What is the ideal duration of maintenance therapy for lupus nephritis?

KEYWORDS:

• Duration
• maintenance
• lupus nephritis
• corticosteroids
• mycophenolate
• azathioprine
• biologics
• calcineurin inhibitors

Preventing disease relapse is an important objective in the management of patients with lupus nephritis (LN) since nephritic flares result in progressive attrition of nephron mass and increase the risk of progressive chronic kidney disease (CKD) [1]. Treatment of LN flares also increases the risk of cumulative toxicities of immunosuppressive medications. Maintenance immunosuppression consolidates treatment response and plays a pivotal role in preventing disease flares. However, the potential trade-off is treatment-related toxicities that result in damage accrual. Despite the well-recognized importance of maintenance therapy, except for the general agreement that treatment should continue for a number of years, there is uncertainty on its optimal duration and rate of tapering, and which immunosuppressive medication to discontinue first. A lack of high-quality evidence from clinical trials has contributed to this knowledge gap, and the considerable variability between patients adds to the challenge in clinical management.

What do current clinical management guidelines say about the duration of maintenance therapy? The 2019 Update of the Joint EULAR/ERA-EDTA recommendations for the management of lupus nephritis included the recommendation statement ‘Gradual withdrawal of treatment (glucocorticoids first, then immunosuppressive drugs) can be attempted after at least 3 to 5 years therapy in complete clinical response. Hydroxychloroquine should be continued long-term.’ [2]. The rationale for the EULAR/ERA-EDTA recommendation was based on the observation that most renal flares occur within the first 5–6 years [3,4]. Indeed, longer durations of treatment and longer periods of remission were associated with a reduced risk of renal flares in patients who discontinued immunosuppressive therapy after 6 years of treatment [5]. The KDIGO 2021 Guideline for the Management of Glomerular Diseases included Practice Point 10.2.3.2.5 advising that ‘The total duration of initial immunosuppression plus combination maintenance immunosuppression for proliferative LN should not be <36 months’ 6, putting emphasis on the minimum duration based on the results from the ALMS trial, which showed a treatment failure rate of 16–32% and renal flare rate of 13–23% over 36 months in patients receiving maintenance immunosuppression [7]. In a study of 161 Italian patients, maintenance immunosuppression was stopped in 52 (32%) who showed stable remission, and 38% of these patients developed disease flare at a median of 3 years afterward, although most achieved remission again after treatment [8]. In essence, while there is consensus that maintenance immunosuppressive therapy be continued for at least 3 years together with anti-malarial treatment long term [2,9,10], there is uncertainty beyond this time-frame.

Low-dose corticosteroids combined with a mycophenolic acid analog (MPAA) or azathioprine (AZA) is commonly used as maintenance therapy and is recommended by the latest guidelines. For how long should these drugs be continued? In this regard, it is important to note that the choice, and duration, of drugs in maintenance therapy are informed by the initial therapeutic regimen given previously for the treatment of active nephritis. Based on evidence showing increased relapses when MPAA induction was followed by AZA maintenance, EULAR/ERA-EDTA recommended MPAA induction to be followed by MPAA maintenance, while cyclophosphamide induction can be followed by either MPAA or AZA [2]. The KDIGO 2021 guideline recommended MPAA as maintenance therapy in preference to AZA, based on the result from ALMS demonstrating a higher efficacy for MPAA compared with AZA [9]. Our results showed that, following MPAA induction, discontinuation of MPAA maintenance before 24 months was associated with increased risk of flare, while long-term maintenance therapy with low-dose prednisolone (≤5 mg/D) and MPAA was well tolerated and associated with a low flare rate of 0.1 episode per patient-year with relatively favorable kidney survival [3,11,12]. Considering these findings, most of our patients continue with MPAA maintenance for 4–5 years.

Corticosteroids remain an integral component in the treatment of LN, although there is a trend toward reducing steroid exposure with the advent of effective therapeutic agents. There is considerable variation, largely opinion-based, between clinicians on steroid dosing and treatment duration. The 2021 KDIGO guideline advised that corticosteroids be tapered to the lowest possible dose during maintenance and that discontinuation can be considered after patients have maintained a complete clinical renal response for >12 months [9]. However, results from the open-label CORTICOLUP trial showed that discontinuation of prednisone 5 mg/D in 63 (41% with history of LN) of 124 patients with quiescent SLE (quiescence duration 68 ± 7 months) was associated with a five-fold increase in flare rate over 52 weeks of follow-up compared with patients who continued prednisone, and over 20% resumed steroid therapy [13]. Some might opine that the discontinuation of corticosteroids in this study was relatively abrupt, while encouraging results have been obtained following a slow and closely monitored tapering regimen [14–16]. In this regard, our standard practice is to reduce the dose of prednisolone to 5 mg daily by 5–6 months after starting treatment for active nephritis, then reduce it by 1 mg daily approximately every 6 months. Close monitoring of clinical and serological parameters is obligatory, as there have been patients who developed reactivation of disease while on prednisolone 3 mg daily or below despite prior quiescence.

There is insufficient data to recommend whether one should withdraw low-dose steroid or immunosuppressive medications such as MPAA or AZA first in stable patients, and both approaches are adopted in clinical practice. This should be a joint decision between the clinician and the patient, largely informed by the risk or damage profile of individual patients. For example, steroid withdrawal may be preferred in patients with osteoporosis, diabetes mellitus, or vascular complications. We taper the two alternately, with most patients stopping MPAA earlier than corticosteroids. Nevertheless, we acknowledge that there is no ‘evidence proof’ for this approach, and that other clinicians might stop corticosteroids earlier than MPAA or other immunosuppressants.

Are there newer approaches in managing patients with stable quiescent disease? Emerging data suggested that repeat kidney biopsy may help identify patients with apparent clinical quiescence but who still demonstrate histological features of activity, therefore deemed unsuitable for further tapering or discontinuation of immunosuppression [17–19]. While repeat kidney biopsy provides valuable data to risk-stratify patients for treatment tapering, its invasive nature and potential for sampling error are valid concerns. Novel therapeutic options might have a long-lasting impact on the disease course and flare risk. For example, there is preliminary data to suggest that biologics targeting the B cell repertoire are associated with a reduced incidence of disease flare [20,21]. Recent data also suggest that biologics and voclosporin may facilitate minimization of exposure to corticosteroids, although it remains unclear whether rebound of proteinuria might follow discontinuation of calcineurin inhibitors, such as voclosporin or tacrolimus, especially in patients with membranous histopathologic features.

To conclude, the lack of reliable noninvasive marker(s) that accurately predict relapse remains a key challenge in clinical decisions regarding maintenance immunosuppression. A history of repeated flares and failure to achieve complete disease quiescence are recognized risk factors for subsequent flares, while long periods of sustained clinical remission are a favorable factor; but even in the latter group relapse may still occur with further treatment tapering. An issue that warrants emphasis is individualized consideration of the impact of a nephritis flare on kidney survival, which is also the main determinant of long-term patient survival [22]. CKD is prevalent in LN patients. In patients with reduced renal reserve, an episode of nephritic relapse could precipitate relentless progression toward kidney failure. We therefore prioritize the prevention of LN flare over the side-effects associated with low-dose maintenance immunosuppression and have chosen to adopt a slow and cautious tapering regimen so that most patients continue with maintenance therapy for over 6–8 years. In this regard, our results show a low disease flare rate, and relatively favorable long-term kidney and patient survival relatively favorable long-term kidney and patient survival [3,11,12,22]. Further research is warranted to investigate the strategies for personalized treatment minimization and the impact of novel therapeutic agents on long-term outcomes.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

D Yap received research donations from the Wai Im Charitable Foundation and the Chan Sui Kau Family Benefits and Charitable Foundation. D Yap and T Chan received research funding support from the Mr and Mrs Tam Wing Fun Edmund Renal Research Fund. T Chan received research funding support from the Wai Hung Charitable Foundation, and Mr S Ho. T Chan received research funding from Astellas Pharma Inc.