Non-renal Systemic Lupus Erythematosus Research Articles

Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations

ObjectivesTo analyse the new evidence (2018–2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.MethodsSystematic literature reviews were...

Symposium 6

The ultimate goal of treatment of systemic lupus erythematosus (SLE) is to prolong survival without compromising the quality of life. The survival rates of SLE have plateaued since the 2000s’ and morbidities related to disease activity and treatment are still problematic. A big unmet need for SLE therapy is to develop strategies that can enhance efficacy, reduce disease flares and drug related complications. Cocktail immunosuppressive therapies for the synergistic effect of individual drugs may enhance efficacy and enable dosage reduction. However, risk of infective complications, adoption of a step-up or step-down approach and the choice of agents are still controversial, partly because of the issue of cost-effectiveness. Belimumab is the first biological agent licensed for pediatric and adult patients with renal and non-renal SLE, based on several pivotal randomized controlled trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, BLISS-LN). The continuous use of belimumab enables reduction of disease flares, glucocorticoid doses and organ damage. Anifrolumab, a monoclonal antibody against type I interferon receptors, has shown efficacy for non-renal SLE in the TULIP studies. It is recently licensed for moderate to severe SLE patients who are receiving standard therapies. Although rituximab did not show benefit in renal and non-renal SLE, it is commonly used off-label to treat refractory lupus manifestations. The newer generation anti-CD20 biologic, obinutuzumab, shows promising preliminary results in a phase 2 lupus nephritis (LN) trial. Combination of anti-CD20 and anti-BAFF is being studied in LN but the results are conflicting hitherto. Ianalumab, a monoclonal antibody against BAFF receptor that exhibits dual mechanisms of action (BAFF inhibition and B cell depletion), is being studied in LN. The updated 2023 EULAR recommendations for SLE have included the role of biological agents in the treatment algorithm. Belimumab and anifrolumab may be considered in non-major organ SLE, including skin disease, that is refractory to hydroxychloroquine with or without other immunosuppressive agents. Initial combination therapy of glucocorticoids, mycophenolate mofetil or low dose cyclophosphamide, with belimumab is an option for the treatment of severe LN, and belimumab may be used as long-term maintenance therapy of SLE/LN. In this talk, the evidence and the role of the older and newer biologic and targeted agents in SLE/LN will be reviewed.

Lupus and the Bottom Line: Why we Need to Talk About the Economic Impact

Lupus and the Bottom Line: Why we Need to Talk About the Economic Impact

Lupus nephritis: clinical characteristics, serological associations, pattern of pro- and anti-inflammatory markers

The present study aimed to investigate the prevalence, clinical, and laboratory characteristics of renal involvement in a large cohort of Ukrainian patients with systemic lupus erythematosus (SLE).
 Methods. A total of 380 patients with SLE were enrolled in this cross-sectional study, including 176 with lupus nephritis (LN) and 204 with non-renal SLE. Patients were reviewed for demographic details, clinical SLE manifestations, SLE Disease Activity Index 2000 (SLEDAI-2K), and SLICC/ACR Damage Index. Laboratory evaluations included complete blood count with an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), anti-CRP antibodies, serum creatinine, complement C3 and C4 levels, urinalysis, 24-hour urine protein, specific autoantibodies, interleukin-6 (IL-6), IL-10.
 Results. There was a significantly higher frequency of malar rash, lymphadenopathy, splenomegaly, serositis, pulmonitis, fever, necrotizing vasculitis, and a history of arterial/venous thrombosis in patients with LN; while Raynaud’s phenomenon, Sjogren’s syndrome, peripheral nervous system manifestations occurred more often in patients with non-renal SLE. Patients with LN were found to have higher ESR levels and lower IL-10 levels. Either frequency of anti-dsDNA positivity and its titer were higher in the LN group with no differences regarding other autoantibodies. C3 and C4, CRP, hs-CRP, anti-CRP, and IL-6 levels showed no significant difference between the groups.
 Multivariate analysis demonstrated that LN was positively associated with pulmonitis (OR 5.34 (95% CI 1.88-15.10), p=0.002), arterial/venous thrombosis (OR 6.80 (95% CI 1.87-24.70), p=0.004), anti-dsDNA positivity (OR 6.22 (95% CI 1.89-20.50), p=0.003), higher SLEDAI-2K score (OR 1.15 (95% CI 1.08-1.23), p<0.001) and negatively associated with Raynaud’s syndrome (OR 0.20 (95% CI 0.08-0.49), p<0.001) and younger age at disease onset (OR 0.96 (95% CI 0.93-0.99), p=0.003).
 In the LN group, 27 patients (15.3%) had nephrotic syndrome. In multivariate logistic analysis, male sex (OR 5.21 (95% CI 1.77-15.30), p=0.003) and higher SLICC/ACR score (OR 2.12 (95% CI 1.45-3.09), p<0.001) were associated with increased risk of nephrotic syndrome, whereas lymphadenopathy (OR 0.31 (95% CI 0.12-0.80), p=0.02) was associated with decreased risk of nephrotic syndrome development.
 Conclusions. Our cohort of Ukrainian LN patients showed different characteristics in demographic, clinical, and laboratory findings compared to patients with non-renal SLE. These features are mostly on par with LN patients of other nationalities around the world.

Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review.

Off-label rituximab is commonly used for patients with systemic lupus erythematosus (SLE) with extrarenal disease activity. The outcomes and tolerability of rituximab in adult patients with non-renal SLE treated at our hospital from 2013 to 2020 were described. Patients were followed-up until December 2021. Data were retrieved from electronic medical records. Response was classified into complete, partial or no response according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2 K)-based definitions. A total of 44 cycles were administered to 33 patients. Median age was 45 years and 97% were female. Median follow-up was 5.9 years (IQR 3.7-7.2). The most frequent symptoms that motivated rituximab use were thrombocytopenia (30.3%), arthritis (30.3%), neurological manifestations (24.2%) and cutaneous lupus (15.2%). After most treatment cycles a partial remission was achieved. The median SLEDAI-2 K score declined from 9 (IQR 5-13) to 1.5 (IQR 0-4) (p < 0.00001). The median number of flares significantly declined after receiving rituximab. Platelet counts significantly improved in patients with thrombocytopenia and patients with skin disorders or neurological manifestations also had a partial or complete response. Only 50% of patients with a predominant joint involvement had either a complete or a partial response. The median time to relapse after the first cycle was 1.6 years (95% CI, 0.6-3.1). Anti-dsDNA levels decreased significantly after rituximab from a median of 64.3 (IQR 12-373.9) to 32.7 (IQR 10-173), p = 0.00338. The most frequent adverse events were infusion-related reactions (18.2%) and infections (57.6%). All patients needed further treatment to maintain remission or to treat new flares. A partial or complete response was documented after most rituximab cycles in patients with non-renal SLE. Patients with thrombocytopenia, neurolupus, and cutaneous lupus had better response than those with a predominant joint involvement.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Associated with Disease Activity and Risk of Incident Cardiovascular Disease in Patients with Systemic Lupus Erythematosus.

To study the relationship of serum PCSK9 and disease activity and major adverse cardiovascular events (MACEs) in systemic lupus erythematosus (SLE). Consecutive patients who fulfilled ≥ 4 ACR criteria for SLE and consented for a biomarker study in 2009-2013 were included. Stored serum samples were assayed for PCSK9. PCSK9 levels were correlated with SLE disease activity scores. Patients were divided into two groups according to the median PCSK9 level and new MACEs over time were evaluated. The effect of PCSK9 level on MACEs and mortality was studied by Cox regression, adjusted for confounders. A total of539 SLE patients were studied (93% women, age 41.9 ± 14.0 years). The median PCSK9 level at baseline was 220 ng/ml. Patients with higher PCSK9 (≥ 220 ng/ml; n = 269) had significantly higher SLE disease activity index (SLEDAI) than those with lower PCSK9 (< 220 ng/ml; n = 270). PCSK9 levels were significantly higher in patients with active renal than active non-renal SLE, which in turn were significantly higher than those with inactive SLE or healthy controls. PCSK9 level correlated with SLEDAI in the overall population (ρ = 0.30; p < 0.001). Over 91.3 ± 18.6 months, 29 patients developed 31 MACEs and 40 patients succumbed (25% for vascular events). The cumulative incidence of MACEs at 5 years was 4.8% in the higher PCSK9 and 1.1% in the lower PCSK9 group (HR2.51[1.11-5.70]; p = 0.03). Cox regression revealed higher PCSK9 was significantly associated with MACEs (HR1.003[1.000-1.005] per ng/ml; p = 0.02) independent of age, sex, renal function, baseline disease activity score, traditional atherosclerotic risk factors, antiphospholipid antibody and the use of aspirin/warfarin, statins and immunosuppressive drugs. PCSK9 level was also independently associated with all-cause (HR1.002[1.000-1.004] per ng/ml; p = 0.03) and vascular mortality (HR1.004[1.000-1.007]; p = 0.04). We concluded that serum PCSK9 level correlates with SLEdisease activity. Higher serum PCSK9 levels are associated with increased risk of cardiovascular events and mortality in SLE.

Urine Galectin-3 binding protein reflects nephritis activity in systemic lupus erythematosus.

Lupus nephritis (LN) is a major and severe organ involvement in systemic lupus erythematosus (SLE), whose diagnosis and treatment necessitate to perform kidney biopsy, which is an invasive procedure. Non-invasive urine biomarkers are an active area of investigation to support LN diagnosis and management. To investigate the role of urinary galectin-3 binding protein (u-Gal-3BP) as a candidate biomarker of renal disease in biopsy proven LN. Levels of u-Gal-3BP were investigated in a cross-sectional fashion by ELISA in 270 subjects: 86 LN patients, 63 active SLE patients with no kidney involvement, 73 SLE patients with inactive disease and 48 age and sex-matched population-based controls (PBC). Moreover, urine samples were analysed separately by ELISA for additional markers of kidney pathology: neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule-1 (KIM-1) and galectin-3 (Gal-3). The concentrations of all studied molecules were normalized to urine creatinine levels. In 10 patients, post-treatment levels of the biomarkers were measured. Normalized u-Gal-3BP levels were higher in LN patients compared to the other groups (p < .0001). Comparing different LN classes, u-Gal-3BP levels were higher among patients with proliferative (class III/IV) and membranous (class V) as compared to mesangial (class II) forms (p = .04). In proliferative forms, u-Gal-3BP levels correlated with the activity index in renal biopsies (r = 0.42, p = .004). Moreover, in a subset of 10 patients with repeated kidney biopsy and urine sampling before and after induction treatment, a significant decrease of u-Gal-3BP was observed (p = .03). Among the other markers, KIM-1 was also able to discriminate LN from the other groups, while NGAL, OPN and Gal-3 could not in this cohort. Given its ability to discriminate LN patients from active non-renal and inactive SLE patients, the observed correlation with the activity index in renal biopsies, and its levels declining following treatment, u-Gal-3BP shows promise as a non-invasive urinary biomarker to help detecting and to monitor renal involvement in SLE patients and should be validated in larger cohorts.

Autoantibodies in lupus nephritis useful in distinguishing proliferative nephritis from membranous nephritis.

This study was conducted to determine autoantibodies associated with lupus nephritis, especially those useful in diagnosing proliferative and membranous nephritis. 106 patients with lupus nephritis and 63 patients with SLE but no nephritis were enrolled. 55 patients were selected from the lupus nephritis group and were divided into two groups: proliferative nephritis patients (n=36) and membranous nephritis patients (n=19). The autoantibody profiles of patients' sera were evaluated using the EUROLINE ANA profile 3 (IgG) kit. A higher positivity rate of anti-dsDNA antibody and anti-histone antibody were seen in lupus nephritis patients compared to non-renal SLE patients. In comparing between proliferative and membranous nephritis, positivity of anti-nucleosome antibody was higher in proliferative nephritis compared to membranous nephritis, although it was not statistically significant. However, anti-nucleosome antibody-positive patients with lupus nephritis had higher prevalence of hematuria and pyuria, which are strong indications of proliferative nephritis. Also, a significantly higher positivity rate of anti-RNP70 antibody was seen in membranous nephritis compared to proliferative nephritis. Our results showed anti-nucleosome antibody and anti-RNP70 antibodies may be predictive non-histological factors for discriminating between proliferative and membranous lupus nephritis.

Current Insights on Biomarkers in Lupus Nephritis: A Systematic Review of the Literature.

Lupus nephritis (LN) is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). However, promising emerging biomarkers pave the way toward an improved management of patients with LN. We have reviewed the literature over the past decade, and we herein summarise the most relevant biomarkers for diagnosis, monitoring, and prognosis in LN. An initial systematic search of Medline was conducted to identify pertinent articles. A total of 104 studies were selected to be included in this review. Several diagnostic biomarkers, including MCP-1, TWEAK, NGAL, and uric acid, exhibited good ability to differentiate LN patients from non-renal SLE patients. Several cytokines and chemokines, including IL-10, IL-17, MCP-1, and IP-10, hold promise for assessing LN disease activity, as do cell adhesion molecules (CAMs). Angiogenesis-related and haemostasis-related proteins have also displayed potential for monitoring disease activity. Biomarkers of responses to therapy include Axl, CD163, and BAFF, whereas VCAM-1, ALCAM, and ANCAs have been reported as prognostic markers, along with traditional markers. In addition, novel renal tissue biomarkers may prove to be a useful complement to histological evaluations. The overall heterogeneity of the inclusion criteria and outcome measures across different studies, along with a lack of validation in multi-centre cohorts, call for future collaborative efforts. Nevertheless, we foresee that several biomarkers hold promise toward optimisation of the management of LN, with the use of integrated omics and panels of less invasive biomarkers paving the way towards personalised medicine.

Interleukin (IL) 16: a candidate urinary biomarker for proliferative lupus nephritis

ObjectiveLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential...

B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools.

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

Disease Flare of Systemic Lupus Erythematosus in Patients With Endstage Renal Disease on Dialysis.

Although systemic lupus erythematosus (SLE) disease activity diminishes after starting dialysis, flares have been documented during dialysis. Hence, we studied the various clinical and therapeutic variables of patients with SLE who had a disease flare while on dialysis. The medical records of patients with SLE who received dialysis at 2 tertiary referral hospitals in South Korea were reviewed. The disease activity was analyzed in terms of the nonrenal SLE Disease Activity Index (SLEDAI), and the factors associated with SLE flares were evaluated. Of the total of 121 patients with SLE on dialysis, 96 (79.3%) were on hemodialysis (HD) and 25 (20.7%) were on peritoneal dialysis (PD). During a median follow-up of 45 months (IQR 23-120) after the initiation of dialysis, 32 (26.4%) patients experienced an SLE flare (HD, n = 25; PD, n = 7). The most common features of SLE flare were hematologic (40.6%; thrombocytopenia [31.2%] and leukopenia [21.8%]) and constitutional manifestations (40.6%). Fever was the most common (34.3%) feature among the constitutional symptoms. Treatments for disease flares were based on corticosteroids, and 11 (34.3%) patients required additional immunosuppressants, including cyclophosphamide and mycophenolate mofetil. Nonrenal SLEDAI score before dialysis initiation (HR 1.24, 95% CI 1.12-1.36; P = 0.001) was a significant risk factor for disease flare during dialysis. More than a quarter of the patients with SLE experienced a disease flare during dialysis, which most commonly had hematologic manifestations, particularly thrombocytopenia. Continued follow-up and appropriate treatments, including immunosuppressants, should be considered for patients with SLE receiving dialysis.

A glimpse into the future of systemic lupus erythematosus.

This viewpoint article on a forecast of clinically meaningful changes in the management of systemic lupus erythematosus (SLE) in the next 10 years is based on a review of the current state of the art. The groundwork has been laid by a robust series of classification criteria and treatment recommendations that have all been published since 2019. Building on this strong foundation, SLE management predictably will take significant steps forward. Assessment for lupus arthritis will presumably include musculoskeletal sonography. Large-scale polyomics studies are likely to unravel more of the central immune mechanisms of the disease. Biomarkers predictive of therapeutic success may enter the field; the type I interferon signature, as a companion for use of anifrolumab, an antibody against the common type I interferon receptor, is one serious candidate. Besides anifrolumab for nonrenal SLE and the new calcineurin inhibitor voclosporin in lupus nephritis, both of which are already approved in the United States and likely to become available in the European Union in 2022, several other approaches are in advanced clinical trials. These include advanced B cell depletion, inhibition of costimulation via CD40 and CD40 ligand (CD40L), and Janus kinase 1 (Jak1) and Tyrosine kinase 2 (Tyk2) inhibition. At the same time, essentially all of our conventional therapeutic armamentarium will continue to be used. The ability of patients to have successful SLE pregnancies, which has become much better in the last decades, should further improve, with approaches including tumor necrosis factor blockade and self-monitoring of fetal heart rates. While we hope that the COVID-19 pandemic will soon be controlled, it has highlighted the risk of severe viral infections in SLE, with increased risk tied to certain therapies. Although there are some data that a cure might be achievable, this likely will remain a challenge beyond 10 years from now.

The Economic Burden of Lupus Nephritis: A Systematic Literature Review.

IntroductionFew studies have evaluated the economic burden of lupus nephritis (LN). The aim of this systematic literature review (SLR) was to assess the economic burden (direct and indirect costs, and healthcare resource utilization [HCRU]) associated with LN, with particular focus on the burden of renal flares and end-stage kidney disease (ESKD).MethodsThis SLR (GSK study 213531) was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches of the MEDLINE and Embase databases were conducted for English language publications reporting cost or HCRU data in patients with LN (regardless of age or LN histological class) until December 10, 2019. Handsearching of conference proceedings and keyword-based searches in PubMed, Google, and Google Scholar were also conducted.ResultsTwenty-two studies were identified from 28 publications reporting the cost (n = 19) and HCRU (n = 13) associated with LN. Most studies were from North America (n = 13) and many used administrative claims data (n = 9). LN was associated with substantially higher direct costs (e.g., total annual, hospitalization, and ESKD-related direct costs), total indirect costs, and HCRU (e.g., hospitalization, outpatient services, and medication use) compared with patients without systemic lupus erythematosus (SLE) or non-renal SLE controls. ESKD and dialysis were significant contributors to economic burden. No studies described the cost of renal flares.ConclusionsThe consensus across the 22 studies was that the economic burden of LN is substantial, particularly in active or severe disease, or if there is progression to ESKD. Total direct cost may be underestimated in claims data given the challenges of identifying patients with LN. Further studies are vital to ascertain the cost of renal flares; a renal flare is likely to result in a period of increased HCRU, which could be mitigated by treatments that extend renal remission.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00368-y.

Cross-sectional study of plasma Axl, ferritin, IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium.

To evaluate the performance of 4 plasma protein markers for detecting disease activity in childhood-onset systemic lupus erythematosus (SLE) patients. Eighty-three consecutive pediatric patients fulfilling ≥4 ACR criteria for SLE and twenty-five healthy controls were prospectively recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using SLEDAI-2000 score. Fifty-seven patients had clinically active SLE (SLEDAI score ≥4, or having a flare). The plasma concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE. Plasma Axl levels were significantly higher in active renal versus active non-renal SLE patients. Levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores. Levels of Axl, IFGBP4 and sTNFR2 inversely correlated with plasma complement C3 levels. Only plasma Axl and ferritin levels correlated with degree of proteinuria. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA antibody titer or decreased C3. Ferritin and IGFBP4 levels were more specific for concurrent active lupus nephritis than anti-dsDNA or C3. Plasma ferritin was the best monitor of global SLE activity, followed by C3 then Axl, while both Axl and C3 were best monitors of clinical lupus nephritis activity. In childhood-onset SLE patients, plasma ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these plasma markers should be explored further in longitudinal cohorts of SLE patients.

Anti-dsDNA, anti-nucleosome, anti-C1q, and anti-histone antibodies as markers of active lupus nephritis and systemic lupus erythematosus disease activity.

IntroductionPrevious studies of anti‐dsDNA, nucleosome (Nucl), histone (His), and C1q antibodies have revealed their clinical value in systemic lupus erythematosus (SLE). However, the correlation between four autoantibodies and SLE activity, lupus nephritis (LN) remains controversial, and data are insufficient on longitudinal monitoring. This study aimed at evaluating the value of these autoantibodies in active LN, and their performance on cross‐sectional evaluating and longitudinal monitoring of SLE disease activity.MethodsSerum levels of four autoantibodies in 114 SLE patients, 219 other autoimmune disease patients (OAD), and 59 healthy controls were assayed by a quantitative immunoassay. Sera of 38 inpatients were obtained again after treatment.ResultsWe found that serum levels of four autoantibodies were significantly higher in SLE than OAD patients (p < 001), active LN than non‐renal SLE patients (p < .05), and higher in SLE patients with moderate and severe disease activity than mild disease activity (p < .01). Horizontally, serum level of each autoantibody was correlated with SLE disease activity index (SLEDAI) (p < .05), and correlation coefficient of anti‐dsDNA was the highest (r = .585). For longitudinal monitoring, the decreased levels of four autoantibodies were found following treatment (p < .001). Serum level variations of these antibodies were positively correlated with variations of SLEDAI (p < .05). The correlation coefficient of anti‐Nucl was the highest (r = .629). Although the levels of C3 and C4 increased after treatment, the change was not related to the change of SLEDAI (p > .05).ConclusionsAnti‐C1q, anti‐dsDNA, anti‐Nucl, and anti‐His perform well in diagnosing active LN and monitoring SLE disease activity. They could be indicators of active LN and SLE disease activity.

Association Between Urinary Epidermal Growth Factor and Renal Prognosis in Lupus Nephritis.

To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN). A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long-term follow-up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected. Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8-12.3 in patients with active LN versus median 48.0, IQR 45.3-64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme-linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P < 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman's r = -0.67, P < 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end-stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of <5.3 ng/mg. Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long-term kidney outcomes.

Assessment of serum macrophage migration inhibitory factor (MIF), adiponectin, and other adipokines as potential markers of proteinuria and renal dysfunction in lupus nephritis: a cross-sectional study

BackgroundTo date, the association of serum macrophage migration inhibitory factor (MIF) and serum adipokines with lupus nephritis is controversial.ObjectiveTo assess the utility of serum MIF, leptin, adiponectin and resistin levels as markers of proteinuria and renal dysfunction in lupus nephritis.MethodsCross-sectional study including 196 systemic lupus erythematosus (SLE) patients and 52 healthy controls (HCs). Disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Renal SLE involvement was investigated by renal-SLEDAI. MIF, adiponectin, leptin and resistin levels were quantified by ELISA. We assessed the correlations of quantitative variables by Spearman correlation (rs). Multivariable linear regression adjusted the variables associated with the severity of proteinuria.ResultsSLE patients had higher MIF (p = 0.02) and adiponectin (p < 0.001) than HCs. Patients with renal SLE involvement (n = 43) had higher adiponectin (19.0 vs 13.3 μg/mL, p = 0.002) and resistin (10.7 vs 8.9 ng/mL, p = 0.01) than patients with non-renal SLE (n = 153). Proteinuria correlated with high adiponectin (rs = 0.19, p < 0.009) and resistin (rs = 0.26, p < 0.001). MIF (rs = 0.27, p = 0.04). Resistin correlated with increased creatinine (rs = 0.18, p = 0.02). High renal-SLEDAI correlated with adiponectin (rs = 0.21, p = 0.004). Multiple linear regression showed that elevated adiponectin (p = 0.02), younger age (p = 0.04) and low MIF (p = 0.02) were associated with the severity of proteinuria. Low MIF and high adiponectin levels interacted to explain the association with the severity of proteinuria (R2 = 0.41).ConclusionsHigh adiponectin combined with low MIF concentrations int+eract to explain the severity of proteinuria in renal SLE. These findings highlight the relevance of adiponectin, resistin and MIF as markers of LN.

Plasma C4d Correlates With C4d Deposition in Kidneys and With Treatment Response in Lupus Nephritis Patients.

ObjectiveTo examine whether C4d plasma levels correlate with treatment response and C4d kidney deposition in systemic lupus erythematosus (SLE) with lupus nephritis (LN).MethodsC4d plasma levels were analyzed by a unique assay specifically detecting C4d arising from complement activation and C4 plasma levels were quantified with competitive ELISA. SLE patients with LN (71) and active SLE patients without LN (22) plus 145 controls were included. For 52 LN patients samples were available both at baseline and after immunosuppressive treatment. C4d kidney deposition was detected using immunohistochemistry in two matching kidney biopsies of 12 LN patients.ResultsIn comparison to population-based controls, plasma C4d levels were significantly increased in SLE patients (0.33 mg/L versus 0.94 mg/ml, p < 0.0001) with significantly higher levels in LN patients (1.02 mg/L) than in non-renal SLE patients (0.57 mg/L, p = 0.004). The C4d/C4 ratio was also significantly higher in LN (11.2) than in non-renal SLE patients (2.5, p = 0.0002). According to ROC curve analysis, C4d was found to be an accurate marker to discriminate LN from non-renal SLE patients (p = 0.004). The C4d/C4 ratio displayed even higher specificity, sensitivity and overall accuracy as marker for LN than C4d and C4 alone. At baseline, C4d levels correlated significantly with urine-albumin to creatinine ratio (rs = 0.43, p = 0.011) and with renal activity index (rs = 0.37, p = 0.002). Immunohistochemical staining showed glomerular deposits of C4d in kidney biopsies, which strikingly correlated with plasma C4d levels (rs = 0.7, p = 0.0002). Plasma C4d declined significantly after treatment in patients that experienced favorable clinical and histopathological response (p < 0.0001), while levels remained mainly unchanged in non-responders.ConclusionPlasma C4d discriminates LN from active non-renal SLE, correlates with C4d kidney deposits and appears valuable in monitoring responsiveness to various treatments. The C4d/C4 ratio might be superior to C4d alone.

Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus.

ObjectivesThe incidence of serious infections is poorly defined in patients with lupus nephritis (LN). It is also unclear if LN influences risk of serious infections in a longitudinal analysis. The aim of this study was to determine the incidence of serious infections in patients with SLE and LN, compared with patients with SLE without LN.MethodsA multicentre retrospective cohort study was conducted. Patients with LN identified at two tertiary centres were matched where possible with age and gender-matched patients with SLE without LN.Any infection requiring inpatient admission, occurring in the 6 months following index clinical visit, was considered serious. Cox regression was employed to investigate the association between risk of serious infection and LN status, and other relevant covariates.ResultsA total of 173 patients were included within the analysis (n=87 LN, n=86 SLE only). A total of 9.2% (n=8) of patients with LN experienced at least one serious infection within the study period, compared with 5.8% (n=5) of patients without LN, equivalent to 19.5 and 12.0 infections per 100 patient-years with and without LN, respectively. Univariable and multivariable analyses found no significant increased risk of serious infection in patients with LN versus controls (HR 1.61; 95% CI 0.53 to 4.92 and adjusted HR (aHR) 0.91; 95% CI 0.27 to 3.06, respectively). Increased prednisone dose and modified SLE comorbidity index were strongly associated with serious infection (aHR (per 5 mg) 1.21; 95% CI 1.07 to 1.37; p=0.003 and aHR 1.13; 95% CI 1.02 to 1.25; p=0.018, respectively).ConclusionsIn this cohort, adjusting for cofactors, the presence of LN alone does not appear to increase the risk of serious infections compared with patients with SLE without LN. However, increased prednisone dose at baseline visit and increasing comorbidity were independently associated with the incidence of serious infection.