Lupus nephritis (LN) develops in as many as two-thirds of patients with systemic lupus erythematosus (SLE) within 5 years of SLE onset. Once LN occurs, it is associated with worse morbidity, health-related quality of life, and mortality. Kidney failure is a major concern.
“ESKD still develops in 5-30% of patients with LN within 10 years of diagnosis, suggesting an unmet need to improve the efficacy-to-toxicity balance of current therapeutics,” Chi Chiu Mok, MD, of Tuen Mun Hospital in Hong Kong, China, and colleagues noted in a recent review published in Nature Reviews Rheumatology.
The authors wrote the review to outline current and potential treatments for LN, consensus, and future directions.
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Standard of Care
LN guidelines vary among countries due to differences in ethnic makeup and available resources, according to the authors. Hydroxychloroquine is universally recommended for initial therapy but requires dosage adjustment in patients with low estimated glomerular filtration rate (eGFR).
Guidelines from major rheumatology and nephrology associations agree that conventional induction therapies for severe LN include high doses of glucocorticoids with either cyclophosphamide or mycophenolate mofetil (MMF). Dosages vary, however, due to concerns over toxicity. In the full review, the authors compared and contrasted guideline recommendations for patients with class 3 and 4, pure class 5, and refractory LN.
Tacrolimus, a calcineurin inhibitor, is recommended as second-line therapy for LN in Asian patients who cannot tolerate cyclophosphamide or MMF. Rituximab, a B cell-targeted therapy, is recommended for rescue therapy. Maintenance therapy for LN should continue for 3 to 5 years to minimize renal flares. All major guidelines recommend MMF or azathioprine for maintenance therapy, and some suggest a low-dose calcineurin inhibitor as an alternative.
As yet, there is no consensus on treating patients with rapidly progressive LN, such as crescents or fibrinoid necrosis.
Cessation of maintenance therapy is still being debated. A randomized controlled trial (Clinicaltrials.gov NCT04449991) is currently investigating whether histological remission on a repeat renal biopsy suffices for treatment discontinuation.
Novel Therapeutics
Clinical trials are investigating novel biological agents or targeted small molecules in combination with standard of care in LN. New-generation anti-CD20 biologic agents, type I interferon antagonists, and rituximab-belimumab combination regimens show promise, according to the authors.
Voclosporin, a novel calcineurin inhibitor, induces renal response when added to standard of care MMF and glucocorticoids, with no increased risk of infection. Voclosporin is not recommended for patients with an eGFR of 45 mL/min/1.73 m2 or less or in combination with cyclophosphamide.
Belimumab, a monoclonal antibody against B cell activating factor (BAFF), was tested as an add-on therapy to standard regimens of glucocorticoids plus MMF or cyclophosphamide plus azathioprine. Belimumab increased renal response and decreased the risk of renal flares and eGFR decline. The drug was less effective in patients with membranous LN, a urinary protein to creatinine ratio greater than 3.0, or Asian or African ancestry. It was also less effective with cyclophosphamide treatment.
Other steroid-sparing, B cell-targeting regimens under investigation include rituximab plus MMF and obinutuzumab, a newer generation anti-CD20 biologic, plus MMF.
Several trials are investigating belimumab and rituximab combination therapy, the authors noted. CALIBRATE studied sequential administration of rituximab-cyclophosphamide and belimumab in patients with refractory LN. Patients experienced a decline in total and autoreactive naive B cells without an increase in adverse events compared with rituximab-cyclophosphamide alone. BEAT-LUPUS confirmed the safety of the combination of rituximab followed by belimumab in patients with refractory SLE. BLISS-BELIEVE examined rituximab as add-on treatment to subcutaneously administered belimumab in patients with active SLE without other immunosuppression. Patients with SLE with renal involvement achieved long-term proteinuric remission.
Investigators are also exploring an intensified dosage regimen of anifrolumab, a monoclonal antibody directed against the type I interferon receptor subunit 1 on T cells. Herpes zoster infection is a concern.
Dual-action monoclonal antibodies also show promise, according to the authors. Rozibafusp alfa is a first-in-class bispecific antibody-peptide conjugate that binds both BAFF and inducible T cell co-stimulator ligand (ICOSL). The drug blocks B cell maturation, T cell activation, and communication between T cells and B cells. It is being explored for nonrenal SLE. Ianalumab, a dual-action biologic that targets the BAFF receptor and mediates direct ADCC-mediated B cell depletion, is being explored in the SIRIUS-LN trial (NCT05126277), which is now recruiting.
A host of other drugs with cellular and cytokine targets are being investigated in trials. These target surface antigens and growth factors of B cells, surface molecules and intracellular proteins of T cells, surface molecules of dendritic cells, surface molecules and immunoproteasomes of plasma cells, cytokines and their receptors, intracellular downstream signaling pathways, complement pathways, and the neonatal Fc receptor.
Non-Immunosuppressive Therapies
Patients with lupus nephritis benefit from blood pressure control, reduction of albuminuria, and a healthy lifestyle involving healthy eating, exercise, and smoking cessation, the authors recapitulated. Clinicians should treat diabetes mellitus, hyperlipidemia, and metabolic syndrome, while avoiding nephrotoxic drugs, they noted. As with other kidney diseases, consider renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors, unless contraindicated.
Precision Medicine
In addition to LN histological class, activity and chronicity, selection of LN therapy varies by age, ethnicity, LN history and course, kidney function, and comorbidities, the authors pointed out.
“Molecular profiling, gene-signature fingerprints and urine proteomic panels could enhance the accuracy of patient stratification for treatment personalization in the future,” Dr Mok and colleagues wrote.
Future guidelines are expected to address when to ‘step-up’ versus ‘step-down’ on LN treatment.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Mok CC, Teng YKO, Saxena R, Tanaka Y. Treatment of lupus nephritis: consensus, evidence and perspectives. Nat Rev Rheumatol. 19(4):227-238. doi:10.1038/s41584-023-00925-5
