By Dr. Paolo Nikolai So
Nephrology Fellow
Philippine General Hospital, Philippines

What factors should be considered when choosing a CYC- or MPA-based induction regimen?

IV CYC may be considered if cost is an issue. Increased adherence to treatment may be observed in selected patients with intermittent IV therapy rather than daily oral medication. For patients with severe LN requiring dialysis, there is anecdotally more confidence with the use of CYC in terms of efficacy than MMF. Whereas CYC is dialyzable, MMF is not, making its pharmacokinetics more unpredictable in this patient population. In contrast, mycophenolate mofetil may be more effective than CYC in high-risk populations (e.g., African Americans, Hispanics). Current data are also insufficient for using a reduced-dose IV CYC regimen in the Asian population. Some Asian regions, however, may encounter barriers to access to MMF. Ultimately, the choice of induction therapy is based on an extensive patient-physician discussion on medication risk-benefit profile, health economics and access, and patient preference and adherence.

* The cost estimates relate to the Australian health system
Adapted from Dr. Joanna Kent’s GlomCon Virtual Fellowship presentation, 10^th December /2020

For patients who have achieved clinical remission after induction therapy, the duration of maintenance treatment ranges from 6 months to more than 2.5 years. The optimal duration of maintenance immunosuppression has not yet been established, as the use of clinical markers (e.g., urinary protein, serum creatinine, complement, anti-dsDNA levels) may not accurately estimate actual histologic remission. Basing maintenance immunosuppression duration on arbitrary timeframes or on clinical parameters may lead to premature discontinuation of maintenance immunosuppression leading to LN flares, or to undue exposure to immunosuppressive medications along with their potential side effects.

Would protocolized kidney biopsies be helpful in guiding the management of maintenance immunosuppression?

In a recent study, biopsy-guided maintenance immunosuppression was shown to be informative in identifying patients whose immunosuppressive therapy can be safely withdrawn. It displayed an exceptionally low rate of LN flare, but head-to-head studies are still underway to rationalize the routine use of such an invasive approach. REBIOLUP (NCT04449991) is an ongoing randomized clinical trial comparing post-induction management of patients with incident biopsy-proven proliferative or membranous LN with or without a per-protocol repeat kidney biopsy in terms of renal outcomes.

Most patients with proliferative LN respond well with standard therapy. A lack of response often reflects incomplete adherence to medications. Repeat kidney biopsy may be considered for patients with worsening disease to assess the histologic burden and to exclude other renal pathology. For rare cases of refractory LN, the following treatment options may be considered:

• switch between MMF and CYC,
• rituximab as an add-on or alternative therapy,
• a combined calcineurin inhibitor (CNI) multitarget therapy,
• prolonged courses of IV CYC, or
• enrollment in clinical trials.

What advances in LN therapy could we expect down the pipeline?

Calcineurin inhibitors are currently being used as an alternative therapy for lupus nephritis, especially in those with a membranous component (i.e., class V ± III/IV). Multitarget therapy with TAC and MMF was shown to be more effective in inducing remission than IV CYC, while TAC combined with corticosteroids has been suggested to have a role as a long-term maintenance agent. Long-term data regarding the efficacy of these regimens with respect to outcomes like renal flare rate and progression to ESKD are awaited. In recent years, low-dose voclosporin as an add-on immunosuppressant for induction showed better clinical response than standard treatment alone based on the AURA-LV (Phase 2) and AURORA (Phase 3) studies. The success of CNIs in LN treatment partly stems from their ability in stabilizing the actin cytoskeleton, thereby causing an additional anti-proteinuric effect on top of their role in immunosuppression.

B cell-depleting agents are also being used in the management of LN. Although rituximab failed to show an increase in renal response rates in the LUNAR study, belimumab added to standard therapy was shown in BLISS-LN to have a better primary efficacy renal response in patients with active LN than standard therapy alone. Obinutuzumab was also shown to have improved renal responses when added to SOC therapy in the NOBILITY trial (Phase 2) (NCT02550652) and is currently being investigated in REGENCY (Phase 3) (NCT04221477).

Key learning points:

• Development in LN treatment is currently evolving.
• Initial choice of standard induction regimen is individualized based on medication risk-benefit profile, health economics and access, and patient preference and compliance.
• Biopsy-guided maintenance immunosuppression shows promise in reducing LN flares.
• Management of refractory LN involves evaluating medication adherence, consideration of a repeat biopsy (to distinguish between ongoing histological activity versus chronic damage), and a change in therapy.
• Emerging novel therapies targeting specific pathways are presently undergoing randomized clinical trials, with positive results emerging.

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