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Objective Smoking can induce autoantibodies in persons who are genetically predisposed to rheumatoid arthritis. We investigated the association between smoking and antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE), a question not previously addressed. Further, we explored the relationship between smoking, aPL and vascular events (arterial and venous, VE). Methods In this cross-sectional study, clinical evaluation and questionnaire data were collected from 367 prevalent SLE patients. At the same time, we measured aPL (anticardiolipin (aCL), anti-β2 glycoprotein1( aβ2GP1) antibodies IgG/IgM/IgA, and lupus anticoagulant (LA)), and a large set of other SLEassociated autoantibodies for comparison. Association analyses using logistic regression models with smoking, (ever, former and current with never as reference) and antibody status as outcome variable were performed. As a secondary outcome, we investigated the associations between aPL, smoking and VE. Results In multivariable-adjusted models ever, and in particular former, cigarette smoking was associated with the most pathogenic aPL; LA, aCL IgG and aβ2GP1 IgG. Other SLE-associated autoantibodies were not associated with smoking. The combination of smoking and aPL was strongly associated with VE. We noted a positive interaction between smoking-LA and smoking-‘triple aPL’ positivity for previous VE. Conclusions We investigated a large set of commonly occurring autoantibodies in SLE, but only aPL were positively associated with a history of smoking. This association was especially apparent in former smokers. Among ever regular smokers who were aPL positive, we observed a strikingly high frequency of former VE. The underlying mechanisms and temporality between smoking, aPL and VE need further investigations.

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.

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.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS−), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2–10 times more abundant in SLE blood compared to controls. PS− MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS− MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS− MPs, suggests a generalized disturbance in SLE. MPs may be regarded as “liquid biopsies” to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis.

Objective Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases that predominantly affect female patients, and therefore fewer investigations have been conducted in men. The aim of this study was to analyze sex hormone levels in male patients with SLE and those with SSc, compared to matched controls, in relation to the use of corticosteroids and cyclophosphamide (CYC). Methods Sex hormone levels were measured in fasting blood samples from male patients with SLE (n = 71) and those with SSc (n = 29) and compared to population-based, age-matched male controls. Relevant hormone profiles were identified using cluster analysis. Results Male SLE patients had higher levels of luteinizing hormone (LH) (P

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). It remains unclear whether antiphospholipid antibodies (aPL) alter the course of LN. We thus investigated the impact of aPL on short-term and long-term renal outcomes in patients with LN. We assessed levels of aPL cross-sectionally in SLE patients diagnosed with (n = 204) or without (n = 294) LN, and prospectively in 64 patients with active biopsy-proven LN (52 proliferative, 12 membranous), before and after induction treatment (short-term outcomes). Long-term renal outcome in the prospective LN cohort was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease (CKD) stage, after a median follow-up of 11.3 years (range: 3.3-18.8). Cross-sectional analysis revealed no association between LN and IgG/IgM anticardiolipin or anti-β2-glycoprotein I antibodies, or lupus anticoagulant. Both aPL positivity and levels were similar in patients with active LN and non-renal SLE. Following induction treatment for LN, serum IgG/IgM aPL levels decreased in responders (p

The 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.Five 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.In 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 ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($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 score3 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.Based 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 $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.

Background: Recent studies indicate a central role for the IL-23/IL-17 axis in the pathogenesis of lupus nephritis (LN) but the importance in the context of treatment outcome is unknown. We studied various cytokines, including the IL-23/IL-17 axis, in association to histopathology and response to therapy. Methods: Fifty-two patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-10, IL-17, IL-23 and TGF-beta were analysed at both biopsy occasions and in 13 healthy controls. IL-17 expression in renal tissue was assessed by immunohistochemistry. Biopsies were evaluated regarding WHO-classification and renal disease activity was estimated using the BILAG-index. Improvement of 2 grades in renal BILAG was regarded complete response, and 1 grade partial response. Results: At baseline, all patients had high disease activity (BILAG A/B). Baseline levels of IL-6, IL-10, IL-17, IL-23 (p < 0.001) and IFN-gamma (p = 0.03) were increased in patients vs. controls. In contrast, TGF-beta was lower in patients compared to controls (p < 0.001). Baseline levels of IL-17 were higher in patients with persisting active nephritis (WHO III, IV, V) after treatment, i.e. a poor histological response, vs. WHO I-II (p < 0.03). At follow-up, IL-23 were higher in BILAG-non-responders vs. responders (p < 0.05). Immunostaining of renal tissue revealed IL-17 expression in inflammatory infiltrates. Conclusions: High baseline IL-17 predicted an unfavourable histopathological response, and BILAG-non-responders had high IL-23, indicating that that a subset of LN-patients has a Th-17 phenotype that may influence response to treatment and could be evaluated as a biomarker for poor therapeutic response.

Since carvedilol has been claimed to possess antioxidative effects, this drug might affect functional responses, including nitric oxide (NO) generation, of polymorphonuclear neutrophils (PMN) and macrophages. When we assessed the effects of carvedilol on PMN responses in vitro, we observed that carvedilol dose dependently modulated generation of superoxide ions by NADPH oxidase when induced by the formylpeptide formyl-methionyl-leucyl-phenylalanine (fMLP) or the phorbol ester phorbol myristate acetate. This effect was not coupled to diminished phospholipase C activity. In contrast to the effect on NADPH oxidase, neither the fMLP-elicited NO generation by PMN nor the response of the murine macrophage cell line J774 to lipopolysaccharide was affected. There was no evidence from cell-free assay systems that carvedilol is a scavenger for superoxide ions or NO. Moreover, carvedilol did not affect other reactions dependent on NO, e.g. spontaneous or fMLP-stimulated PMN migration or lipoxin A(4)-, fMLP-, or A23187-induced neutrophil cytotoxicity for human umbilical vein endothelial cells. Thus, these effects point to the possibility that carvedilol modulates the NADPH oxidase of PMN but leaves the nitric oxide synthase of phagocytes intact.

Objectives: A renal biopsy is generally recommended for diagnosis and is necessary for classification of lupus nephritis (LN), but second biopsies after immunosuppressive therapy are seldom a routine procedure. We investigated how repeat biopsies contribute to the evaluation of treatment response and long-term outcome in LN. Methods: Sixty-seven patients with active LN were included. Renal biopsies were performed at diagnosis and after standard induction immunosuppressive therapy in all patients (median 8 months), regardless of clinical outcome. Biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification. Clinical response was defined as complete (CR), partial (PR) or non-response (NR) according to recent definitions. Histological response (HR) was defined as Class I, II or III/IV-C on repeat biopsies. Long-term renal outcome was determined in 55 patients after a median of 10 years. Results: CR was demonstrated in 25%, PR in 27% and NR in 48% of patients. HR was shown in 42% and histopathological non-response (HNR) in 58% of patients. Twenty-nine per cent of CR and 61% of patients with PR had active lesions on repeat biopsies, that is, were HNR. Poor long-term renal outcome was associated with high chronicity index at repeated biopsies, but not with clinical or histological response. Conclusions: Despite apparent clinical response to immunosuppressive therapy, repeated biopsies revealed persisting active nephritis in almost half of the patients, thus providing additional information to clinical response criteria. Repeated renal biopsies may be a tool to improve the evaluation of treatment response in LN.

OBJECTIVE To investigate the long-term clinical, histological and serological affects of B-cell-depleting therapy (BCDT) in patients with LN refractory to conventional treatment. METHODS Twenty-five patients, followed for a mean time of 36 months (9-95 months), were included. Renal disease activity was evaluated with the BILAG index and renal response was determined according to the LN European consensus statement. Renal biopsies were performed for histological evaluation at baseline and follow-up. RESULTS Partial response (PR) or complete renal response (CR) was observed in 22 of 25 after a median of 12 months. Sixteen patients achieved CR after a median of 24 months. Six patients experienced a renal relapse. Proteinuria decreased significantly (P = 0.0002) from baseline to 36 months. A noteworthy histological improvement was seen in nearly all patients with a significant reduction in activity index (P = 0.01). Longer depletion time and low baseline values of IgM were indicative of achieving clinical remission during the first year after treatment (P = 0.03 and P = 0.04, respectively). CONCLUSION In therapy-resistant LN, BCDT induced clinical and histological improvements in the majority of patients. Transition from PR to CR was mainly seen during the second year of follow-up. Patients with longer depletion time and low baseline levels of IgM were more likely to gain a faster remission, suggesting that the clinical benefit may be linked to suppression of autoreactive plasmablasts. Although formal evidence of BCDT in LN is lacking, our data may provide guidance to clinicians considering therapeutic options in patients with refractory LN.

Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

Background Lupus nephritis (LN) is a major organ manifestation of Systemic Lupus Erythematosus (SLE). Renal biopsy is the current gold standard for assessment of renal pathology in LN, as non-invasive reliable markers are lacking. Ferritin is found in most tissues as a cytosolic protein that stores iron. Small amounts are secreted into the serum, where ferritin functions as an iron carrier. Ferritin is considered an acute phase protein, as it increases in response to stresses. Studies have reported elevated serum concentrations in patients with active compared to patients with inactive SLE, and also associations with LN. Objectives We assessed serum ferritin levels in patients with LN, in order to clarify its role in this SLE subset. Methods Serum levels of ferritin were determined by ELISA (Raybiotech Inc.) in 64 patients with biopsy-proven active LN (52 proliferative LN, PLN; 12 membranous LN, MLN), 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, and inactive urinary sediment. Histopathological responders (HR) were defined by ≥50% improvement of renal Activity Index in post-treatment biopsies. Results Serum levels of ferritin decreased following induction therapy for LN in the entire cohort (p Conclusions Our data suggest ferritin as a marker of histopathological response to induction treatment in patients with LN. In patients with MLN in particular, high baseline ferritin levels predicted unfavourable clinical response to induction treatment, and, despite being initially lower, baseline ferritin levels decreased in CR. This implies a role of ferritin in the pathogenesis of this LN subset and warrants further investigation. Disclosure of Interest None declared

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 Type I interferons (IFN), particularly IFN-αs, are considered to have a pivotal role in SLE. Recently, increased levels of type III IFNs (IFN-λs) have been described to be also associated with SLE. Objectives We measured circulating levels of IFN-λ, IL-17, IL-23, IP-10 and also IFN-α, in a cohort of SLE patients and investigated their association with clinical and laboratory manifestations of the disease. Population controls were investigated as comparators. Methods 261 SLE patients and 276 population controls, identified through the population registry and matched for age, sex, and region of living, were included. All participants were examined by clinician rheumatologist and assessed for current organ manifestations and disease related organ damage. Sera were collected at inclusion and stored at -70* C until analysis. Serum levels of IFN-α, IFN- λ, IL-17, IL-23 and IP-10 were measured in sera by commercial ELISA. Results IFN-λ was detected in 76 (29,1%) patients and IFN-α in 115 (44%). In 108 patients (41.4%) neither of the cytokines was detected. Both IFN-λ and IFN-α were detected more often and in higher levels in patients. IFN-λ levels did not correlate to the levels of IFN-α, and only in 38 (14.5%) patients had detectable levels of both. Levels of IL-17, IL-23 and IP-10 correlated with each other and with IFN-λ. In comparison, only a weak correlation between levels of IFN-α and IL-23 was observed. Detectable levels of IFN-λ were associated with lower incidence of fever, photosensitivity and also arthritis. Patients with detectable IFN-α had active mucocutaneous disease, serositis and lower levels of C3 and C4, and also presence of anti-Ro/SSA and anti-La/SSB. Incidence of nefritis and DVT was lower in this group. Co-detection of IFN-α and IFN-λ was significantly associated with lymphadenopathy, serositis, cortical dysfunction and presence of antiphospolipid antibodies. IFN-α was associated with overall lower disease damage. However, IFN-λ was associated with lower incidence of musculoskeletal, but higher frequency of cerebrovascular damage. The triple detection of IFN-λ, IL-17 and IL-23 was significantly associated with overall higher disease damage score, and particularly higher incidence of renal damage. Conclusions Our study demonstrates that in SLE patients the levels of IFN-α and IFN-λ do not correlate, but rather dissect patient9s groups with different target organs. Triple positivity for IFN-λ, IL-17 and IL-23 is associated with the higher disease damage, in particular kidney damage. References Interferon-lambda1 induces peripheral blood mononuclear cell-derived chemokines secretion in patients with systemic lupus erythematosus: its correlation with disease activity. Wu Q, Yang Q, Lourenco E, Sun H, Zhang Y. Arthritis Res Ther. 2011 Jun 16. Disclosure of Interest None declared

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

To evaluate the agreement and performance of two tests for aPLs with regard to association with manifestations of the APS in patients with SLE.We investigated 712 SLE patients and 280 population controls. Cardiolipin and β(2) glycoprotein-I antibodies were measured with routine ELISA and a new automated method. Three positivity cut-offs (99%, 90% of controls and recommended cut-off by manufacturers) were used. Associations with previous thrombotic events, thrombocytopenia and, in a subgroup of patients, obstetric morbidity (n = 296) were evaluated. Results were compared with the LA test, performed in 380 patients.Inter-test agreement was moderate (demonstrated by κ-values 0.16-0.71). Performance of the two tests was similar: at the 99th percentile cut-off, sensitivity for any thrombotic event ranged from 3.7% to 24.8%, while specificity was 84.7-97.7%. Regardless of assay, IgG isotypes were associated with venous thrombosis and ischaemic cerebrovascular disease, whereas aPLs of IgM isotype were weakly associated with ischaemic heart disease. Associations were greatly affected by aPL level. LA performed better than the specific aPL tests. LA was associated with any thrombotic event, odds ratio 5.4 (95% CI 3.1, 9.4), while the specific aPL tests ranged from non-significant to an odds ratio of 1.9 (95% CI 1.03, 3.4) using criteria cut-off. LA was also convincingly associated with other APS manifestations.In relation to thrombotic manifestations, there was moderate agreement but no clear advantages when comparing a routine aPL ELISA with an automated method. APL isotype and titre as well as LA positivity are important for risk assessment in SLE patients.

Background and objectivesVascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.Methods665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.ResultsHLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL—cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04—while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.ConclusionsThe HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.

Introduction: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). Methods: The exons of complement inhibitor genes CD46 and CFH (factor H) were fully sequenced using the Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and in healthy controls (n = 523). Results: We found nonsynonymous, heterozygous mutations in CFH in 6.1% patients with nephritis, in comparison with 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two nonsynonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients versus 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in noncoding regions of CD46, which were previously implicated in aHUS. Conclusions: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.

New 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.We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration1 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 CT20080004.487 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.In 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.Swedish Rheumatism Association, Schering-Plough.

Background Microparticles (MPs) are circulating cellular blebs released by activated and apoptotic cells. MPs have been associated with autoimmune diseases (1) and with vascular events in the general population (2). Objectives We investigated the number and phenotype of MPs in patients with systemic lupus erythematosus (SLE) and population based controls. We hypothesised that the MP profile could identify SLE subgroups with previous vascular events and/or antiphospholipid syndrome (APS). Methods 290 consecutive SLE patients and 290 controls, individually matched to the patients were included. Previous vascular events, clinical characteristics and presence of antiphospholipid antibodies (aPL) were tabulated. MPs positive for phosphatidylserine (PS) were identified with lactadherin and measured by flow cytometry. They were phenotyped according to cellular origin (platelet, endothelial or leukocyte) and protein expression (CD40 ligand=CD40L, tissue factor=TF, vascular cell adhesion molecule 1=VCAM-1 or high-mobility group protein B1=HMGB1). C4d expression was measured on endothelial and platelet MPs, regardless of PS expression. Results There was a highly significant difference between SLE patients and controls for all MPs, regardless of origin, p Conclusions Patients with SLE had 2-10 times elevated levels of MPs of various cellular origins in blood. Associations with borderline p-values between MPs of endothelial origin and previous vascular events were found but the subgroup with APS could not be identified by MP profile. Though, analytical challenges remain; the remarkably high levels of MPs in SLE patients may provide new insights into the pathogenesis of SLE, and MPs merit further evaluation as candidate diagnostic biomarkers for SLE. References Pisetsky DS, Ullal AJ, Gauley J, Ning TC. Microparticles as mediators and biomarkers of rheumatic disease. Rheumatology (Oxford). 2012;51(10):1737-46. Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost. 2013;11 Suppl 1:24-35. Acknowledgements The work in this abstract will be part of Dr Vikerfors thesis, defended 24 Feb and distributed both electronically and in paper format 30 Jan. Disclosure of Interest None declared

Background Lupus nephritis (LN) is a major manifestation of Systemic Lupus Erythematosus (SLE). The burden of antiphospholipid antibodies (APLA) in LN has not been clarified. Objectives We investigated a potential role of APLA levels as a biomarker of severity in renal lupus. Methods Serum levels of APLA (antibodies to cardiolipin (aCL) and β 2 -glycoprotein 1 (anti-β 2 -GP1); reference values 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 Percentages of APLA positive patients in the active LN cohort at baseline (aCL: 12.5% IgG, 9.4% IgM; anti-β 2 -GP1: 20.3% IgG, 9.4% IgM) were comparable to the ones in the cross-sectional SLE cohort (entire cohort: 20.1% IgG, 7.1% IgM aCL, 21.3% IgG, 7.3% IgM anti-β 2 -GP1; patients with renal involvement, n=200: 22.5% IgG, 6% IgM aCL, 24% IgG, 6.5% IgM anti-β 2 -GP1; patients without renal involvement, n=295: 18.6% IgG, 8.1% IgM aCL, 19.7% IgG, 8.1% IgM anti-β 2 -GP1), but lower in the LN cohort following induction treatment (aCL: 9.4% IgG, 1.6% IgM; anti-β 2 -GP1: 10.9% IgG, 3.1% IgM). APLA titers showed significant decreases following treatment (p 2 -GP1; HR, n=43: p=0.001 for aCL, p=0.002 for anti-β 2 -GP1) but not in non-responders. IgG titers decreased significantly in all response groups, with the exception of IgG aCL in clinical non-responders (p=0.068). In the membranous LN subgroup, APLA levels remained unchanged regardless of treatment outcome. IgM titers decreased significantly in all treatment groups. IgG titers decreased significantly in patients given cyclophosphamide and mycophenolate mofetil, but remained unchanged in rituximab-treated patients. CKD stage at discharge correlated significantly with the duration of follow-up (p=0.15, r=0.3) but did not correlate with either APLA levels or positivity. Conclusions APLA levels were comparable in SLE patients with or without renal involvement and in patients with active LN, but decreased significantly following induction therapy given for LN. In proliferative LN, IgG and IgM titers were affected differently by immunosuppression with regard to treatment response: IgG titers decreased regardless of treatment outcome while IgM decreased only in responding patients. As expected, renal damage increased with disease duration; however, neither APLA levels nor positivity correlated with long-term renal outcome. Investigation of the association between APLA and treatment response in larger LN cohorts might give further insight. Disclosure of Interest None declared

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

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 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

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-b 2 glycoprotein-1 (ab 2 GP1)) 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 ab 2 GP1 IgG, and this association was primarily driven by former smokers (p 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

Background There are several problems with the current methods for detection of antiphospholipid antibodies (aPL) and there is an on-going discussion about the interpretation of different aPL-tests in everyday practice. (1) Objectives I. To evaluate agreement and performance of two tests for aPL, including a new automated assay. II. To study the importance of isotypes and titers with respect to thrombotic events in patients with Systemic Lupus Erythematosus (SLE). Methods We investigated 712 SLE-patients and 280 controls. Antibodies against cardiolipin and b 2 glycoprotein-I were analysed by a routine ELISA method (Orgentec, Mainz, Germany) and a new, automated method (Elia Cardiolipin IgG/IgM, Elia –β 2 –Glycoprotein I IgG/IgM performed on Phadia 250, Phadia AB, now Thermo Fisher Scientific, Germany). We used three cut-offs for positivity and calculated specificity, sensitivity and odds ratio (OR) for objectively verified previous thrombotic events. Results were compared with outcomes for Lupus anticoagulant (LAC) performed in 380 of the patients. Results Agreement between and performance of both aPL-methods were modest with no strong advantage in performance for either test. Using a cut-off corresponding to established criteria (2) sensitivity for the individual aPL-tests for any previous thrombosis ranged from 3.7 to 24.8% while specificity ranged from 84.7% to 97.7%. Regardless of assay, antibodies of IgG-isotype were associated with venous thrombosis and ischemic cerebrovascular disease while IgM-antibodies were associated with ischemic heart disease. Associations were highly affected by the positivity cut-off-level. ORs for LAC were generally higher than for the specific aPL-tests. For any previous thrombosis, OR (95% Confidence Interval) for LAC was 5.4 (3.1-9.4) while OR for the individual aPL-tests using a cut-off corresponding to established criteria ranged from non-significant to 1.9 (1.03-3.4) with the highest OR for routine ELISA cardiolipin IgG. Conclusions The most interesting finding in this study is that aPL of IgG and IgM isotypes were associated with different types of thrombotic events. Only moderate agreement between, but no clear advantage in relation to thrombotic manifestations, was observed when comparing a routine ELISA for aPL with a new automated method. The LAC test performed better than both aPL-assays. References Galli M. Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome. Semin Thromb Hemost. 2008 Jun;34(4):329-34. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. Disclosure of Interest None Declared

Association of STAT4, IRF5 and BLK polymorphisms with severity and outcome in lupus nephritis

Cytokines in lupus nephritis, levels of IL-17 and IL-23 in association to histopathology and response to treatment

Ischemic vascular disease and antiphospholipid antibodies are associated with HLA-DRB1 *04/*13 alleles in systemic lupus erythematosus

Introduction: High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a proinflammatory mediator following extracellular release. HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE). However, the local expression of HMGB1 in active lupus nephritis (LN) is not known. Here we aimed to study both tissue expression and serum levels of HMGB1 in LN patients with active disease and after induction therapy. Methods: Thirty-five patients with active LN were included. Renal biopsies were performed at baseline and after standard induction therapy; corticosteroids combined with immunosuppressive drugs. The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index. Serum levels of HMGB1 were analysed by western blot. HMGB1 expression in renal tissue was assessed by immunohistochemistry at baseline and follow-up biopsies in 25 patients. Results: Baseline biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B). Follow-up biopsies showed WHO I to II (n = 14), III (n = 6), IV (n =3 ) or V( n = 12), and 15/35 patients were regarded as renal responders (BILAG C/D). At baseline HMGB1 was significantly elevated in serum compared to healthy controls (P < 0.0001). In all patients, serum levels decreased only slightly; however, in patients with baseline WHO class IV a significant decrease was observed (P = 0.03). Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium. There was no clear difference in HMGB1 expression comparing baseline and follow-up biopsies or any apparent association to histopathological classification or clinical outcome. Conclusions: Renal tissue expression and serum levels of HMGB1 were increased in LN. The lack of decrease of HMGB1 in serum and tissue after immunosuppressive therapy in the current study may reflect persistent inflammatory activity. This study clearly indicates a role for HMGB1 in LN.

Introduction Renal involvement is a severe complication in systemic lupus erythematosus (SLE). Moreover, a subset of SLE patients develop the anti-phospholipid syndrome (APS), characterised by the occurrence of anti-phospholipid antibodies in combination with macro- and microvascular thrombotic manifestations, including acute and chronic antiphospholipid-associated nephropathy (APLN). Clinical presentations of lupus nephritis and APLN are similar and a renal biopsy is necessary to differentiate between the conditions. Our aim with this study was to investigate the occurrence of histopathological findings consistent with APLN (hAPLN) in renal biopsies from SLE patients and to investigate associations with anti-phospholipid antibody specificities, clinical manifestations, HLA-DRB1 alleles, and long-term renal outcome. Method Consecutive renal biopsies from 112 SLE patients with renal involvement were investigated and evaluated for findings of hAPLN; in all there were 236 renal biopsies. Data from biopsy reports and clinical information were collected. Autoantibodies against cardiolipin and β2-glycoprotein-1 were measured by enzyme-linked immunosorbent assay. A lupus anticoagulant test was determined with a modified Dilute Russel Viper Venom method. HLA genotyping was performed by sequence-specific primer PCR. Renal outcome was determined at study end. Results The prevalence of hAPLN was 14.3% among SLE patients with renal involvement. Compared to patients with pure lupus nephritis, occurrence of hAPLN was associated with intima changes (odds ratio (OR) = 24; 95% confidence interval (CI), 3.0 to 189.8; P < 0.0001), hypertensive vascular changes (OR = 7.8; 95% CI, 1.6 to 39.4; P = 0.01), inflammatory infiltrates (OR = 6.5; 95% CI, 1.7 to 25.1; P = 0.007) and tubular atrophy (OR = 13.1; 95% CI, 1.7 to 103.6; P = 0.002). hAPLN was associated with the presence of cardiolipin antibodies (OR = 3.3; 95% CI, 1.0 to 10.8; P = 0.05) and triple anti-phospholipid antibody positivity (OR = 4.2; 95% CI, 1.3 to 13.7; P = 0.02). Patients with hAPLN were more hypertensive (OR = 3.8; 95% CI, 1.2 to 12.3; P = 0.03) and had higher levels of creatinine as compared to lupus nephritis patients (median 116 versus 75 μmol/L; P < 0.0001). We found significantly higher frequency of HLA-DRB1*13 (OR = 5.1; 95% CI, 1.7 to 15.4; P = 0.03) and development of end-stage renal disease (OR = 5.8; 95% CI, 1.7 to 19.7; P = 0.008) in hAPLN compared with lupus nephritis. Conclusion hAPLN is a severe and often unrecognized condition in SLE patients with renal involvement. We have demonstrated an increased risk for development of renal impairment and a genetic predisposition in hAPLN patients compared to lupus nephritis patients.

Introduction Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients. Methods Thirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index. Results At baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found. Conclusions In the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis. Original Publication:Christopher Sjöwall, Agneta Zickert, Thomas Skogh, Jonas Wetterö and Iva Gunnarsson, Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis, 2009, Arthritis Research & Therapy, (11), 6, R188.http://dx.doi.org/10.1186/ar2880Licensee: Biomed Central / BioMed Centralhttp://www.biomedcentral.com/