/or obesity were associated with impaired physical and/or mental HRQoL aspects in the SLE population of two large clinical trials.Methods:We utilised pooled baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) clinical trials of belimumab (N=1684). Access to data was granted by GlaxoSmithKline. The patients were stratified into four groups based on their body mass index (BMI), according to WHO guidelines. We conducted comparisons between non-overweight versus overweight, and non-obese versus obese SLE patients. HRQoL was self-reported using the Medical Outcomes Study (MOS) short form 36 (SF-36) health survey, the functional assessment of chronic illness therapy (FACIT)-Fatigue scale and the three-level EuroQol- 5 Dimension (EQ-5D) questionnaire. We explored whether the differences in scores were clinically meaningful using previously determined thresholds for minimal clinically important differences (MCIDs). The non-parametric Mann-Whitney U test was used for comparisons between different BMI groups. Linear regression analysis was next applied to test independence in multivariable models, adjusting for age, sex, ethnicity, disease duration, disease activity, organ damage and standard of care treatment.Results:Forty-four per cent (44%) of the patients had a BMI score over the normal range, and 18% were obese. The overweight group performed worse than the non-overweight with regard to FACIT-Fatigue scores (mean ± standard deviation: 27.7 ± 12.1 vs 32.0 ± 11.3; PIn multivariable linear regression analysis, the overweight and obese group showed worse PCS scores (standardised coefficient: β=-0.09; PConclusion:BMI above normal was highly associated with HRQoL impairment, especially in physical aspects. Further survey to examine causality is warranted to support structured weight control strategies as an intervention towards a more favourable HRQoL.Disclosure of Interests:None declared

Background: Patients with systemic lupus erythematosus (SLE) suffer an impaired health-related quality of life (HRQoL), and the majority of them experience fatigue as a major problem. Traditionally, treatment of SLE has been symptomatic, and antimalarial agents (AMA) are considered a cornerstone of SLE treatment. In previous literature, results regarding the effect of antimalarial agents on HRQoL have been conflicting. Objectives: In this study, we aimed at investigating the potential influence of AMA on SLE patients’ self-perception of HRQoL aspects. Methods: We utilised pooled baseline data from the BLISS-52 and BLISS-76 clinical trials of belimumab (n=1684). Access to data was granted by GlaxoSmithKline. The patients’ HRQoL and fatigue were self-reported using the Medical Outcomes Study (MOS) short form 36 (SF-36) health survey, the functional assessment of chronic illness therapy (FACIT)-Fatigue scale and the three-level EuroQol- 5 Dimension (EQ-5D) questionnaire. Minimal clinically important difference (MCID) was set to ≥5.0 points for SF-36 subscales, ≥2.5 points for SF-36 component summary scores, and ≥4 points for FACIT-Fatigue scores. High disease activity was defined as a SELENA-SLEDAI score ≥10. Organ damage was assessed using the SLICC/ACR Damage Index (SDI). The non-parametric Mann-Whitney U test was used for comparisons between AMA users and non-users. Linear regression models were next used in order to adjust for possible confounding factors; these included age, sex, ethnic origin, SLE disease activity, SLE duration, organ damage, corticosteroid use and use of other immunosuppressive agents. Results: Results are presented as mean values ± standard devation. Patients receiving AMA (n=1098) performed better than patients who did not receive AMA (n=586) with regard to SF-36 physical component summary (PCS) scores (39.6 ± 9.5 versus 38.1 ± 9.9; P=0.001), physical functioning (61.1 ± 24.9 versus 55.0 ± 26.5; P Conclusion: AMA use contributes to better physical functioning in patients with SLE, independently of other factors. Acknowledgement: The authors would like to thank GlaxoSmithKline (Uxbridge, UK) for granting access to the data from the BLISS-52 and BLISS-76 trials (ClinicalTrials.gov identifiers NCT00424476 and NCT00410384, respectively) through the Clinical Study Data Request (CSDR) consortium. Disclosure of Interests: None declared

Recently, two different studies1 2 applied the criteria of the Lupus Low Disease Activity State (LLDAS)3 to the data sets of the BLISS-524 and BLISS-765 phase III trials of belimumab. The studies reported similar LLDAS attainment frequencies at key time points; however, not identical. We herein discuss possible explanations in order to guide future usage of the LLDAS. In the study by Parodis et al ,1 LLDAS at week 52 was achieved by 10.0% of the patients in BLISS-52 and 7.1% in BLISS-76, with a greater percentage within patients who received belimumab 10 mg/kg compared with patients who received placebo in BLISS-52 (11.9% vs 6.2%; p=0.030), but not in BLISS-76 (8.3% vs 6.4%; p=0.473). In the study by Oon et al ,2 LLDAS at week 52 was attained by 12.5% and 14.4% in the belimumab 10 mg/kg arm versus 5.8% and 7.8% in the placebo arm in BLISS-52 (p=0.02) and BLISS-76 (p=0.04), respectively. The small-scale differences …

Background Patients with systemic lupus erythematosus (SLE) suffer an impaired health-related quality of life (HRQoL), and the majority of them experience fatigue as a major problem. Traditionally, treatment of SLE has been symptomatic, and antimalarial agents (AMA) are considered a cornerstone of SLE treatment. In previous literature, results regarding the effect of antimalarial agents on HRQoL have been conflicting. In this study, we aimed at investigating the potential influence of AMA on SLE patients self-perception of HRQoL aspects. Methods We utilised pooled baseline data from the BLISS-52 and BLISS-76 clinical trials of belimumab (n=1684). Access to data was granted by GlaxoSmithKline. The patients HRQoL and fatigue were self-reported using the Medical Outcomes Study (MOS) short form 36 (SF-36) health survey, the functional assessment of chronic illness therapy (FACIT)-Fatigue scale and the three-level EuroQol- 5 Dimension (EQ-5D) questionnaire. The non-parametric Mann-Whitney U test was used for comparisons between AMA users and non-users. Linear regression models were next used in order to adjust for possible confounding factors; these included age, sex, ethnic origin, SLE disease activity, SLE duration, organ damage, corticosteroid use and use of other immunosuppressants. Results Patients receiving AMA performed better than patients who did not receive AMA with regard to SF-36 physical component summary (PCS) scores (p=0.001), physical functioning (p Conclusions AMA use contributes to better physical functioning in patients with SLE, independently of other factors. Funding Source(s): The study was supported by grants from the Swedish Research Council, Professor Nanna Svartz Foundation (2017–00213), Swedish Rheumatism Association, King Gustaf Vs 80 year Foundation, Ingegerd Johanssons Fund, Stockholm County Council and Karolinska Institutet Foundations.

Background:Myocardial infarction (MI) is estimated to be 2- to 3-fold elevated in systemic lupus erythematosus (SLE) as compared to gender- and age-matched controls (1-2). Even though some risk factors have been purposed, mechanisms of increased MI incidence remains to be determined.Objectives:To explore underlying mechanisms, we compared MI characteristics and risk factors between SLE patients with MI (MI-SLE), MI patients without SLE (MI-nonSLE) and SLE patients without MI (nonMI-SLE).Methods:We performed retrospective medical file review including angiography and echocardiography reports in 34 MI-SLE patients, 34 MI-nonSLE patients and 34 nonMI-SLE patients – all individually matched for gender and age in a ratio of 1:1:1.Results:Median age was 61 years and 88% were females. MI-SLE patients had more coronary arteries involved (table 1; p=0.038), and ≥50% coronary atherosclerosis/occlusion at MI was numerically more common compared to MI-nonSLE controls (88% versus 66%; p=0.065). The left anterior descending artery was most frequently involved in both MI groups (73% versus 59%; p=0.11). Decreased (Conclusion:We demonstrate that non-procedural MIs in SLE are in 88% of cases associated with significant coronary atherosclerosis. Increased prevalence of CAD prior MI and higher number of coronary arteries involved at MI, suggest accelerated coronary atherosclerosis in SLE patients. This calls for attentive surveillance of CVD and early atheroprotective treatment in this patients group.References:[1]Hak AE et al. Systemic lupus erythematosus and the risk of cardiovascular disease: Results from the nurses’ health study. Arthritis and rheumatism 2009;61:1396-402.[2]Fischer LM et. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction. The American journal of cardiology 2004;93:198-200.Table 1.MI characteristicsMI-SLENtotalMI-nonSLENtotalP-valueECG findingsNSTEMI23 (72%)3221 (66%)321.0 STEMIPresence of atherosclerosis9 (28%)3211 (34%)32 0-VD3 (12%)2610 (35%)290.065 MI-CAD (≥1-VD)Number of involved arteries23 (88%)2619 (66%)29 0-VD3 (12%)2610 (35%)290.038 1-VD13 (50%)269 (31%)29 ≥2-VD10 (39%)2610 (35%)29Involvement of specific arteriesLMCA3 (12%)260 (0%)290.50 LAD19 (73%)2617 (59%)290.11 RCA7 (27%)269 (31%)290.75 Cx6 (23%)266 (21%)291.0Left ventricular ejection fraction 13 (45%)2912 (36%)330.79 ≥50%16 (55%)2921 (64%)330-VD = 0-Vessel disease. 1-VD = 1-Vessel disease. 2-VD = 2-Vessel disease. Cx = Circumflex artery. LAD = Left anterior descending artery. LMCA = Left main coronary artery. MI-CAD = MI with coronary artery disease. NSTEMI = Non-ST-elevation MI. RCA = Right coronary artery. STEMI = ST-elevation MI.Disclosure of Interests:Isak Samuelsson: None declared, Ioannis Parodis Grant/research support from: The author declare that he has no conflict of interest related to this work, Iva Gunnarsson Grant/research support from: The author declare that she has no conflict of interest related to this work, Agneta Zickert: None declared, Claes Hofman-Bang: None declared, Håkan Wallén Grant/research support from: The author declare that he has no conflict of interest related to this work, Elisabet Svenungsson Grant/research support from: The author declare that she has no conflict of interest related to this work

Background:In patients with lupus nephritis (LN), clinical response to treatment and renal histopathology have been shown to be discordant. No clinical or laboratory markers have to date been shown to reliably portend renal prognosis, in particular renal function impairment.Objectives:To investigate whether per-protocol repeat renal biopsies are predictive of LN relapses and long-term impairment of renal function.Methods:Forty-two patients with an incident biopsy-proven active proliferative (class III/IV ± V) LN from the LN database of the Université catholique de Louvain were included in the present retrospective study. Per-protocol repeat kidney biopsies were performed in all patients after a median time of 24.3 (IQR: 21.3–26.2) months. The NIH activity index (AI) and chronicity index (CI) scores were assessed in both baseline and repeat biopsies. We defined acute glomerular lesions as cellular proliferation, fibrinoid necrosis or karyorrhexis, cellular crescents, hyaline thrombi or wire loops, and leucocyte infiltration, and chronic glomerular lesions as glomerular sclerosis and fibrous crescents, in alignment with the NIH activity and chronicity indices. Similarly, we defined acute tubulointerstitial lesions as mononuclear cell infiltration and chronic tubulointerstitial lesions as interstitial fibrosis and tubular atrophy.Results:Despite a moderate correlation between urinary protein/creatinine (U-P/C) ratios and AI scores at repeat biopsy (r=0.48; P=0.001), ten patients (23.8%) with U-P/C ratios 3). High AI scores in repeat (but not baseline) kidney biopsies were associated with an increased probability and/or shorter time to renal relapse (N=11) following the repeat biopsy (HR: 1.2; 95% CI: 1.1–1.3; P=0.007), independently of proteinuria levels. This association remained significant for the NIH activity index items within the glomerular but not the tubulointerstitial compartment of the kidney biopsies. High NIH CI scores in repeat (but not baseline) kidney biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR: 1.8; 95% CI: 1.1–2.9; P=0.016) through a median follow-up time of 131.5 (IQR: 73.8–178.2) months, being the case also for acute and chronic tubulointerstitial lesions in repeat but not baseline kidney biopsies.Conclusion:Our results highlight the usefulness of per-protocol repeat biopsies as an integral part of the treatment evaluation, also in patients who have shown adequate clinical response. Glomerular lesions consistent with active renal disease portend LN relapses, while tubulointerstitial lesions consistent with active disease and chronic damage portent long-term renal function impairment.Disclosure of Interests:Ioannis Parodis: None declared, Christina Adamichou: None declared, Selda Aydin: None declared, Alvaro Gomez: None declared, Nathalie Demoulin: None declared, Julia Weinmann-Menke: None declared, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Farah Tamirou: None declared

Background Accumulating evidence supports an impaired health-related quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE). The impact of modern therapeutic interventions on patients‘ perception of HRQoL has not been explored in depth. Objectives The aim of this study was to investigate the effects of two biologic treatments – belimumab and rituximab – on SLE patients’ HRQoL, fatigue and functional ability. Methods Patients with SLE from the Karolinska University Hospital treated with either belimumab (n=34) or rituximab (n=35) were included. Data were collected prospectively at treatment initiation and at months 3, 6, 12 and 24; these included the Medical Outcome Study short form-36 (SF-36) version 2, functional assessment of chronic illness therapy (FACIT)-Fatigue scale version 4, EuroQol research foundation 5-dimension (EQ-5D) health questionnaire, and Stanford health assessment questionnaire disability index (HAQ-DI). Results Substantial reductions compared to Swedish norms were observed across all SF-36 subscales at baseline (figure 1). SF-36 mental component summary scores were higher in patients who were on antimalarial agents (mean: 42.7; SD ±11.8; n=29) compared to patients who were not (mean: 34.0; SD ±14.7; n=32; p=0.019). Accordingly, patients who were on antimalarial agents performed better in SF-36 social functioning (mean: 63.7 versus 46.5; p=0.022) and mental health (mean: 68.7 versus 53.4; p=0.023) compared to patients who were not. Belimumab-treated patients reported gradual improvements in the SF-36 physical summary component (significant from month 12; p=0.023) and FACIT-Fatigue (significant by month 24; p=0.001), no changes in EQ-5D scores, and improvements in HAQ-DI by month 6 (p=0.014). Rituximab-treated patients reported rapid improvements in the SF-36 mental summary component and FACIT-Fatigue by month 3 (p=0.031 and p=0.007, respectively), which declined at month 12, as well as improvements in EQ-5D at month 6 (p=0.016) and HAQ-DI at month 3 (p=0.033), which were not maintained at later time points. Conclusions HRQoL was considerably impaired in SLE patients compared to population-based norms at baseline, and was not fully compensated during follow-up. Patients’ perceptions of HRQoL showed treatment-specific patterns over time, and could prove useful when evaluating the effects of biologics in SLE. Early evaluation of belimumab might underestimate improvements in HRQoL and fatigue. In severe SLE, antimalarial agents may have favourable effects on mental HRQoL aspects. Disclosure of Interest None declared

Background Anti-drug antibodies (ADA) to rituximab (RTX) have been reported to a limited extent in rheumatoid arthritis (RA,4%–11%) and in multiple sclerosis (MS, 26%–37%), in the latter being associated with incomplete B-cell depletion.1 In SLE, data on the clinical significance of ADA are lacking. Objectives To define the frequency and consequences of ADA to RTX in a SLE population by setting a disease specific threshold using a sensitive ADA method. Methods SLE patients fulfilling the 1982 ACR classification criteria who received RTX treatment at the Karolinska University Hospital during the years 2001–2015 were included. Stored serum samples obtained prior to and after six months from initiation of treatment were analysed for the detection of ADA using a GSK-developed and validated electrochemiluminescence assay. Disease specific screening and confirmation cut-point for SLE samples (1.44 AU and 29% respectively) were used. Clinical and laboratory data were retrieved from electronic medical charts. SLE activity was measured using SLE disease activity index 2000 (SLEDAI-2K). We defined treatment response according to the SLE responder index (SRI).2 Results Thirty-eight patients (89.5% females, median age 35.0 years; IQR: 27.7–55.0) were included in this retrospective analysis. The median disease duration was 6.2 years (IQR: 2.1–11.6) and the baseline median SLEDAI-2K was 6.9 (IQR: 7.0–16.5). The indications for RTX were active lupus nephritis (65.8%), CNS involvement (10.5%), arthritis (13.2%), haematological manifestations (7.9%), or mucocutaneous involvement (2.6%). Twenty-six patients (68.4%) received RTX according to the lymphoma regimen (375 mg/m2 at day 1, 7, 14, 28) while 12 (31.6%) according to the arthritis regimen (2 infusions at a dose of 1 g, 14 days apart). Intravenous corticosteroids and cyclophosphamide were given in 65.8% and 63.2% of the patients, respectively. ADA were detected in 18 patient samples (47.4%) at follow-up and stratified into reactive samples (confirmed positive but with a titer 51 AU/mL; n=5). We found no association between the occurrence of ADA and either SRI response (p=0.26, Fisher exact test) nor the concomitant use of high dose IV 6-methylprednisolone (p=0.56, c2test) or IV cyclophosphamide (p=0.11, c2test). At follow-up, patients positive for ADA had higher levels of CD19 +B cells (median: 0.03 × 109 cells/L; IQR: 0.01–0.13) compared to negative patients (median: 0.01 × 109 cells/L; IQR: 0.005–0.01; p=0.007, Mann-Whitney test). Conclusions ADA to RTX in SLE are more frequent than in RA and MS and occur irrespective of treatment response and cotreatments, but are associated with higher counts of CD19 +B cells at follow-up. Such finding could reflect either incomplete B-cell depletion in ADA positive patients, or earlier repopulation. Further studies should address the relation between ADA titers and clinical outcomes as well as immunological consequences. References [1] Dunn N, et al. Mult Scler2017. [2] Navarra SV, et al. Lancet2011. Disclosure of Interest None declared

Background Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its prevalence and contributing factors, including B cell related cytokines and growth factors of the myeloid lineage, in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital (n=107) were enrolled. LON was defined as an absolute neutrophil count Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days (IQR: 66.8–322.0). Thirteen patients were admitted to the hospital; ten developed fever, and three developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/mL; IQR: 0.42–1.07) through the post-treatment measurement, both in patients who developed LON (median: 1.73 ng/mL; IQR: 1.03–2.56; p=0.005) and patients who did not (median: 1.03; IQR: 0.65–1.55; p=0.001), with significantly higher BAFF levels in the LON group (p=0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/mL; p=0.027) and post-treatment (median: 2.39 versus 1.11 ng/mL; p=0.011). IL-6 and GM-CSF levels decreased in the non-LON group (p Conclusion Post-rituximab LON is a common complication in SLE. Although the phenomenon was self-limiting in most cases, a few patients developed life-threatening conditions; this highlights the importance of regular surveillance for neutrophil counts, fever and infections. Distinct roles of BAFF and APRIL are implicated; BAFF might contribute to granulopoiesis disruptions, whereas APRIL might have a value in distinguishing predisposed patients.

Introduction Patients with systemic lupus erythematosus (SLE) are affected by morbidity and premature mortality from cardiovascular disease (CVD) – commonly defined as myocardial infarction (MI), coronary artery disease (CAD), stroke and/or peripheral arterial disease (PAD). To date, neither MI subtypes, locations nor risk factors for MI specifically have been fully investigated in SLE. Aims To study the subtypes, locations and risk factors of the first-time MI in patients with SLE. Material and methods SLE patients with a first-time MI (SLE-MI), meeting the Third Universal Definition of MI, were included in a cross-sectional investigation of our SLE cohort (n=650). As comparators, MI-free SLE patients (SLE-nonMI) from the same cohort were individually matched for age and gender. Data were collected through retrospective medical record review, including reports on ECG, echocardiography and coronary angiography. Potential risk factors for MI were investigated; previous CVD, including CAD (comprising stable CAD and unstable angina), ischaemic stroke and PAD, venous thromboembolism, diabetes, smoking habits, anti-phospholipid syndrome (APS), lupus nephritis, estimated glomerular filtration rate, prednisone equivalent dosage at MI, plasma/serum albumin, CRP and erythrocyte sedimentation rate. Paired tests, McNemar’s and Wilcoxon’s signed rank tests, were used as appropriate. Results MI was diagnosed in 43/650 patients, 41/43 had a non-iatrogenic MI – i.e. MI not related to percutaneous coronary intervention, stent thrombosis or coronary artery bypass grafting. Of these, non-ST-elevation MI (NSTEMI) and MI with significant coronary atherosclerosis were the most prevalent subtypes (69% and 89%, respectively). Furthermore, atherosclerosis in the left anterior descending artery (LAD) was present in 75% of patients. The following factors differed between SLE-MI and SLE-nonMI: CVD (43% versus 20%; p=0.03), CAD (30% versus 0%; p=0.0002), diabetes (15% versus 0%; p=0.001), and albumin levels (35 g/L versus 40 g/L; p=0.0004). 23% of SLE-MI and 10% of SLE-nonMI patients met the criteria for definite APS prior to MI (p=0.17); post-MI, APS prevalence increased in patients with SLE-MI (43% versus 10%; p=0.0009). Conclusions NSTEMI with angiography-verified atherosclerosis, most commonly in LAD, was the most prevalent MI subtype. Previous CVD (especially CAD), APS, diabetes, and decreased albumin levels distinguished SLE patients with MI from SLE patients without MI.

Post hoc analyses of the phase III trials of belimumab BLISS-521 and BLISS-762 revealed superiority of belimumab over placebo in patients with systemic lupus erythematosus (SLE) with high baseline disease activity, positive anti–double-stranded (ds)DNA titres and low complement levels, as well as in patients receiving corticosteroids.3 Later, real-life observations demonstrated that established organ damage prior to treatment initiation predicted reduced belimumab efficacy.4 We aimed at validating this finding in the BLISS-52 and BLISS-76 SLE populations. Access to data was granted by GlaxoSmithKline (Uxbridge, UK). In total, 1684 patients were included in the analysis. The BLISS-52 trial comprised 865 and the BLISS-76 trial 819 patients with SLE who were randomised to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo, along with standard-of-care treatment. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).5 Response to treatment was defined as fulfilment of the SLE responder index 4 (SRI-4) conditions at week 52 (primary endpoint of the BLISS trials).1 2 Patients who withdrew or required changes in the background therapy other than those permitted by protocol …

Background Rituximab-mediated late-onset neutropenia (LON) has been studied in various diseases, but data from systemic lupus erythematosus (SLE) are limited. Objectives To study the prevalence and contributing factors for LON following treatment with rituximab in patients with SLE, including B cell related cytokines and growth factors of the myeloid lineage. Methods Patients from the Karolinska SLE cohort treated with rituximab (n=107) were enrolled in this observational study. Rituximab was given according to the lymphoma course (weekly for four weeks), the arthritis course (at week 0 and 2), or as a single infusion, with or without concomitant pulses of cyclophosphamide. LON was defined as an absolute neutrophil count Results Thirty-four of 107 patients developed LON after a median time of 222 days (IQR: 105–355 days). BLyS levels increased from baseline (median: 0.62 ng/mL; IQR: 0.42–1.07 ng/mL) through the post-treatment measurement, both in patients who developed LON (median: 1.73 ng/mL; IQR: 1.03–2.13 ng/mL; P=0.005) and patients who did not (median: 1.03; IQR: 0.67–1.56 ng/mL; P Conclusions The prevalence of rituximab-mediated LON within the SLE patients of the current study (31.8%) was higher compared to previous reports on patients with lymphoma (3–27%), ANCA-associated vasculitis (11.9%) and rheumatoid arthritis (3%). Our results imply a role of the BAFF/APRIL pathway in the immunologic mechanisms underlying this phenomenon and demonstrate that LON following rituximab treatment is a common complication in SLE patients. Disclosure of Interest None declared

Background and aims Belimumab is the first biologic drug approved for Systemic Lupus Erythematosus (SLE). Here, we aimed to investigate the effects of belimumab on clinical and serologic outcomes, and sought to identify predictors of treatment response in three Swedish real-life settings. Methods Fifty-eight patients were enrolled at initiation of belimumab and followed longitudinally for up to 53 months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100 mm Visual Analogue Scales for Physician’s Global Assessment (PGA), fatigue, pain and general health, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Assessment of treatment response included the SLE responder index (SRI). B lymphocyte stimulator (BLyS) levels were determined using ELISA. Results SLEDAI-2K (median baseline score: 8.0; IQR: 4.0–13.8), PGA and corticosteroid use decreased during therapy, and patients reported improvements on fatigue, pain, and general health (p 1 showed decreased probability and prolonged time to attain SRI response (HR: 0.449; 95% CI: 0.208–0.967), as did current smokers compared with non-smokers (HR: 0.103; 95% CI: 0.025–0.427). In contrast, baseline BLyS levels≥1.2 ng/mL predicted increased probability and shorter time to attain SRI response (HR: 2.566; 95% CI: 1.222–5.387). Conclusions Disease activity and corticosteroid usage decreased, patient-reported outcomes improved, and no significant organ damage was accrued during follow-up. Smoking and organ damage predicted reduced treatment efficacy. These findings might contribute to a better selection of patients who are likely to benefit from belimumab.

Background and aims Belimumab is a monoclonal antibody that inhibits soluble B lymphocyte stimulator (BLyS, also known as BAFF), approved for the treatment of systemic lupus erythematosus (SLE). Here, we sought to identify B cell alterations during belimumab treatment. Methods Twenty-three SLE patients treated with belimumab were enrolled. Peripheral blood mononuclear cells were collected and cryopreserved at treatment initiation and at regular follow-up visits for up to 3 years. The samples were simultaneously assayed using mass cytometry. Cell counts were adjusted for total lymphocyte counts. Results CD20 + B cells decreased over time (p + CD20 + IgD + IgM + CD27 - ) and age-associated B cells (CD19 + CD20 + CD11c + CD21 - ) already at the first follow-up visit (month 3), followed by a continuous decrease (p + CD20 + IgD - CD27 - ) declined significantly first at month 6 (p=0.033) and pre-switching B cells (CD19 + CD20 + IgD + CD27 + ) showed a trend towards a decrease (p=0.052). Plasma cells (CD138 + CD38 + CD27 + CD19 + CD3e - CD20 - ) and switched memory B cells (CD19 + CD20 + CD27 + IgD - ) remained stable during the study period, as did T cells and monocytes (p>0.2). Despite continuously decreasing SLE Disease Activity Index, immunological changes correlated with clinical improvements only during early time points (month 0–3). Interestingly, high baseline B cell counts were predictive of non-attaining Lupus Low Disease Activity State at month 24 (area under the ROC-curve: 0.95). Conclusions B cell alterations betided in two distinct phases, a rapid early and a gradual late phase. Late clinical improvements might reflect preceding immunological changes, implying that early treatment evaluation and discontinuation might underestimate delayed improvements reflecting the late B cell changes.

We investigated the performance of soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of renal activity, damage, treatment response, and long-term outcome in lupus nephritis (LN).Serum sTNFR2 levels were assessed in 64 LN patients (52 proliferative, 12 membranous) before and after induction treatment, and in 314 non-lupus controls. In LN patients, renal biopsies were performed at baseline and post-treatment. Patients with ≥ 50% reduced proteinuria, normal or improved estimated glomerular filtration rate (eGFR) by ≥ 25%, and inactive urinary sediment were considered clinical responders (CRs). Patients with ≥ 50% improved renal activity index were considered histopathological responders (HRs). Long-term renal outcome was determined using the chronic kidney disease (CKD) stage after a median follow-up of 11.3 years.sTNFR2 levels were elevated in LN patients versus controls both at baseline (p 0.001) and post-treatment (p 0.001), and decreased following treatment (p 0.001). Baseline sTNFR2 correlated with Chronicity Index scores in both baseline (r = 0.34, p = 0.006) and post-treatment (r = 0.43, p 0.001) biopsies. In membranous LN, baseline sTNFR2 levels were higher in CRs (p = 0.048) and HRs (p = 0.03) than in non-responders, and decreased only in CRs (p = 0.03). Both baseline (p = 0.02) and post-treatment (p = 0.03) sTNFR2 levels were associated with decreasing eGFR throughout long-term follow-up, and post-treatment levels were higher in patients with long-term follow-up CKD stage ≥ 3 versus 1-2 (p = 0.008).Our data suggest serum sTNFR2 as a marker of kidney tissue damage and a predictor of long-term prognosis in LN, and merit further evaluation of sTNFR2 as a predictor of clinical and histopathological treatment outcomes in membranous LN.

Belimumab is the first biologic drug approved for Systemic Lupus Erythematosus (SLE). Here, we aimed to investigate the effects of belimumab on clinical and serologic outcomes, and sought to identify predictors of treatment response in three Swedish real-life settings.Fifty-eight patients were enrolled at initiation of belimumab and followed longitudinally for up to 53months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100mm Visual Analogue Scales for Physician's Global Assessment (PGA), fatigue, pain and general health, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Assessment of treatment response included the SLE responder index (SRI). B lymphocyte stimulator (BLyS) levels were determined using ELISA.SLEDAI-2K (median baseline score: 8.0; IQR: 4.0-13.8), PGA and corticosteroid use decreased during therapy, and patients reported improvements on fatigue, pain, and general health (p0.0001 for all). SDI scores remained stable (p=0.08). Patients with baseline SDI scores1 showed decreased probability and prolonged time to attain SRI response (HR: 0.449; 95% CI: 0.208-0.967), as did current smokers compared with non-smokers (HR: 0.103; 95% CI: 0.025-0.427). In contrast, baseline BLyS levels ≥1.2ng/mL predicted increased probability and shorter time to attain SRI response (HR: 2.566; 95% CI: 1.222-5.387).Disease activity and corticosteroid usage decreased, patient-reported outcomes improved, and no significant organ damage was accrued during follow-up. Smoking and organ damage predicted reduced treatment efficacy. These findings might contribute to a better selection of patients who are likely to benefit from belimumab.

Axl is a receptor tyrosine kinase with important functions in immune regulation. We investigated serum levels of soluble (s)Axl in lupus nephritis (LN) in association with renal disease activity, tissue damage and treatment response. We surveyed 52 patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III/IV LN and 20 healthy controls. Renal biopsies were performed at the time of active LN and post-treatment. Patients were classified as clinical responders (CRs) or clinical non-responders based on the American College of Rheumatology (ACR) criteria. Improvement by ≥50% in renal activity index scores defined histological responders (HRs). sAxl levels were elevated in patients compared to controls (median: 18.9 ng/mL), both at baseline (median: 45.7; P5 times higher probability of histology-based response (odds ratio, OR: 5.5; 95% confidence interval, CI: 1.2–25.1). High post-treatment sAxl levels were associated with worsening in chronicity index scores (P = 0.025); low levels predicted favourable renal outcome (creatinine ≤88.4 μmol/L) 10 years after the baseline renal biopsy (area under the curve: 0.71; 95% CI: 0.54–0.89). In conclusion, sAxl may prove useful as a marker of renal activity, histological response to immunosuppression, and renal damage progression in LN. Persistently high sAxl levels after completion of treatment may be indicative of a need for treatment intensification.

Objectives Interferon (IFN)-α is thought to be central in the pathogenesis for lupus nephritis (LN) and recent studies also indicate a role for IFNλ. Little is known about these cytokines in the context of treatment response. We studied levels of IFNα and IFNλ in patients with LN in association with clinical and histological response (HR) to treatment. Methods Fifty-six patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive therapy. Serum levels of IFNα and IFNλ were analysed at both biopsy occasions and in 163 controls. The biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification. Clinical response was defined according to recent definitions. HR was defined as class I, II or III/IV-C on repeat biopsies. The expression of IFNλ in renal tissue was assessed by immunohistochemistry. Results At baseline, serum levels of both IFNα and IFNλ were higher in patients versus controls (p=0.01 and p=0.03, respectively). There was no correlation between IFNα and IFNλ. Overall, IFNα decreased after treatment (p=0.003) but IFNλ remained unchanged. However in patients with HR, IFNλ decreased (p=0.01). The highest levels of IFNλ were seen in patients with poor HR. Immunostaining of renal tissue revealed expression of IFNλ, particularly in crescent formations, inflammatory infiltrates and tubular cells. Conclusions The study supports a role for IFNλ in LN, both in circulation and at a tissue level. Levels of IFNα and IFNλ did not correlate and were affected differently by immunosuppression, indicating that they are differently involved in subgroups of LN. Persistent increased levels of IFNλ were associated to an unfavourable HR to treatment.

Background Lupus nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE). Renal biopsy is the gold standard for evaluation of renal activity and damage in LN. Evaluation of new biomarkers for non-invasive assessment of renal pathology is warranted. Insulin-like growth factor-binding protein 2 (IGFBP2) has been found to be a robust diagnostic and prognostic biomarker in malignancies. In animal models, IGFBP2 expression was increased in anti-glomerular basement membrane (anti-GBM) glomerulonephritis and MRL/lpr lupus mice. Objectives We aimed to investigate the role of IGFBP2 in LN. Methods Serum levels of IGFBP2 were assessed by ELISA (R&D Systems) in 64 patients with biopsy-proven active LN (52 proliferative, 12 membranous), before and after completion of induction treatment. Post-treatment renal biopsies were performed after a median time of 7.7 months. Clinical responders (CR) were defined by ≥50% reduced proteinuria, normal or ≥25% improved estimated glomerular filtration rate (eGFR), and inactive urinary sediment. Histopathological responders (HR) were defined by ≥50% improvement of renal Activity Index (AI) in post-treatment biopsies. Long-term renal outcome after a median time of 11.3 years (range: 3.3–18.8) was determined by the last eGFR. Results Serum IGFBP2 levels decreased following induction therapy (p Conclusions The decreases in serum IGFBP2 levels following induction therapy in responding, but not in non-responding, patients suggest serum IGFBP2 as a marker of disease activity and response to treatment in LN. Interestingly, baseline IGFBP2 levels were associated with renal function deterioration following treatment, despite an overall improvement in eGFR. Post-treatment, but not baseline, levels mirrored both global SLE activity and histopathological findings, which together with the observed correlation with proteinuria levels suggests IGFBP2 as a marker of activity in patients with history of LN and no or low-grade proteinuria. Disclosure of Interest None declared

Background Lupus nephritis (LN) affects up to 50% of patients with Systemic Lupus Erythematosus (SLE). The B-lymphocyte is pivotal in SLE and autoantibody production. B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are important for the activation and maintenance of B-cells. Objectives The aim of this study was to investigate serum levels of BLyS and APRIL in patients with LN, in order to clarify how these levels are affected by conventional immunosuppression. Through comparison with clinical data and correlation with autoantibodies, we further aimed to evaluate BLyS and APRIL as potential biomarkers for LN in comparison to conventional serology. Methods Sixty-four patients with active biopsy-ascertained LN (52 proliferative LN, PLN; 12 membranous LN) and 64 individually matched controls were included. After induction therapy a follow-up biopsy was performed. Serum samples at baseline and follow-up were analyzed for BLyS, APRIL, autoantibodies and complement levels. The renal biopsies were assessed according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system for LN 1 and scored for Activity Index (AI) and Chronicity Index (CI) 2 . Clinical response (CR) was defined as ≥50% reduction in proteinuria, normal or improved renal function and inactive urinary sediment. Histopathological response (HR) required ≥50% improvement in AI. Results Comparing patients to controls, baseline BLyS levels were significantly higher in patients (p No correlation was found between BLyS/APRIL and anti-dsDNA, anti-C1q, C3 or C4, at either baseline or follow-up. However, significant correlations were found between DBLyS and Danti-dsDNA in the combined patient group (r s =0.47, p s =0.49, p Conclusions Our results indicate that APRIL is of importance in PLN, and stress the need to evaluate BLyS as a candidate non-invasive prognostic biomarker of treatment response in LN. References Weening JJ, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Journal of the American Society of Nephrology: JASN. 2004 Feb;15(2):241-50. Austin HA, 3rd, et al. Prognostic factors in lupus nephritis. Contribution of renal histologic data. The American journal of medicine. 1983 Sep;75(3):382-91. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.3863

Background Belimumab is a recombinant monoclonal antibody that specifically binds to soluble B-lymphocyte stimulator, thereby reducing autoantibody levels. It is the only biologic agent approved for treatment of Systemic Lupus Erythematosus (SLE). Objectives The aim of this study was to investigate the effects of belimumab given as an add-on to patients with active SLE despite standard-of-care therapy, with focus on low-active lupus nephritis (LN) patients. Methods Fourteen patients were included. Clinical data were acquired at baseline and week 12, 26 and 52. Disease activity was assessed using SLE Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus Activity Measure (SLAM). The primary organ manifestations comprised arthritis (n=9), skin involvement (n=11), serositis (n=3), involvement of the central nervous system (n=4) and cytopenias (n=3). Nine patients with former LN were included (median proteinuria at baseline 0.2 g/day, range 0.01-0.4 g/day). Results At baseline, all patients received oral prednisolone (mean dose 11, range 5-20 mg/day), 9 received antimalarials, 3 mycophenolate mofetil, 2 azathioprine, and 1 cyclosporine. The median SLEDAI and SLAM scores were 10 (range 2-24) and 12 (range 5-23), respectively. One patient withdrew due to allergic reaction. Significant decreases of SLAM and SLEDAI were seen at week 26 (p=0.001 and p=0.007, respectively) and 52 (p=0.028 and p=0.012, respectively). Prednisolone dosages were significantly decreased compared to baseline at week 26 (p=0.003) and 52 (p=0.008). Ten patients had low complement at baseline. We observed no significant increase in C3/C4 levels. In the patients with former LN, no renal flare was observed during the observation period. The grade of proteinuria remained unchanged at week 26 (median 0.14 g/day, range 0.01-0.5 g/day) and 52 (median 0.13 g/day, range 0.02-0.24 g/day). No severe adverse events were noted. Conclusions Belimumab treatment decreased SLE disease activity and reduced corticosteroid usage. Despite the limited number of patients, our observations indicate that belimumab may prevent renal flares and may be used in patients with former LN and persistent low-grade proteinuria. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3876

Background Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) affecting up to 60% of the patients. IFN-α is a central cytokine in the pathogenesis for LN, and recent studies also indicate a role for IFN-λ1/3. However little is known about these cytokines in the context of treatment response and how they are affected by immunosuppressive therapy in LN. Objectives We studied serum levels of IFN-α and IFN-λ1/3 in patients with LN, both at active disease and after induction treatment. Associations with clinical and histological response to treatment were evaluated. Methods Fifty-six patients with active LN, 45 proliferative- (PN) and 11 membranous nephritis (MN), were included. Renal biopsies were performed at baseline and after induction immunosuppressive treatment (median 7 months). Clinical and routine laboratory data were collected, and serum levels of IFN-α and IFN-λ1/3 were analysed by ELISA at both biopsy occasions and in 163 healthy controls. The cut-off for IFN-α was 0.02 pg/l and for IFN-λ1/3 0.3 pg/l. Biopsies were evaluated according to the ISN/RPS classification and scored for activity and chronicity indices. Clinical response was defined according to recent definitions [1]. Histological response (HR) was defined as Class I, II or III/IV-C on repeat biopsies. Results At baseline, serum levels of both IFN-α and IFN-λ1/3 were higher in patients vs. controls (p=0.01 and 0.03 respectively). There was no correlation between IFN-α and IFN-λ1/3. There was a trend towards higher levels of IFN-α in patients with PN vs. MN (p=0.06) and higher IFN-λ1/3 in MN vs. PN (0.09). In PN, 73% of the patients had detectable IFN-α vs.36% in MN (p=0.02). In all patients, IFN-α decreased after treatment (p=0.002) but IFN-λ1/3 remained unchanged. However in patients with HR, levels of IFN-λ1/3 decreased (p=0.01). Of histological non-responders, 31% had detectable levels of IFN-λ1/3 at follow-up, vs 10% of HR (p=0.05). IFN-α was positively correlated to anti-DNA and anti-C1q-antibodies and negatively to C3 and C4, but no correlations were seen for IFN-λ1/3. Neither IFN-α, nor IFN-λ1/3 correlated to proteinuria or creatinine and there was no clear association to clinical response. Conclusions Our results support a role for IFN-λ1/3, and also confirms previous findings of involvement of IFN-α, in LN. Interestingly, IFN-α and INF-λ1/3 did not correlate to each other and their levels were affected differently by immunosupressive treatment, and also differed between MN and PN. Persistently elevated levels of IFN-λ1/3 indicated poor histological response to treatment. The study indicates that IFN-α and IFN-λ1/3 may be differently involved in subgroups of LN and that IFN-λ1/3 may be a potential biomarker for treatment response. References Gordon C, Jayne D, Pusey C, et al. European consensus statement on the terminology used in the management of lupus glomerulonephritis. Lupus 2009;18(3):257-63 Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5505