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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 Sjogren´s syndrome occurs in isolation (primary Sjogren´s syndrome, pSS), but it is also often secondary (sSS) to, and sometimes difficult to delineate from systemic lupus erythematosus (SLE). Consequently there is a need to investigate similarities and differences between SLE patients with (SLE-sSS) and without sSS (SLE-noSS). Objective To investigate the occurrence of sSS in a large cohort of SLE patients and to explore clinical and laboratory characteristics associated with SLE-sSS as compared to SLE-noSS and controls. Methods We included 504 consecutive SLE patients and 322 population controls, matched for age and gender. All patients fulfilled the 1982 revised ACR criteria for SLE. SLE-sSS was defined according to the American-European consensus criteria (AECC). Subjective and objective quantifications of sicca symptoms were recorded. All underwent a thorough clinical investigation. SLE-associated autoantibodies, (ANA screening by BioPlex 2200 system, Bio-Rad) and Rheumatoid factor (Rf, Phadia Immunocap 250) were determined, Routine laboratory workup and a panel of cytokines (MSD 30-plex cytokine assays, performed on samples from 433 consecutive SLE patients and 319 controls) were measured. Results SLE-sSS, occurred in 23% of the SLE patients. Compared to SLE-noSS the SLE-sSS group was older, both at inclusion (55 vs 43 years, p Conclusion Frequency of SLE-sSS increases with age and affects roughly ¼ of SLE patients. Nephritis was less common while leucopenia and peripheral neuropathy were more common. We report higher levels of six pro-inflammatory. These findings demonstrate that, though often regarded as a milder version of SLE, patients with SLE-sSS are characterised by a state of chronic systemic inflammation.

Background Serum induced IFN gene expression (IFN-score) is considered a golden standard to assess IFN activity in SLE. So far, IFN-scores have not been compared to serum levels of type I, II and III IFNs. Aim To investigate how IFN-scores and SLE manifestations relate to serum levels of IFNs type I (alphas), II (gamma) and III (lambda 1). Methods 461 SLE patients and 322 controls were included. IFN-score was measured by WISH cell assay. INF-alphas and IFN-lambda1 were measured by ELISA. IFN-gamma was measured by MSD 30-plex assay. Results SLE patients had higher IFN-scores and higher levels of IFN-alphas, IFN-gamma and IFN-lambda1 (p 3 rd quartile) of each IFN/IFN-score. The group with high IFN-scores had higher disease activity (SLAM, SLEDAI): weight loss (41%), fatigue (33%), fever (39%), rash (44%), lymphadenopathy (45%), arthritis (40%), nephritis (55%) (p The characteristics of IFN-gamma high group included higher disease activity (SLAM, SLEDAI), and specifically: active nephritis (52%), lymphadenopathy (40%), arthritis (42%), lymphopenia (37%), anaemia (35%) and positivity for Sm (41%), SmRNP (36%) and RNP68 (45%), Ro52 (35%) and Ro60 (33%) (p The common features of IFN-alpha high group included younger age, shorter disease duration, active rash (34%), lymphadenopathy (43%), Ro52 (38%) and La (43%) (p=0.01). Presence of aPL abs and previous vascular events were lower and renal affection was uncommon (p In general, high IFN-scores reflected SLE manifestations that could be further stratified by high IFN-gamma levels and to a lesser extent by high IFN-alpha. High IFN-lambda1 did not define any phenotype of active SLE, except presence of anti-nucleosome abs. Conclusion We demonstrate that high IFN-score associate more strongly with type II rather than type I IFNs. Importantly, major manifestations of SLE: active nephritis and arthritis, and also anti-Sm/SmRNP antibodies associate with IFN-gamma; while rash associate with IFN-alpha. Our findings are of major importance while tailoring clinical trials with anti-IFN therapies and demonstrate that importance of IFN-gamma has so far been underscored.

SLE is a heterogeneous disease including diverging clinical symptoms, autoantibodies and genetic susceptibility. Hitherto unrecognised patterns may define sub-phenotypes with different pathogenesis and specific treatment needs. Based on autoantibody profile we therefore investigated phenotypic clusters and explored cluster associations with clinical manifestations and one of the most important genetic risk factors for SLE, HLA-DRB1 alleles. 908 SLE Caucasian patients and 3654 age- gender- and ethnicity-matched healthy controls (HC) were included. We determined the occurrence of 13 autoantibodies: dsDNA, nucleosomes, ribosomal P, RNP68, RNPA, Sm, Sm/RNP, SSA52, SSA60, SSB, aCL-IgG/IgM and aB2GP1. HLA-DRB1 typing was performed by sequence-specific primer polymerase chain reaction assay. Cluster analysis was done using Gower distance matrix, followed by partition around medoids cluster calculation and Silhouette metric for number of clusters validation. Chi-square test, odds ratios (OR), 95% confidence intervals and false discovery rate p value (p) were calculated for the association tests. Four clusters were defined based on autoantibody occurrence. 29%, dominated by anti–SSA52/60/SSB positivity is strongly associated with HLA–DRB1*03 when compared to HC (4.1[3.4–4.9] p=6.4E–56) and other clusters (OCs) (2.9[93.3–3.6] p=1.1E–19). Discoid lesions were more common vs OCs (1.8[1.3–2.6] p=0.02). 29%, dominated by anti–SmRNP/Sm/DNA/RNPA/RNP68/nucleosome, was specifically associated with HLA–DRB1*15 when compared to HC (1.7[1.6–2.1] p=5.7E–6) and other clusters (1.5[1.1–1.9] p=0.01). Nephritis was common vs OCs (1.9[1.4–2.7) p=2.E–03) 24%, dominated by anti–B2GP1/aCL–IgG/IgM, was associated with HLA–DRB1*04 when compared with other clusters (1.8[1.4–2.4] p=2E–4). More thrombotic events vs OCs were observed in this group (1.84 [1.3–2.6] p=0.01) 18% was negative for the 13 tested autoantibodies and was not associated with any specific HLA–DRB1 alleles and it was not associated as risk factor for any of the evaluated clinical manifestations. We demonstrate that immune-phenotypes/clusters in SLE can fit into a frame of HLA-DRB1 alleles and that the overall association between SLE and HLA-DRB1*03 and HLA-DRB1*15 seems to be driven mainly by clusters 1 and 2, respectively. We also confirm previous observations that autoantibody clusters associate with clinical symptoms. We believe that these results could be used to redefine SLE, determine predictive biomarkers and inclusion criteria for clinical trials.

Background Belimumab is a biologic agent approved for the treatment of systemic lupus erythematosus (SLE). Recently, we demonstrated decreasing SLE activity during belimumab treatment in patients from three Swedish clinical settings. In the present study, we aimed to investigate the effects of belimumab on mucocutaneous and articular SLE in relation to smoking status. Methods Sixty-two patients with active SLE treated with belimumab between 2011 and 2017 were enrolled. We assessed the mucocutaneous disease using the mucocutaneous SLEDAI-2K and the cutaneous lupus erythematous disease area and severity index (CLASI). Musculoskeletal activity was evaluated by the arthritis SLEDAI-2K descriptor and the 28-joint count. Results At baseline, 44/62 (71.0%) patients had a mucocutaneous SLEDAI-2K score 2 or more (mean mucocutaneous SLEDAI-2K: 2.3; range 0–6; n=62). The mean baseline CLASI activity was score: 8.4 (range: 0–39; n=33). We observed decreased mucocutaneous SLEDAI-2K scores at month 6 (p Conclusion In line with previous reports, belimumab treatment was effective in limiting mucocutaneous and articular symptoms in patients with SLE. A history of past or current smoking was found to reduce the efficacy of belimumab in mucocutaneous manifestations. Further survey on the impact of smoking on the efficacy of belimumab at a mechanistic level is merited.

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 Interferon (IFN)-αs are pivotal in systemic lupus erythematosus (SLE), and type III IFNs (IFN-λs) were recently also associated with SLE. We investigated levels of IFN-α and IFN-λ1, and related cytokines in SLE patients and controls. Methods We included 261 SLE patients and 261 population controls. All were examined and assessed for current organ manifestations and disease activity/damage using SLAM, SLEDAI and ACR/SDI scales. Levels of IFN-λ1, IFN-α, IL-17A, IL-23 and IP-10 were measured by ELISA. Results IFN-λ1 and IFN-α were detected in 29% and 44% of patients respectively, but their levels did not correlate. High serum levels of IFN-λ1 were positively associated with anti-nucleosome antibodies and lymphopenia, but negatively with musculoskeletal damage. Positive correlations between levels of IFN-λ1, IL-17A and IL-23 were observed. Patients with high levels of these three cytokines had more disease damage, especially renal. High levels of IFN-α were associated with mucocutaneous disease, leukopenia, low complement, Ro/SSA and La/SSB, whereas vascular events and antiphospholipid antibodies (aPL) were uncommon. We identified two subgroups with high disease activity: one double IFN-λ1 and IFN-α high and another IP-10 high. The former had more neuropsychiatric manifestations, while the latter had more arthritis. Conclusions Measurements of circulating IFN-λ1 and IFN-α define SLE patients with different characteristics. Levels of IFN-λ1 correlate with Th17 cytokines and identify a subgroup with more damage. Disease activity is associated with either upregulation of both type I and III IFNs, or independently with IP-10. Our findings could be of major importance when tailoring therapy for SLE patients with agents targeting IFN-pathways.

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.