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Stopping versus continuing maintenance immunosuppressive therapy in lupus nephritis at 2-3 years

Comment on: “Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial” (Ann Rheum Dis. 2022 Jun 20; doi: 10.1136/annrheumdis-2022-222435)
Commented by: Maria G. Tektonidou, Professor of Rheumatology, First Department of Propaedeutic Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Greece

Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus (SLE), with a significant impact on disease morbidity and prognosis. The treatment of proliferative LN traditionally consists of an initial (induction) phase for the first 3-6 months, followed by a longer subsequent (maintenance) phase aiming to consolidate remission and prevent relapses. While this treatment paradigm is universally followed, the optimal duration of maintenance immunosuppressive treatment (IST) in LN remains largely unknown. No randomised study has been performed to test different durations of IST in patients that reach remission following the induction phase. The WIN-Lupus investigator-initiated, randomised study was designed to test whether IST discontinuation after 2‒3 years is non-inferior to IST continuation for two more years in proliferative LN.
To be included in the study, patients had to i) have experienced a first flare or relapse of biopsy-proven proliferative LN, ii) have received induction treatment with high-dose corticosteroids and intravenous cyclophosphamide or mycophenolate mofetil and current maintenance IST with either azathioprine (≥50mg/day) or mycophenolate mofetil (≥1000mg/day) for at least 2 years and a maximum of 3 years, iii) be in complete (proteinuria ≤0.2g/day) or partial (proteinuria ≤0.5g/ day, or stable and considered to be related to chronic damage) renal remission, with inactive urinary sediment and normal or stable eGFR, and iv) currently receive prednisone daily dose ≤10mg/day. They were randomly assigned (1:1) to the IST continuation or IST discontinuation group and the primary efficacy endpoint was the percentage of patients with relapse of proliferative LN in the 2 years following randomisation. Among others, a key secondary outcome was the percentage of patients with a severe SLE flare (renal or extrarenal) during the same time period.
A total of 96 patients were included in the study, 48 in each group. During the 2-year study period, a relapse of proliferative LN occurred in 5/40 (12.5%) patients from the IST continuation group and in 12/44 (27.3%) patients from the IST discontinuation group (p=0.710, Δ (95%CI): 14.8 (−1.9 to 31.5). Nοn-inferiority of IST discontinuation was not demonstrated. Additionally, there were significantly more severe SLE flares in patients in the IST discontinuation group compared with the IST continuation group (14/44 (31.8%) vs 5/40 (12.5%) patients, p=0.035, Δ (95%CI) 19.3% (CI 1.3% to 35.7%), and time to severe SLE flares was shorter in patients in the IST discontinuation group. No difference in adverse events were observed between groups.
Results from the WIN-Lupus study can add a significant knowledge regarding the optimal timing of IST discontinuation in LN. The EULAR-ERA recommendations for the management of LN propose a gradual withdrawal of treatment after at least 3-5 years in patients with a complete clinical response, while the 2021 KDIGO guidelines also recommend for at least 3 years of IST treatment; however, both recommendations are largely based on expert opinion. A study using repeat kidney biopsy in patients in clinical remission showed that residual histologic activity is a risk factor for a subsequent renal flare, underlining the value of histologic re-assessment to guide continuation or not of IST. On the other hand, the present study also identified clinical parameters at baseline which were predictive of renal relapse, including, among others, a higher SLEDAI, higher proteinuria and low C3. These data highlight the need to identify those patients who are at higher risk for relapse, rather than universally recommending long-term IST in patients with LN.

Reference: Jourde-Chiche N, Costedoat-Chalumeau N, Baumstarck K, et al. Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial. Ann Rheum Dis. 2022 Jun 20; doi: 10.1136/annrheumdis-2022-222435. Online ahead of print.

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