A. Zickert

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

BACKGROUNDnNew treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis.nnnMETHODSnWe undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004.nnnFINDINGSn487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group.nnnINTERPRETATIONnIn patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs.nnnFUNDINGnSwedish Rheumatism Association, Schering-Plough.

Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy

Objectives Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response. Methods Sixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index. Results Baseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment (p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5u2005ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline. Conclusions BLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.

Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts

OBJECTIVESnThe main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden.nnnMETHODSnFive cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency.nnnRESULTSnIn total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK (

FRI0014 Multiplex Screening of Cytokines in The Search for Disease Activity Markers of SLE

33,369 = 22,941€), of which direct cost was 63,672kr (

THU0183 Cigarette smoking and antiphospholipid antibodies in systemic lupus erythematosus

10,188 = 7004€) and the indirect cost was 144,883 SEK (

PS7:132 Smoking reduces the efficacy of belimumab in mucocutaneous lupus

23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs.nnnCONCLUSIONnBased on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at

Smoking reduces the efficacy of belimumab in mucocutaneous lupus

188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.

The impact of belimumab and rituximab on health-related quality of life in patients with systemic lupus erythematosus

Background There is presently no consensus on how to best measure disease activity in systemic lupus erythematosus (SLE). Available validated measures, such as SLE Disease Activity Index (SLEDAI) and SLE Activity Measure (SLAM), are composite scores that in addition to laboratory tests require investigation by a physician. These scores are insensitive to change and have failed to differentiate treatment responses in clinical trials. It would be an important step forward, for clinical practice and for clinical trials, if one or several biomarkers could be used as proxies for disease activity in SLE. Objectives Our objective is to evaluate cytokines, in combination with basic laboratory tests, as potential disease activity biomarkers. Methods In a cross-sectional setting we examined 433 patients with SLE (fulfilling four or more of the 1982 revised ACR criteria) and 322 age and gender matched population controls. Disease activity was assessed according to both SLEDAI and SLAM by a rheumatologist. Basic laboratory tests and analyses on MSD 30-plex cytokine assay (Mesoscale Discovery, K15054D) were performed on fasting blood samples (total >50 potential biomarkers). The discriminatory power for investigated biomarkers was tested between patients and controls. Spearman correlations with SLAM/SLEDAI scores were calculated among patients. Results Many potential biomarkers discriminated between patients and controls. Best discriminatory power was observed for TNF-α (p=7x10–63), IL-6 (p=2.5x10–40), orosomucoid (p=7.1x10–38), plasma (P)-albumin (p=1.6x10–36) and sedimentation rate (SR) (p=5.6x10–34). The strongest correlations with SLEDAI/SLAM were observed for TNF-α (Spearman ρ=0.32, p=6.0x10–12 for SLEDAI and Spearman ρ=0.34, p=5.0x10–13 for SLAM), and for P-albumin (Spearman ρ=-0.33, p=9.0x10–13 for SLEDAI and Spearman ρ=-0.31, p=5.0x10–11 for SLAM). As SR is part of SLAM, expected positive correlations were observed (Spearman ρ=0.27, p=7.7x10-9 for SLEDAI and Spearman ρ=0.48, p=4.0x10–25 for SLAM). Conclusions Of more than 50 investigated biomarkers TNF-α was the best discriminator between SLE patients and controls. Furthermore TNF-α was the biomarker, which correlated best with disease activity. These correlations were further improved by the ratio between TNF-α and P-albumin. We propose that the TNF-α/P-albumin ratio merits further investigations as a clinically useful biomarker for diagnostic and surveillance purposes in SLE. Disclosure of Interest None declared

237 Ischaemic stroke in systemic lupus erythematosus, -distribution of subtypes and a risk genotype in the stat4 gene

Background Patients with systemic lupus erythematosus (SLE) have an increased risk for cardiovascular disease (CVD). In previous prospective studies both smoking and antiphospholipid antibodies (aPL) had a significant impact on CVD risk in SLE. Smoking can in other settings induce autoantibodies. Objectives To investigate the potential association between smoking and aPL in SLE patients. Methods 367 prevalent SLE patients from a single center were included. Clinical evaluation and data on smoking habits were recorded at inclusion. aPL (anticardiolipin antibodies (aCL) IgG/IgM, anti-b2 glycoprotein-1 (ab2GP1)) and the lupus anticoagulant (LAC) were measured using standard methods. Logistic regressions evaluated the association between smoking (ever, former, current) at inclusion and antibody status. Never smokers were used as reference. Results In multivariable models adjusted for age, sex and age at disease onset, ever smoking was associated with LAC, aCL IgG and ab2GP1 IgG, and this association was primarily driven by former smokers (p<0.05 for all). Conclusions Smoking is known to accelerate atherosclerosis, additionally we demonstrate that a history of smoking is associated with pro-thrombotic aPL among SLE patients. This association was particularly evident among former smokers. Further studies are needed to investigate mechanisms behind these observed associations. Disclosure of Interest None Declared

233 Defining subsets in sle: the interplay among ifn-λ1, ifn-α and th17 axis cytokines

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<0.001) and month 12 (p<0.001) compared to baseline. CLASI activity scores also decreased from baseline to month 6 (p<0.001) and 12 (p<0.001). No significant worsening in CLASI damage scores was observed at either month 6 or 12. Patients with a baseline mucocutaneous SLEDAI-2K score 2 or more with a history of current or previous exposure to tobacco smoking (n=17) displayed a more than six times higher probability of poor response to belimumab compared to never smokers (n=22) (OR: 6.4; 95%u2009CI: 1.5–27.4; p=0.012). We observed decreased SLEDAI-2K scores for the arthritis domain both at month 6 (p<0.001) and 12 (p<0.001). From baseline to month 6, the mean tender joints count decreased from 5.7 to 2.7 (p=0.010), and the swollen joints count from 3.6 to 0.7 (p<0.001); the decreases were sustained through month 12 (p=0.001 for both counts). No impact of smoking habits on treatment outcomes in relation to articular SLE was observed. 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.