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ObjectivesA 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.MethodsSixty-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.ResultsCR 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.ConclusionsDespite 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.

BackgroundRecent 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.MethodsFifty-two patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of TNF-α, IFN-γ, IL-6, IL-10, IL-17, IL-23 and TGF-β 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.ResultsAt 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-γ (p = 0.03) were increased in patients vs. controls. In contrast, TGF-β 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.ConclusionsHigh 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.

Background and aim Interferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features. Methods Four hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients’ measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis. Results All IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE. Conclusions High functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways. Electronic supplementary material The online version of this article (10.1186/s13075-019-1878-y) contains supplementary material, which is available to authorized users.

IntroductionSerum 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.MethodsThirty-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.ResultsAt 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.ConclusionsIn 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.

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 = 3.7×10−9, 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 (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (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  = 1.6×10−3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

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ObjectivesComposite criteria/indices are presently used to diagnose and monitor patients with systemic lupus erythematosus (SLE). Biomarkers for these purposes would be helpful in clinical practice. We therefore evaluated a large panel of cytokines and basic laboratory tests and investigated their performance as discriminators versus controls and as biomarkers of disease activity (DA).MethodsWe examined 437 patients with SLE, fulfilling American College of Rheumatology-82 criteria, and 322 matched controls. DA was assessed according to both SLE DA Index 2000 (SLEDAI-2K) and SLE Activity Measure (SLAM). British Isles Lupus Activity Group (BILAG) was used to assess renal DA. Additionally, 132 patients self-assessed their Global Disease Activity (PtGDA). Mesoscale Discovery 30-plex cytokine assay and routine blood chemistry was performed on fasting EDTA-plasma.ResultsOf 26 tested biomarkers, we identified TNF-α as the superior discriminator between patients with SLE and controls (median=4.5 pg/mL, IQR=3.1–6.2 vs median=2.3 pg/mL, IQR=2.0–2.8). The strongest correlations to SLEDAI-2K and SLAM were obtained with TNF-α (Spearman rho (ρ)=0.32 and ρ=0.34, respectively), partly driven by the nephritis subgroup, and with p-albumin (ρ=−0.33 and ρ=−0.31, respectively). P-albumin was decreased and TNF-α was increased in patients with kidney involvement (renal BILAG A/B vs C/D/E, p=4×10–16 and p=6×10–9 respectively). IP-10 was increased in patients with joint involvement (SLAM item 24≥2 vs ≤1, p=0.0005) but did not differ when comparing patients with active/inactive kidney involvement. The most powerful correlations to PtGDA was observed with p-albumin (ρ=−0.42), IL-6 (ρ=0.30) and TNF-α (ρ=0.29).ConclusionTNF-α and p-albumin both performed well as discriminators between patients with SLE and controls and as proxies for DA according to both rheumatologists’ and patients’ assessments. In particular, renal DA was well reflected by TNF-α. We propose that the TNF-α and p-albumin merit further investigations as clinically useful biomarkers in SLE. We also observed that the pattern of activated cytokines varies with organ involvement.