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Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE., Competing Interests: Competing interests: RvV has received consulting fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, Janssen, Pfizer, Sanofi, Servier, UCB and Vielabio; speaker honoraria with AbbVie, Galapagos, GSK, Janssen, Pfizer and UCB, and support for educational programmes and institutional grants from Pfizer and Roche. ADA has received consulting fees from AbbVie, Amgen, Aurinia, AstraZeneca, BMS and GSK; and has been an investigator for GSK, Janssen, Pfizer, UCB, Vielo, AstraZeneca and Eli Lilly. ASB has received consulting fees from Alexion, Principio, Calliditas, Aurinia, Catalyst, Travere, GSK, Visterra, Silence, Novo Nordisk, Otsuka, ChemoCentrx and Novartis. INB is a National Institute for Health Research (NIHR) Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre. His institution has received research grants from GSK and Genzyme/Sanofi and consultancy fees from GSK, UCB, Eli Lilly, BMS, Merck Serono, Aurinia and IL-TOO. INB has received speaker fees from GSK, AstraZeneca and UCB. MD’E has received consulting fees from Aurinia, AstraZeneca, Biogen, Gilead, Pfizer and GSK. AS has received research grant support from GSK, Novartis and Pfizer; and has been an advisory board and speaker bureau member for GSK. MBU has received research grant support from GSK and has been an advisory board and speaker bureau member for GSK, and an advisory board member for AstraZeneca, Eli Lilly and UCB. M-HZ has been a consultant or advisory board member for GSK, AstraZeneca and Roche. RF has received research support from GSK and is an advisory board member for GSK. AC, MD, RAL and HAQ are employees of GSK and hold stocks and shares in the company., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The overall kidney survival among lupus nephritis patients has improved with currently used induction immunosuppression regimens of corticosteroids and either cyclophosphamide or mycophenolate mofetil; however, there still remains a significant number of lupus nephritis patients who do not achieve remission with these regimens. Investigators have looked at other immunosuppressive regimens for lupus nephritis, and there has been interest in the use of calcineurin inhibitors in this regard. Calcineurin inhibitors are potentially an attractive option because of their established ability to inhibit T cell function, attenuate proteinuria through non-immunologic means, and their safety in pregnancy and lactation. In this review, we discuss the findings and limitations of selected trials that evaluated the use of calcineurin inhibitors in the treatment of lupus nephritis, either with corticosteroids alone or as a component of multitarget therapy when combined with mycophenolate mofetil. There may be a role for calcineurin inhibitors among patients with heavy proteinuria, as well as younger patients with refractory lupus nephritis. The multitarget therapy trials reveal higher rates of remission compared with mycophenolate mofetil alone and cyclophosphamide; however, some trials highlight the possibility of more infectious adverse events. We discuss the need for further study of calcineurin inhibitors in more diverse patient populations and the need for trials with longer follow-up with "hard" endpoints beyond proteinuria reduction, such as worsening CKD or repeat protocol biopsies, given the calcineurin inhibitors ability to reduce proteinuria non-immunologically and thus increased rate of relapse when the drug is tapered. While there may indeed be a space for calcineurin inhibitors to help increase remission rates in lupus nephritis patients, more work is needed to help address the questions the studies available to date have yet to answer., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this "stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis., Design, Setting, Participants, & Measurements: Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed., Results: Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98., Conclusions: In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis., (Copyright © 2019 by the American Society of Nephrology.)

In systemic lupus erythematosus, nephrotic-range proteinuria typically signals the presence of a proliferative lupus nephritis (class III/IV) and/or membranous lupus nephritis (class V, with or without concomitant class III or IV lesions). However, in rare instances, systemic lupus erythematosus patients with nephrotic syndrome have kidney biopsy findings of normal glomeruli or focal segmental glomerulosclerosis lesions, with or without mesangial proliferation, on light microscopy; the absence of subepithelial or subendothelial deposits on immunofluorescence and electron microscopy; and diffuse foot process effacement on electron microscopy. This pattern, termed lupus podocytopathy, is a unique form of lupus nephritis that mimics minimal change disease or primary focal segmental glomerulosclerosis and represents approximately 1% of lupus nephritis biopsies. Here we review the clinical features, histological manifestations, diagnostic criteria and classification, pathogenesis, treatment, and prognosis of lupus podocytopathy., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Most of the attention paid to lupus nephritis, in the medical literature and in clinical trials, has primarily focused on proliferative forms of lupus nephritis (class III and IV lesions), but with lower thresholds to biopsy and rebiopsy patients with lupus, clinicians are encountering more cases with purely mesangial disease (class I and II) or membranous nephropathy patterns (class V). These lesions often will be associated with milder disease courses but still require dedicated follow-up by a nephrologist and focused therapeutic strategies that, at times, will include immunosuppression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The disease manifestations and outcomes in lupus nephritis are exceptionally heterogeneous. In particular, some ethnic populations are disproportionately affected by the most severe forms of the disease. A new study exploring NF-κB dysregulation and its associated genetic variants might help explain the link between ancestry and outcomes in lupus nephritis.

In the setting of an IgG-dominant immune complex-mediated glomerulonephritis, there are multiple pathological findings that strongly suggest the diagnosis of lupus nephritis (LN) including (i) 'full-house' immunofluorescence staining for IgG, IgM, IgA, C3 and C1; (ii) extraglomerular immune deposits; (iii) combined mesangial, subendothelial and subepithelial immune deposits and (iv) the presence of endothelial tubuloreticular inclusions. We report four female adult patients with renal biopsy findings which are highly suggestive of LN but without extrarenal signs, symptoms or serologies of systemic lupus erythematosus at the time of biopsy or over a mean follow-up period of 3 years. Despite aggressive therapy, outcomes were poor in this small cohort. We refer to these cases as renal-limited 'lupus-like' nephritis.

Kidney involvement is a frequent and dreaded consequence of systemic lupus erythematosus. While historically this condition was devastatingly morbid, over the past thirty years an improved understanding of the disease's pathobiology has accompanied increasingly effective treatment regimens that have dramatically improved the prognosis for affected patients. Induction and maintenance of remission can now be obtained in the majority of patients, although at least 20-30% may be refractory to treatment. What's more, the standard drugs in use for lupus nephritis remain fairly broad immunosuppressants, and carry notable risks and side effects. Recent years have witnessed an explosion in the number of novel immunomodulatory drugs being developed, with increasingly specific targets of action in the immune system. These molecules hold promise for a range of autoimmune disorders, including lupus nephritis, and several are already being actively investigated for that purpose. Here we review the current state of the art in the treatment of lupus nephritis, highlight the limits of standard treatments, and discuss the most promising of the novel therapies coming down the pipeline.

The treatment of lupus nephritis has changed significantly over the past decade in large part because of data from well-conducted randomized clinical trials. The concept of two phases of therapy-induction and maintenance-is widely accepted. The histopathologic classification of lupus nephritis continues to guide therapy, and treatment for all major classes of lupus nephritis has seen some shift in management during this time. New regimens using lower doses and shorter treatment durations of intravenous cyclophosphamide have been advanced to reduce toxicity without sacrificing efficacy of therapy. Mycophenolate mofetil has emerged as a viable alternative to cyclophosphamide for induction therapy of both proliferative and membranous lupus nephritis. Combination induction treatment with multiple agents has also been successful. Large controlled trials using mycophenolate mofetil and azathioprine for maintenance therapy have been performed. Here, we review recent additions to the growing body of literature on how to most effectively treat lupus nephritis with the least amount of toxicity. We discuss new treatment strategies currently being explored in clinical trials.