Treatment Of Lupus Nephritis Research Articles

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production.ResultsWe found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Adoptive Cord Blood T Regulatory Cell Therapy Leads to Resolution of Inflammation and Decreased Proteinuria in Lupus Nephritis

Background. Systemic lupus erythematosus (SLE) is associated with widespread inflammation with multi-organ involvement where renal failure is the most dreaded and fatal complication. Adoptive therapy with cord blood (CB) derived T regulatory cells has been shown to improve outcomes in disease driven by inflammation including graft versus host disease (GvHD), inflammatory bone marrow disorder, COVID-19 induced acute respiratory distress syndrome. We hypothesize that CB Treg therapy can treat lupus nephritis. Methods. The suppressive abilities of CB Tregs expressing CD4+CD25highCD127lowFoxP3+ were assayed by human cytokines assay kits (IL-10, IFN-γ, IP-10, TNF-α, IL-6, and IL-17A) in the cell culture supernatants. For examining the efficacy of CB Tregs in vivo, SLE xenograft model was created with female Rag2-/-γc-/- mice transplanted with 3x106 human SLE-peripheral blood mononuclear cells (PBMCs) by intravenous injection on day 0. The mice were allowed to develop disease and on day 30 post-transplant, they were divided into 2 groups: i) control and ii) treatment. 1x107 ex vivo-expanded, cryopreserved, allogeneic, non-HLA matchedCB Tregs were injected into SLE xenografts intravenously once per week for 4 weeks through the tail vein. Serial blood draws were performed for the phenotypic analysis, cytokine assay and anti-double stranded (ds)DNA IgG antibody analysis. Serial examination of the urine samples was performed for creatinine and albumin quantification. Histopathologic examination of the harvested organs was performed at the time of planned euthanasia at 13 weeks. Results. Co-culture of CB Tregs with the pathogenic SLE-PBMCs decreased the secretion of inflammatory cytokines including IFN-γ, IP-10, TNF-α, IL-6, and IL-17A (Figure A) with a reciprocal increase in the secretion of the anti-inflammatory IL-10 cytokine (Figure B). Adoptive therapy with CB Treg cells led to a significant decrease in circulating CD8+ effector T cells and an increase in CD4+ helper T cells (Figure C). CB Treg recipients showed preserved weight gain (Figure D), lower GvHD score (Figure E) and improved overall survival (Figure F). A significant decrease in proteinuria at 9 weeks post-transplant (Figure G) correlated with a decrease in anti-dsDNA IgG Ab levels (Figure H) and soluble CD40 ligand levels (Figure I). Histopathological results from two index cases from each arm (Figure J) demonstrated that CB Treg recipients show reduced T-cells (CD3+) (Figure K) and B-cells (CD20+) (Figure L) in the kidneys, as well as a decrease in the lymphoid infiltration into glomeruli and renal parenchyma as compared to the control arm (Figure M). Conclusion. We are the first to demonstrate the benefit of allogeneic CB Treg cell therapy for treatment of lupus nephritis. We propose to examine such a strategy in the clinical setting. Figure Disclosures Nishimoto: Janssen Pharmaceutical K.K.:: Research Funding; Bayer Yakuhin, Ltd:: Research Funding. Sadeghi:Cellenkos Inc.: Current Employment. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Research in Brief

Belimumab, a recombinant IgG-1λ monoclonal antibody that inhibits B-cell activating factor, might be an effective treatment for lupus nephritis, according to a multicentre phase 3 trial by Richard Furie and colleagues. 448 patients were enrolled across 21 countries and randomly assigned to receive intravenous belimumab (10 mg/kg; n=224) or placebo (n=224) in addition to standard therapy (mycophenolate mofetil or cyclophosphamide–azathioprine). At week 104, 96 (43%) of 223 patients in the belimumab group had a primary efficacy renal response (the primary endpoint; defined as a urinary protein to creatinine ratio of ≤0·7, an estimated glomerular filtration rate no worse than 20% below the pre-flare value or ≥60 ml per min per 1·73 m2 of body-surface area, and no use of rescue therapy) versus 72 (32%) of 223 patients in the placebo group (odds ratio [OR] 1·6, 95% CI 1·0–2·3; p=0·03). The safety profile for belimumab plus standard therapy was similar to that of standard therapy alone.

Intrarenal injection of mesenchymal stem cell for treatment of lupus nephritis in mice - a pilot study.

The current project is to explore feasibility of direct intra-renal injection of human bone marrow derived mesenchymal stem cells (hMSC) for treatment of lupus nephritis in mice. The treatment protocol involved aged male BXSB (20 weeks) injected with 1 × 106 hMSC unilaterally under the renal capsule. Mice were harvested after 10 weeks follow-up for postmortem exam. Controls included untreated age matched male BXSB and healthy C57Bl/6. At the end of follow-up period, the survival of treated BXSB was 10 folds higher at 62.5% compared to survival of untreated control at 6.3%. The survival of C57Bl/6 remained at 100% with or without similar treatment. The renal pathology review was most significant for decreased tissue inflammation in treated BXSB compared to untreated controls. Renal tissue expression of IL-1b, IL17 were decreased and CTLA-4 was increased by RT PCR among treated compared to untreated BXSB. Thus, direct delivery of hMSC by intrarenal injection is a promising route for treatment of lupus nephritis as shown in this xenogeneic model. Further studies -using expanded numbers of mice to include other lupus strains- are warranted to investigate the mechanisms involved and to optimize treatment protocol for safety and efficacy.

Upregulation of FoxO3a expression through PI3K/Akt pathway attenuates the progression of lupus nephritis in MRL/lpr mice

FoxO3a plays key roles in inflammation and autoimmunity, and the PI3K-Akt-FoxO3a pathway has been proposed to modulate diverse biological processes. The aim of the present study, using lupus murine models, was to investigate whether FoxO3a contributes to the pathogenesis of lupus nephritis. LY294002 was used as an inhibitor of PI3K/AKT signaling pathway. FoxO3a-targeted small interfering RNA (siRNA) was also used for in vivo intervention. Female MRL/lpr mice were separately injected with LY294002, LY294002+siFoxO3a, and LY294002+siControl for 8 weeks. C57BL/6 mice were normal controls. Disease development, including serum creatinine (CRE), blood urea nitrogen (BUN), proteinuria, and renal pathological changes, was monitored. Levels of anti-dsDNA antibodies and immune complex (IC) deposition in the kidney were also measured. The expression of proteins was evaluated. We found that significant downregulation of FoxO3a was detected in the kidney of MRL/lpr mice as compared with normal control mice. Blockade of p-FoxO3a activation by LY294002 suppressed PI3K/Akt/FoxO3a pathway and the subsequent upregulation of FoxO3a in the nucleus resulting in the severity of inflammation and fibrosis in the kidney of MRL/lpr mice. Also, improved kidney function and decreased circulating anti-dsDNA antibodies were due to the upregulation of FoxO3a. Opposite results were obtained by specific siRNA silencing of Foxo3a in vivo. In conclusion, our research demonstrated that the upregulation of FoxO3a expression through inhibiting PI3K/Akt pathway attenuates murine lupus nephritis (LN). Thus, our results suggest that targeting of FoxO3a can be considered as a novel strategy for the treatment of LN.

Value of Urinary Neutrophil Gelatinase-Associated Lipocalin versus Conventional Biomarkers in Predicting Response to Treatment of Active Lupus Nephritis.

Introduction Lupus nephritis (LN) affects almost two-thirds of systemic lupus erythematosus (SLE) patients. Despite initial aggressive therapy, up to 25% of patients with LN will progress to permanent renal damage. Conventional serum markers for LN lack the sensitivity of an ideal biomarker. Urinary neutrophil gelatinase-associated lipocalin (UNGAL) is an excellent biomarker for early diagnosis of acute kidney injury and predicting renal outcomes. Objective To measure UNGAL among LN patients to correlate its levels with renal disease activity and to investigate its predictive performance in response to induction therapy. Patients and Methods. 40 SLE patients with biopsy-proven LN class III, IV, or V were randomly selected. The study was conducted in the internal medicine department and outpatient clinic in Ain Shams University Hospitals and completed after six months. UNGAL was measured at baseline, three-month follow-up, and after complete induction therapy. Results In LN patients at baseline, the mean serum creatinine was 2.57 ± 0.96 mg/dL and the mean UNGAL was 33.50 ± 18.34 ng/dL. Mean UNGAL levels of complete response, partial response, and nonresponse groups were 14.48 ± 2.99 ng/mL, 34.49 ± 4.09 ng/mL, and 62.07 ± 14.44 ng/mL, respectively. Based on the ROC curve, we found a better performance of baseline UNGAL to discriminate the complete response group from partial and nonresponse groups to predict response to induction, outperforming conventional biomarkers. The area under the curve was 0.943, and the best cutoff level was 26.5 ng/mL (92.31% sensitivity and 88.89% specificity). Conclusion UNGAL performed better than conventional biomarkers in predicting response to treatment of active LN.

Caracterización Clínica, Terapéutica y Pronóstica En Nefritis Lúpica, A Propósito De Un Caso

Introducción: El lupus eritematoso sistémico, es una enfermedad autoinmune crónica caracterizada por la producción de autoanticuerpos contra un amplio rango de autoantígenos,en la mayoría de pacientes están implicados numerosos tejidos y órganos entre los cuales se destacan los riñones, corazón, cerebro, articulaciones y piel. Una de las complicaciones más severas de la enfermedad es la nefritis lúpica convirtiéndose en causa importante de morbilidad y mortalidad.
 Objetivo: Describir un caso clínico enfocado en la nefritis lúpica.
 Material y métodos: Estudio descriptivo retrospectivo, presentación de caso clínico.
 Resultados: Paciente femenina de 29 años con diagnóstico previo de Lupus Eritematoso Sistémico quien acudió por presentar edema de miembros inferiores progresivo bilateral, de aproximadamente un mes de evolución sin causa aparente, de predominio matutino que dejó fóvea, en las últimas 48 horas se exacerbó en forma ascendente llegando a región palpebral, es catalogada con Lupus Eritematoso Sistémico con probabilidad de alta actividad por compromiso renal (Síndrome Nefrótico), con diagnósticos diferenciales de Insuficiencia Cardiaca Congestiva y Crisis Hipertensiva tipo Urgencia, recibió tratamiento inmunosupresor con corticoterapia, y se programó biopsia renal para definir diagnóstico, pronóstico y tratamiento de nefritis lúpica.
 Conclusiones: La presencia de nefropatía lúpica revela un pobre pronóstico, los predictores clínicos como la creatinina sérica, proteinuria y actividad inmunológica influencian el pronóstico a largo plazo.

Comparison between Mycophenolate and Cyclophosphamide in Treatment of Lupus Nephritis

Background: Systemic lupus erythematosus is a chronic inflammatory disease that can affect any organ, but very often injures the kidney. It is more prevalent in women than men across all age groups and populations; the femaleto-male ratio is higher at reproductive age, ranging between 8:1 and 15:1, and is lowest in prepubertal children at about 4:3. Aim of the Work: To study the effect of intravenous cyclophosphamide versus oral mycophenolate (MMF) in the treatment of lupus nephritis (LN). Subjects and Methods: This was a prospective, randomized, comparative study on the efficacy of I.V cyclophosphamide compared to oral MMF in the induction therapy of LN. In this study 40 patients of systemic lupus erythematosus with lupus nephritis, were included. All patients were divided randomly into two groups. The first group included 20 female patients who given Oral Corticosteroid 1mg /kg and intravenous cyclophosphamide 500mg once every two weeks for 6 months. The second group included 20 patients receiving oral corticosteroid 1mg /kg and oral mycophenolate 2-3g/day (1200 mg/m2) for 6 months. Results: - As regard serum creatinine, alb/cr ratio, serum albumin, ESR, Anti DNA, c3, and eGFR there was a highly significant difference between before/after the treatment in each group, with no significant difference comparing the two group to each other. Conclusion: In our study, both MMF and IVC show significant improvement in patients with lupus nephritis with no superiority of one of them to the other.

Comparison of treatment response and serious infection using tacrolimus, tacrolimus withmycophenolate mofetil, in comparison tocyclophosphamide as induction treatment for lupus nephritis.

This study evaluated the relative efficacy and safety of tacrolimus, tacrolimus+mycophenolate mofetil (MMF), and cyclophosphamide (CYC) for lupus nephritis. Randomized controlled trials (RCTs) were included to investigate the effectiveness and safety of tacrolimus, tacrolimus+MMF, and CYC as a lupus induction therapy. We performed a Bayesian network meta-analysis of the random effects to incorporate direct and indirect data from RCTs. Four RCTs met the inclusion criteria, giving a sample size of 543 patients. Tacrolimus+MMF had a significantly higher overall response rate (complete plus partial remission) than CYC (OR 4.22, 95% credible interval (CrI) 11.02-29.23) and was more efficacious than tacrolimus (OR 2.02, 95% CrI 0.24-28.51). Tacrolimus had higher overall response than CYC (OR 2.14, 95% CrI 0.38-12.33). Ranking the treatments based on the surface under the cumulative ranking curve (SUCRA) suggested that tacrolimus+MMF was the best treatment by the overall response (SUCRA = 0.876), followed by tacrolimus (SUCRA = 0.533) and CYC (SUCRA = 0.091). Tacrolimus was the least likely to cause serious infections (-SUCRA = 0.758), followed by CYC (SUCRA = 0.398) and tacrolimus+MMF (SUCRA = 0.345). Tacrolimus+MMF was the most effective induction treatment for patients with lupus nephritis, and tacrolimus was the least likely to cause severe infections.

EP16 Challenges in treating new onset systemic lupus erythematosus with lupus nephritis and COVID-19 infection overlap

Case report - IntroductionCOVID-19 infection caused by a novel coronavirus SARS-coV-2 has made the diagnosis and the treatment of inflammatory diseases incredibly challenging. On the one hand, because of its pro-inflammatory state, that may aggravate or trigger flares in autoimmune diseases such as systemic lupus erythematosus (SLE). On the other hand, the risk of an immunosuppressive therapy during the active phase SARS-coV-2 infection that may lead to catastrophic outcomes. We report a case of a 24-year-old female newly diagnosed with SLE during COVID-19 pandemic who developed COVID-19 infection during her induction treatment for lupus nephritis.Case report - Case descriptionA 24-year-old Nepali female, with no past medical history of note, presented to her regional hospital with a history of flu-like symptoms few days ago, peripheral oedema, acute kidney injury with proteinuria and hypertension. Further investigations showed a high titre of double-stranded DNA antibodies, anti-cardiolipin IgM and B2 microglobulin positive and low C3. She also developed a haemolytic anaemia and thrombocytopenia during her admission. She received pulsed steroid therapy and was started on mycophenolate mofetil (MMF) for a probable lupus nephritis awaiting the results of biopsy, which showed later a lupus nephritis Class IV-G with active lesions. She then developed symptoms of COVID-19 infection and had a positive PCR leading to an interruption of her induction therapy. She was recruited to the RECOVERY trial on the lopinavir-ritonavir arm and made a good recovery.Case report - DiscussionIt is well known that viruses can trigger or aggravate auto-immune response in patients predisposed genetically. However, the role of SARS-coV-2 is not elucidated yet. The EULAR COVID-19 registry showed that rheumatoid arthritis and SLE were the most prevalent rheumatic diseases, and there was an increased risk in those who are on moderate to high dose corticosteroids. In patients with SLE and COVID-19 infection, it is agreed by all the national and international rheumatology societies to interrupt their immunosuppressive therapy until the symptoms resolve, especially those with renal involvement or an active disease. Which is the case in our patient. Luckily, she resumed her MMF a month later after a negative PCR and her renal function has continued to improve.Case report - Key learning pointsLupus nephritis is a major risk factor for overall morbidity and mortality in SLE. It requires an early immunosuppressive treatment to induce remission.Randomized clinical trials showed that MMF is at least equally effective as cyclophosphamide in inducing remission and that it has been associated with a reduced risk of infection and amenorrhea. It seems to be a suitable alternative in women of childbearing age. In patients with concomitant COVID-19 disease, immunosuppressive therapy should be paused until the symptoms improve.

The Emerging Role of Renal Tubular Epithelial Cells in the Immunological Pathophysiology of Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disease that can involve virtually any organ of the body. Lupus nephritis (LN), the clinical manifestation of this disease in the kidney, is one of the most common and severe outcomes of SLE. Although a key pathological hallmark of LN is glomerular inflammation and damage, tubulointerstitial lesions have been recognized as an important component in the pathology of LN. Renal tubular epithelial cells are resident cells in the tubulointerstitium that have been shown to play crucial roles in various acute and chronic kidney diseases. In this context, recent progress has been made in examining the functional role of tubular epithelial cells in LN pathogenesis. This review summarizes recent advances in our understanding of renal tubular epithelial cells in LN, the potential role of tubular epithelial cells as biomarkers in the diagnosis, prognosis, and treatment of LN, and the future therapeutic potential of targeting the tubulointerstitium for the treatment of patients with LN.

Programmed immunoadsorption with regeneration of adsoption columns in the treatment of lupus nephritis

Programmed immunoadsorption (IA) with regeneration of adsoption columns is a promising and safe technique to treat lupus nephritis (LN) in case of ineffective immunosuppressive therapy and its severe adverse reactions. This technique makes it possible to control disease activity, to maintain kidney function, and to ensure a normal quality of life. Due to the reusability of IA columns, it is possible to remove any required amount of IgG and to reduce the cost of an extracorporeal procedure.The paper describes a clinical case of 3-year prolonged IA in a female patient with systemic lupus erythematosus (SLE) and LN with the insufficient efficacy of drug therapy and related complications. Seventy IA sessions were performed during a follow-up period. Combined treatment with glucocorticoids, cytotoxic drugs, and IA resulted in improved clinical and laboratory parameters, lower SLE activity according to SELENA-SLEDAI scores, and better quality of life according to the SF-36 scale. No adverse reactions were recorded during IA sessions.

Comparative efficacy and safety of mycophenolate mofetil and cyclophosphamide in the induction treatment of lupus nephritis: A systematic review and meta-analysis.

Background:Lupus nephritis (LN) remains a predominant cause of morbidity and mortality in SLE. Here we performed a meta-analysis to evaluate the efficacy and safety of the induction treatment with mycophenolate mofetil (MMF) and cyclophosphamide (CYC) for LN.Methods:Relevant literature was searched by computer from the establishment of the database to November 2019. A meta-analysis was conducted to analysis the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients. The primary end-point was response to urine protein, serum creatinine (Scr) and serum complement C3, and the secondary end-points were complete remission and adverse reactions.Results:Eighteen articles were selected for the final meta-analysis, involving 1989 patients with LN, of which the renal biopsy result could be classified into class III–V according to the standards of WHO/ISN. The results revealed that MMF was superior to CYC in increasing the level of serum complement C3 [SMD = 0.475, 95%CI (0.230–0.719)] and complete remission [RR = 1.231, 95%CI (1.055–1.437)]. Furthermore, the subgroup analysis showed that it was in Asian patients, rather than in Caucasian patients, that CYC exerted a better effect on lowering the level of urine protein (UPRO) than MMF [SMD = 0.405, 95%CI (0.081–0.730)]. Besides, when the initial UPRO level was less than 4 g/day, the effect of CYC was better than MMF [SMD = 0.303, 95%CI (0.014–0.591)]. There was no significant difference between MMF and CYC in improving Scr [SMD = 0.090, 95%CI (−0.060–0.239)]. When it came to the comparison of safety between MMF and CYC, the meta-analysis showed that MMF was superior to CYC in decreasing infection in Caucasian patients [RR = 0.727, 95%CI (0.532–0.993)], reducing the risk of leukopenia and menstrual abnormalities in Asian patients and lowering the frequency of gastrointestinal symptoms [RR = 0.639, 95%CI (0.564–0.724)], independent of race.Conclusions:MMF precedes CYC in improving serum complement C3 and complete remission regardless of race, as well as shows fewer adverse drug reactions in the induction treatment of LN belonging to type III–V. But for Asian patients or those initial UPRO levels are less than 4 g/day, CYC may be superior to MMF.

Phoenix from the flames: Rediscovering the role of the CD40-CD40L pathway in systemic lupus erythematosus and lupus nephritis.

Lupus nephritis (LN) is a significant complication of systemic lupus erythematosus (SLE), increasing its morbidity and mortality. Although the current standard of care helps suppress disease activity, it is associated with toxicity and ultimately does not cure SLE. At present, there are no therapies specifically indicated for the treatment of LN and there is an unmet need in this disease where treatment remains a challenge. The CD40-CD40L pathway is central to SLE pathogenesis and the generation of autoantibodies and their deposition in the kidneys, resulting in renal injury in patients with LN. CD40 is expressed on immune cells (including B cells, monocytes and dendritic cells) and also non-haematopoietic cells. Interactions between CD40L on T cells and CD40 on B cells in the renal interstitium are critical for the local expansion of naive B cells and autoantibody-producing B cells in LN. CD40L-mediated activation of myeloid cells and resident kidney cells, including endothelial cells, proximal tubular epithelial cells, podocytes and mesangial cells, further amplifies the inflammatory milieu in the interstitium and the glomeruli. Several studies have highlighted the upregulated expression of CD40 in LN kidney biopsies, and preclinical data have demonstrated the importance of the CD40-CD40L pathway in murine SLE and LN. Blocking this pathway is expected to ameliorate inflammation driven by infiltrating immune cells and resident kidney cells. Initial experimental therapeutic interventions targeting the CD40-CD40L pathway, based on CD40L antibodies, were associated with an increased incidence of thrombosis. However, this safety issue has not been observed with second-generation CD40/CD40L antibodies that have been engineered to prevent platelet activation. With these advancements, together with recent preclinical and clinical findings, it is anticipated that selective blockade of the CD40-CD40L pathway may address the unmet treatment needs in SLE, LN and other autoimmune diseases.

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce. Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6months after kidney biopsy and MMF initiation. Treatment response at 6months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5g/day or 50mg/mmol, and no hematuria. A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44mgh/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60mgh/L. At 6months, 14/25 patients were defined as responders (56%, median MPA-AUC 49mgh/L (40-59)) and 11/25 as non-responders (44%, 29mgh/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30mgh/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45mgh/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p= 0.03). Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45mgh/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.

A novel monoclonal antibody against human B7-1 protects against chronic graft-vs.-host disease in a murine lupus nephritis model.

Lupus nephritis (LN) is the most common complication that causes mortality in patients with systemic lupus erythematosus. The B7-1/B7-2 and CD28/cytotoxic T-lymphocyte associated protein 4 co-stimulatory pathway serves a key role in autoimmune disease and organ transplantation. The aim of the present study was to generate and characterize a monoclonal antibody (mAb; clone 4E5) against human B7-1 and to investigate its potential use for the treatment of LN. The results demonstrated that the 4E5 mAb was successfully generated and able to recognize both human and mouse B7-1. After injection of this mAb into a mouse model with chronic graft-vs.-host disease (cGVHD)-induced lupus-like disease, the expression of CD21, CD23, CD80 and CD86 on B220+ B-cells in the spleen, and the concentrations of serum autoantibodies and urine protein, were decreased. Direct immunofluorescence analysis of the kidneys revealed that immunofluorescence of immune complex deposits was weaker in the 4E5-treated mice and electron microscopy analyses of renal tissues indicated that pathological injury of the kidneys of 4E5-treated mice was decreased compared with that in the model control mice. The results of the present study demonstrated that inhibition of the B7-1/CD28 co-stimulatory signaling pathway with the 4E5 mAb may represent a promising strategy to decelerate the progression of LN that is induced by cGVHD with potential for use in the treatment of other autoimmune diseases.

Outcomes of Mycophenolate Mofetil vs. Intravenous Cyclophosphamide in Induction Therapy of Childhood-Onset Lupus Nephritis

Background: Intravenous cyclophosphamide (IVCY) concomitant with corticosteroids demonstrated better outcomes in therapy of proliferative lupus nephritis albeit adverse effects may occur. Mycophenolate mofetil (MMF) is a newer oral medication for treating lupus nephritis. Objective: To compare renal outcomes between IVCY and MMF in conjunction with corticosteroid for induction therapy of proliferative lupus nephritis. Materials and Methods: The authors reviewed the medical records from four university hospitals of children who received prednisolone with either MMF or IVCY for induction therapy of proliferative lupus nephritis between 2005 and 2014 in the present retrospective cohort study. Results: Twenty-eight and 85 patients were included in the MMF and IVCY group, respectively. The respective mean age at MMF and IVCY initiation was 12.36±2.87 and 11.84±3.04 years. Renal remission was not significantly different between the groups (p=0.690). Non-nephrotic range proteinuria (adjusted OR 2.93, 95% CI 1.23 to 6.94, p=0.015), and high initial GFR (adjusted OR 2.93, 95% CI 1.14 to 7.56, p=0.026) were significantly associated with achieving renal remission. Both infectious (82.1%) and non-infectious complications (96.9%) were more common in the IVCY group. Neither death nor end-stage renal disease (ESRD) occurred during the induction therapy. Conclusion: There was no significant difference in renal remission whether children received MMF or IVCY for induction therapy of lupus nephritis; however, adverse events occurred less frequently in the MMF group. Keywords: Children, Lupus nephritis, Systemic lupus erythematosus, Mycophenolate, Cyclophosphamide, Induction

Mycophenolate mofetil in the treatment of Chinese patients with lupus nephritis: A PRISMA-compliant meta-analysis.

Mycophenolate mofetil (MMF) has been recommended for the treatment of lupus nephritis (LN). Although inter-racial differences exist regarding the appropriate dose and efficacy of MMF in patients with LN, no definitive meta-analysis has yet been conducted in Chinese patients. This analysis investigated the efficacy and safety of MMF in Chinese patients with proliferative LN. A systematic literature search was conducted to select randomized controlled trials that reported at least one of the following: complete remission (CR), partial remission, total remission (TR; defined as complete remission + partial remission), relapse rate, serum creatinine, creatinine clearance, end-stage renal disease, death, infections, amenorrhea, leukopenia, alopecia, gastrointestinal symptoms, or liver damage. Eighteen trials (927 patients) were included; 14 (750 patients) reported CR, partial remission, and TR. Two trials (58 patients) reported relapse rates during maintenance treatment. MMF induction significantly improved CR and TR vs cyclophosphamide (relative risk 1.34, 95% confidence interval: 1.13-1.58; P < .001; relative risk 1.16, 95% confidence interval: 1.02-1.33; P = .03), and was associated with significantly lower risks of infection (P < .001), amenorrhea (P < .001), leukopenia, and alopecia. No significant difference in relapse rate was evident between the MMF and azathioprine groups (P = .66). According to this meta-analysis of 18 trials, MMF is significantly more effective than cyclophosphamide induction, and is associated with reduced incidences of infections, amenorrhea, leukopenia, and alopecia in Chinese patients with proliferative LN.

A review of advances in the understanding of lupus nephritis pathogenesis as a basis for emerging therapies.

Lupus nephritis is an important cause of both acute kidney injury and chronic kidney disease that can result in end-stage renal disease. Its pathogenic mechanisms are characterized by aberrant activation of both innate and adaptive immune responses, dysregulation of inflammatory signaling pathways, and increased cytokine production. Treatment of lupus nephritis remains a challenging issue in the management of systemic lupus erythematosus since the clinical presentation, response to treatment, and prognosis all vary considerably between patients and are influenced by ethnicity, gender, the degree of chronic kidney damage, pharmacogenomics, and non-immunological modulating factors. Elucidation of the various immunopathogenic pathways in lupus nephritis has resulted in the development of novel therapies, including biologics that target specific antigens on B lymphocytes to achieve B cell depletion, agents that modulate B cell proliferation and development, drugs that block co-stimulatory pathways, drugs that target T lymphocytes primarily, and therapies that target complement activation, signaling pathways, pro-inflammatory cytokines, and neutrophil extracellular traps. This review will discuss recent advances in the understanding of disease pathogenesis in lupus nephritis in the context of potential emerging therapies.

Bacteroides fragilis alleviates the symptoms of lupus nephritis via regulating CD1d and CD86 expressions in B cells

Emerging evidences indicated that the dysbiosis of microbiota was related to the onset of systemic lupus erythematosus (SLE). Bacteroides fragilis (B. fragilis) ATCC 25285, a human commensal, was discovered to improve inflammatory diseases. However, whether B. fragilis (ATCC 25285) has the beneficial effects on the treatment of lupus nephritis has still remained elusive. In the present study, oral treatment with B. fragilis (ATCC 25285) ameliorated the activity of MRL/lpr mice, including decreased levels of autoantibodies and symptoms of lupus nephritis. Furthermore, we demonstrated that treatment with B. fragilis (ATCC 25285) could promote CD1d expression in B cells by Est-1 pathway, while inhibit CD86 expression via SHP-2 signaling pathway to repair the immune response of B cells in MRL/lpr mice. In addition, our findings revealed a possible role of treatment with B. fragilis (ATCC 25285) in relieving intestinal inflammation in MRL/lpr mice. Meanwhile, it was uncovered that B. fragilis (ATCC 25285) restored the Th17/Treg balance in MRL/lpr mice that was consistent with the role of B. fragilis in other autoimmune diseases. Overall, the current study may highlight the potential application of B. fragilis (ATCC 25285) to treat manifestations of SLE in high-risk individuals.