Limitations of Standard Immunosuppressive Treatment in ANCA-Associated Vasculitis and Lupus Nephritis

Abstract Background and Aims The reported incidence of lupus nephritis (LN) is approximately 6.1 cases per million population per year in Scotland based on Scottish Renal Registry biopsy data. Despite immunosuppressive treatment, approximately 10-30% of patients will progress to established renal failure (ERF) within 15 years. In December 2007, our unit moved from a protocol of Cyclophosphamide/ steroid induction with Azathioprine/ Prednisolone maintenance to Mycophenolate/ steroid induction and maintenance. We undertook this study to compare remission rates before and after this change. Method A retrospective electronic patient record analysis was performed for all patients in our centre with a documented native renal biopsy showing a histopathological diagnosis of LN, between 1 July 1993 and 31 December 2017. Repeat biopsies were excluded. Baseline demographics, histopathological class and first and second line induction and maintenance therapies were recorded. Endpoints analysed were; partial and complete response (as defined in KDIGO Clinical Practice Guideline for Glomerulonephritis 2012), time to achieve this response, relapse, progression to ERF and death. Results 120 patients who underwent a biopsy during the 24.5-year period received a diagnosis of lupus nephritis. 82.5% of patients were Caucasian. Median duration of follow-up was 72 months. 15% of patients died and 5% developed ERF within the follow-up period, representing one death per 56 patient years and one incident case of ERF per 168 patient years. There were 40 patients in the pre-December 2007 group and 80 in the post-December 2007 group. Those in the earlier group were younger, with a mean age of 35.4 years versus 44.8 years in the later group (p=0.002). 23% had class V in the earlier group compared to 15% in the later group (p=0.31). Proportions of female patients were 80% and 75% in the early and late groups respectively (p=0.54). Median creatinine was 106µmol/L in the pre-December 2007 group and 89.5 µmol/L in the post-December 2007 group (p=0.96). Patients in the pre- and post- December 2007 groups had comparable rates of complete response, at 72% and 71% respectively. However, those diagnosed before December 2007 were slower to respond, with a median time to achieve complete response of 10.5 months, compared to 6 months in those diagnosed after 1 December 2007 (p=0.007). Conclusion Following a change in our immunosuppressive induction regimen from Cyclophosphamide/ steroids to Mycophenolate/ steroids, our response rates have remained similar, however speed of attaining remission has improved.

Download Full-text

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations

RMD Open ◽

10.1136/rmdopen-2020-001263 ◽

2020 ◽

Vol 6 (2) ◽

pp. e001263 ◽

Cited By ~ 1

Author(s):

Myrto Kostopoulou ◽

Antonis Fanouriakis ◽

Kim Cheema ◽

John Boletis ◽

George Bertsias ◽

...

Keyword(s):

Lupus Nephritis ◽

Literature Review ◽

Systematic Literature Review ◽

Immunosuppressive Treatment ◽

Class Iii ◽

High Quality ◽

Class V ◽

High Quality Evidence ◽

Optimal Duration ◽

Quality Evidence

ObjectivesTo analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations.MethodsAccording to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012.ResultsWe identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500–700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b).ConclusionsThere is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

Download Full-text

Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy024 ◽

2018 ◽

Vol 34 (3) ◽

pp. 467-473 ◽

Cited By ~ 3

Author(s):

Desmond Y H Yap ◽

Lorraine P Y Kwan ◽

Maggie K M Ma ◽

Maggie M Y Mok ◽

Gary C W Chan ◽

...

Keyword(s):

Cohort Study ◽

Lupus Nephritis ◽

Immunosuppressive Treatment

Download Full-text

Imbalance of Circulatory T Follicular Helper and T Follicular Regulatory Cells in Patients with ANCA-Associated Vasculitis

Mediators of Inflammation ◽

10.1155/2019/8421479 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Ying Xu ◽

Hongmei Xu ◽

Yu Zhen ◽

Xueting Sang ◽

Hao Wu ◽

...

Keyword(s):

Immunosuppressive Treatment ◽

Antineutrophil Cytoplasmic Antibody ◽

Healthy Controls ◽

Regulatory Cells ◽

Humoral Immune ◽

Tfh Cells ◽

Humoral Immune Responses ◽

Follicular Helper ◽

Anca Associated Vasculitis ◽

Kidney Involvement

Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is characterized by small-vessel inflammation in association with autoantibodies. Balance between T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells is critical for humoral immune responses. Accumulating evidence supports that Tfh and Tfr are involved in autoimmune diseases; however, their roles in AAV are unclear. In this study, we tested the changes of circulatory Tfh and Tfr in patients with AAV. Twenty patients with AAV and twenty healthy controls were enrolled. Sixteen AAV patients had kidney involvement. We found that the AAV patients had increased circulating Tfh cells (CD4+CXCR5+CD25−CD127interm-hi), decreased Tfr cells (CD4+CXCR5+CD25+CD127lo-interm), and elevated Tfh/Tfr ratios compared with healthy controls (P<0.01). The Tfh percentage and Tfh/Tfr ratio, but not Tfr percentage, were positively correlated to proteinuria levels and BVAS scores in patients with AAV (P<0.01). In addition, AAV patients had decreased circulating Tfh1 (CCR6-CXCR3+), but increased Tfh2 cells (CCR6-CXCR3-), compared with healthy controls (P<0.01), indicating a Tfh1-to-Tfh2 shift. Furthermore, remission achieved by immunosuppressive treatment markedly attenuated the increase of total Tfh (P<0.01) and Tfh2 cells (P<0.05), promoted the Tfh1 response (P<0.05), and recovered the balance between Tfh/Tfr cells (P<0.05) and between Tfh1/Tfh2 cells (P<0.05) in patients with AAV. Plasma levels of IL-21, a cytokine secreted by Tfh cells, were elevated in AAV patients compared with healthy controls (P<0.01), which was attenuated by immunosuppressive treatment (P<0.05). Taken together, our findings indicate that circulatory Tfh/Tfr ratios, Tfh2/Tfh1 shift, and plasma IL-21 levels are associated with AAV and disease activity.

Download Full-text

Renal transplantation for lupus nephritis: non-adherence and graft survival

Lupus ◽

10.1177/0961203319842641 ◽

2019 ◽

Vol 28 (5) ◽

pp. 651-657 ◽

Cited By ~ 1

Author(s):

E Ntatsaki ◽

V S Vassiliou ◽

A Velo-Garcia ◽

A D Salama ◽

D A Isenberg

Keyword(s):

Systemic Lupus Erythematosus ◽

Renal Transplantation ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Graft Rejection ◽

Graft Failure ◽

Immunosuppressive Treatment ◽

Poor Adherence ◽

Systemic Lupus ◽

Group 2

Objectives Poor adherence to immunosuppressive treatment is common in patients with systemic lupus erythematosus and may identify those with lupus nephritis (LN) who have a poorer prognosis. Non-adherence has also been reported to be a potential adverse outcome predictor in renal transplantation (rTp). We investigated whether non-adherence is associated with increased rTp graft rejection and/or failure in patients with LN. Methods Patients with LN undergoing rTp in two major London hospitals were retrospectively included. Medical and electronic records were reviewed for documented concerns of non-adherence as well as laboratory biochemical drug levels. The role of non-adherence and other potential predictors of graft rejection/failure including demographics, comorbidities, age at systemic lupus erythematosus and LN diagnosis, type of LN, time on dialysis prior to rTp and medication use were investigated using logistic regression. Results Out of 361 patients with LN, 40 had rTp. During a median follow-up of 8.7 years, 17/40 (42.5%) of these patients had evidence of non-adherence. A total of 12 (30.0%) patients experienced graft rejection or failure or both. In the adherent group 2/23 (8.7%) had graft rejection, whilst in the non-adherent this rose to 5/17 (29.4%, p = 0.11). Graft failure was seen in 5/23 (21.7%) patients from the adherent group and 4/17 (23.5%) in the non-adherent group ( p = 0.89). Non-adherent patients had a trend towards increased graft rejection, hazard ratio 4.38, 95% confidence interval = 0.73–26.12, p = 0.11. Patients who spent more time on dialysis prior to rTp were more likely to be adherent to medication, p = 0.01. Conclusion Poor adherence to immunosuppressive therapy is common and has been shown to associate with a trend towards increased graft failure in patients with LN requiring rTp. This is the first paper to report that shorter periods on dialysis prior to transplantation might lead to increased non-adherence in lupus patients.

Download Full-text

A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211073 ◽

2017 ◽

Vol 76 (8) ◽

pp. 1436-1439 ◽

Cited By ~ 33

Author(s):

DanQi Deng ◽

Peilian Zhang ◽

Yun Guo ◽

Teck Onn Lim

Keyword(s):

Renal Function ◽

Stem Cell ◽

Lupus Nephritis ◽

Mesenchymal Stem Cell ◽

Umbilical Cord ◽

Treatment Effect ◽

Activity Index ◽

Immunosuppressive Treatment ◽

Similar Proportion ◽

Human Umbilical Cord

ObjectiveWe evaluate the efficacy of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) for the treatment of lupus nephritis (LN). Previous reports showed hUC-MSC could have dramatic treatment effect.MethodsEighteen patients with WHO class III or IV LN were randomly assigned to hUC-MSC (dose 2×108 cells) or placebo. All patients received standard immunosuppressive treatment, which consisted of intravenous methylprednisolone and cyclophosphamide, followed by maintenance oral prednisolone and mycophenolate mofetil.ResultsRemission occurred in 9 of 12 patients (75%) in the hUC-MSC group and 5 of 6 patients (83%) in the placebo group. Remission was defined as stabilisation or improvement in renal function, reduction in urinary red cells and protein. A similar proportion of patients on hUC-MSC and placebo achieved complete remission. Improvements in serum albumin, complement, renal function, Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group scores were similar in both groups. One patient on placebo had a stroke and another had ascites. One patient on hUC-MSC had leucopenia, pneumonia and subcutaneous abscess and another died of severe pneumonia. The trial was abandoned after 18 patients were enrolled when it had become obvious it would not demonstrate a positive treatment effect.ConclusionhUC-MSC has no apparent additional effect over and above standard immunosuppression.Trial registration numberNCT01539902; Results.

Download Full-text

Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.131995 ◽

2010 ◽

Vol 69 (12) ◽

pp. 2083-2089 ◽

Cited By ~ 302

Author(s):

Frédéric A Houssiau ◽

David D'Cruz ◽

Shirish Sangle ◽

Philippe Remy ◽

Carlos Vasconcelos ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Lupus Nephritis ◽

Serum Creatinine ◽

Statistical Significance ◽

Immunosuppressive Treatment ◽

Randomised Trial ◽

Target Dose ◽

Renal Flare ◽

Intent To Treat

BackgroundLong-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.MethodsA total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months.ResultsThe baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out.ConclusionsFewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.

Download Full-text

Immunosuppressive Treatment of Lupus Nephritis

InPharma ◽

10.1007/bf03299773 ◽

1986 ◽

Vol 552 (1) ◽

pp. 3-4

Keyword(s):

Lupus Nephritis ◽

Immunosuppressive Treatment

Download Full-text