Steroid Monotherapy for the Treatment for Pure Membranous Lupus Nephritis: A Case Series of 5 Patients and Review of the Literature

Introduction: The benefi t of combination immunosuppression versus steroid monotherapy in pure membranous lupus nephritis (MLN) remains unclear. Steroid monotherapy could potentially reduce exposure to excessive immunosuppression in patients achieving remission with this strategy. The aim of this study was to defi ne patient characteristics and outcomes in MLN treated with steroid monotherapy. Method: A retrospective, observational study identifi ed all biopsy-proven pure MLN cases followed since 1990 in a single center. Demographic, clinical and histological data were gathered for patients treated with daily steroid monotherapy. The primary outcome of interest was the reduction in proteinuria, reported as complete remission (CR), partial remission (PR) or no response. Results: We identifi ed 5 patients who received steroid monotherapy for pure MLN. The patients were 80% female with preserved renal function and little, if any, evidence of chronic interstitial fi brosis on biopsy. The mean follow-up period was 79.4±57.6 months. All cases achieved a clinical remission (CR in two patients and PR in 3 patients). The three patients who achieved only partial remission had a relapse during follow-up, which were successfully treated by addition of further immunosuppression, whereas the two patients who achieved CR did not experience a relapse. The mean estimated GFR was similar at baseline and the latest follow-up, 117±20.7ml/min/1.73m2 vs 111±11.3ml/min/1.73m2, respectively (p=0.61). Conclusion: Daily steroid monotherapy may be an appropriate fi rst-line treatment for pure MLN. Larger, prospective, trials are needed to validate this strategy and identify those patients who are most likely to benefi t. Case Report Steroid Monotherapy for the Treatment for Pure Membranous Lupus Nephritis: A Case Series of 5 Patients and Review of the Literature Frank Ward*, Mohammad Alkhowaiter and Joanne M Bargman Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada Dates: Received: 31 March, 2017; Accepted: 22 April, 2017; Published: 24 April, 2017 *Corresponding author: Frank Ward, Doctor, University Health Network and the University of Toronto, 200 Elizabeth Street, 8N-840, Toronto, Ontario M5G 2C4, Canada, E-mail:


Introduction
Membranous lupus nephritis (MLN) accounts for approximately 10-20% of lupus nephritis (LN) [1]. The clinical presentation of MLN is variable, ranging from isolated subnephrotic proteinuria to nephrotic syndrome with reduced glomerular fi ltration rate (GFR), with or without extrarenal manifestations of SLE, positive lupus serology or hypocomplementemia [2]. Although associated with a better prognosis than proliferative LN, MLN can lead to signifi cant morbidity, including thrombosis and infection associated with the nephrotic syndrome, transition to a proliferative LN in approximately one-third of patients and progression to endstage kidney disease (ESKD) in approximately 10% of patients after 10 years [3].
All patients with LN should receive treatment with hydroxychloroquine, unless there is a contraindication, and renin-angiotensin-aldosterone system blockade should be introduced if there is proteinuria >0.5g/day and/or if anti-hypertensive medication is required to achieve blood pressure control <130/80mmHg [4]. Immunosuppression is typically indicated for persistent nephrotic-range proteinuria or declining renal function as, unlike primary membranous nephropathy, the likelihood of spontaneous remission in MLN is low [5,6]. Steroid monotherapy has been associated with high remission rates and excellent renal survival [7].
However, combination immunotherapy may be superior in inducing remission in MLN with nephrotic proteinuria [8].
There is presently no consensus on which patients may be suitable for a trial of steroid monotherapy in the fi rst instance.
Clinical practice guidelines have highlighted the need for further investigation into the role of steroid monotherapy in LN [9]. In this study, we report the clinical and histological characteristics and clinical outcomes of MLN treated with steroid monotherapy in a single tertiary referral centre and review the available clinical literature on steroid monotherapy in pure MLN.

Outcome measures
The primary outcome measure of interest was renal remission as defi ned by a complete remission (CR), partial remission (PR) or no response based on serial proteinuria measurements. CR was defi ned as a reduction in proteinuria to <0.3g/24h (or uPCR<30mg/mmol), sustained over three months. PR was defi ned as a decline in proteinuria <3g/24h but >0.3g/24h (or uPCR<300mg/mmol and >30mg/mmol) plus ≥50% reduction from the initial level, sustained over three months. Non-response was failure to achieve either CR or PR.
For patients with sub-nephrotic proteinuria, CR was defi ned as above and PR as ≥50% reduction in proteinuria sustained

Clinical outcomes
The mean duration of follow-up was 79.4±57.6 months.
All fi ve patients treated with steroid monotherapy achieved an initial remission (

Discussion
In this series of fi ve patients with pure MLN receiving steroid monotherapy, a clinical remission was achieved in all cases. Both patients who achieved an initial complete remission with steroid monotherapy did not experience a  relapse during follow-up. However, there was a high risk of relapse noted during follow-up for those patients who initially achieved only a partial remission. Relapses were successfully managed by addition of immunosuppressive agents in addition to corticosteroids. The patients who were selected for steroid monotherapy had preserved renal function and similar renal histological characteristics demonstrating little, if any, chronic renal parenchymal damage. The use of RAAS blockade and anti-malarial agents was low in this cohort.
There is limited clinical literature examining the use of steroid monotherapy in pure MLN. A single, small, randomized-controlled trial has evaluated the treatment of pure MLN to date, comparing steroid monotherapy, CsA (plus steroid) and low-dose intravenous cyclophosphamide (IVCY) (plus steroid) [10]. The steroid monotherapy arm (n=15) had a median age of 40 years (range 20-58), median duration of SLE of 11.5months (range 3-120), daily proteinuria 5.7g (range 2.8-10.6) and the majority had normal serum complement levels and normal anti-dsDNA antibody titres. The monotherapy group performed poorly, achieving a 12-month cumulative probability of remission of 27% compared to 60% with IVCY and 83% with CsA. However, prednisone dosing was only on alternating days, which is not refl ective of practice in many centers. Radrakrishnan et al. reported that MMF and IVCY had comparable 6-month remission rates in a pooled analysis of pure MLN patients from two randomized controlled trials [11]. However, both arms also received corticosteroid therapy (0.75-1mg/kg/day) and it is conceivable that there was no difference in the outcomes between the MMF and IVCY groups due to the corticosteroids in each group being the primary active therapeutic agent. Pasquali et al. reported similar remission rates in patients with MLN treated with both corticosteroid monotherapy or combination therapy [12]. In a retrospective cohort of 19 patients, Moroni et al. found that combination immunosuppression appeared more favourable for renal function preservation and a lower relapse rate compared to steroid monotherapy [13].
A systematic review and metanalysis of MLN treatment has suggested that combination therapy is superior to steroid monotherapy, achieving a higher response rate of 81% vs 60%, respectively [8]. The optimal agent to use in addition to steroids was unclear. Subsequent to this report, Bitencourt-Dias et al. compared daily prednisone (n=29) to combination therapy (n=24), using cyclophosphamide or AZA for 6 months, in patients with MLN, mostly with nephrotic proteinuria. The steroid monotherapy group had similar characteristics to our cohort, predominantly young, female patients with preserved renal function and proteinuria <5g/day. Prednisone monotherapy achieved a high remission rate after 6-months, which was comparable with combined therapy, 100% vs 70%, respectively [7]. Renal survival after 8 years was similar between the steroid and combination groups, 86.2% vs 75% respectively. The rate of renal fl ares was high and similar to our fi ndings, 51.7% vs 62.5% in the steroid monotherapy group and combination groups, respectively. Baseline renal histological characteristics were not compared between the groups.
Infection-related mortality remains high in SLE cohorts [14,15]. Hospitalization for serious infections has increased substantially, now estimated to be 12 times higher than in patients without SLE in one national population-based study [16]. Patients with SLE may carry an intrinsically increased susceptibility for infection related to immune dysfunction, which is then further augmented by immunosuppression [17,18]. There is a complex interplay among infection, autoimmunity and immunosuppression in SLE, with the suggestion that immunosuppression may not be the dominant risk factor for infection in all cases [18,19]. However, most would view therapeutic strategies to minimize exposure to immunosuppression, particularly in young patients potentially faced with many years of cumulative treatment, as advisable. Conversely, as persistent proteinuria in LN is a major predictor of progressive chronic kidney disease, those not responding to a less potent regimen should have their immunosuppression intensifi ed [20]. Patients who achieved remission with steroid monotherapy appear to do so within several months, hence, additional immunosuppression could be considered if there is no signifi cant response within 6-12months. The current study, like others, is limited most notably by its small sample size and retrospective, observational design.

Conclusion
Steroid monotherapy may be an effective treatment in MLN, potentially avoiding the need for excessive immunosuppression for some patients. Ultimately, the decision to initiate steroid monotherapy in a patient with MLN will likely depend on their clinical presentation. Our data suggests that, if effective, these patients are likely to enter remission within several months and this could be used to guide the addition of further immunosuppression. The rate of relapse appears high with steroid monotherapy, which is consistent with previously reported cohorts. The present series is limited by design and small sample size, but warrants further investigation into the role of steroid monotherapy in MLN. Future prospective and larger studies should aim to identify which patients are suitable for a trial of steroid monotherapy and which patients are likely to have a favourable response. *reported for those who did not achieve a complete remission **in addition to prednisone.