LUPUS NEPHRITIS ― About 40% of patients with systemic lupus erythematosus (SLE) develop lupus nephritis, and up to 10% of these patients will eventually develop end-stage kidney disease. The prevalence of lupus nephritis is significantly higher in Black and Hispanic/Latino persons than in the general population, and these patients generally have more severe disease.3

STANDARD TREATMENT ― Recently published guidelines on the treatment of active proliferative focal (class III) or diffuse (class IV) lupus nephritis recommend initial treatment with hydroxychloroquine, a renin-angiotensin-aldosterone system inhibitor, and triple immunosuppressive therapy (a glucocorticoid, mycophenolate mofetil, and either belimumab, obinutuzumab, or a calcineurin inhibitor depending on the presence of risk factors such as proteinuria, extra-renal manifestations, or renal impairment); the treatment regimen should be continued for 3-5 years in patients with a complete renal response.3-5

The CD20-directed monoclonal antibodies rituximab (Rituxan, and biosimilars) and ocrelizumab (Ocrevus) have been used off-label for treatment of lupus nephritis, but neither drug has been shown to improve renal response rates in clinical trials.

MECHANISM OF ACTION ― Obinutuzumab binds to the CD20 antigen on B-cell lymphocytes and causes B-cell depletion through several mechanisms, including antibody-dependent cytotoxicity and phagocytosis, apoptosis, and complement-dependent cytotoxicity. B-cell depletion has been associated with improved renal outcomes in patients with lupus nephritis.

CLINICAL STUDIES ― In a double-blind trial (REGENCY), 271 adults with active class III or IV lupus nephritis, with or without class V nephritis, were randomized to receive obinutuzumab (1000 mg IV on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo in addition to mycophenolate mofetil and a corticosteroid. At week 76, a complete renal response (a urinary protein-to-creatinine ratio <0.5 g/g, an eGFR of >85% of baseline, and no intercurrent events), the primary endpoint, occurred in significantly more patients in the obinutuzumab arm than in the placebo arm (46% vs 33%; number needed to treat [NNT] 7.7).6

ADVERSE EFFECTS ― The most common adverse effects of obinutuzumab in clinical trials in patients with lupus nephritis were infusion-related reactions, serious and fatal infections, and neutropenia. The obinutuzumab label includes a boxed warning about the risks of potentially fatal progressive multifocal leukoencephalopathy (PML) and hepatitis B virus (HBV) reactivation.

DOSAGE AND ADMINISTRATION ― The recommended dosage of obinutuzumab for treatment of active lupus nephritis is 1000 mg administered intravenously on day 1, at weeks 2, 24, and 26, and every 6 months thereafter. Premedication with a glucocorticoid, acetaminophen, and an antihistamine is recommended to reduce the risk of infusion-related reactions. Patients should not receive live virus vaccines during treatment with obinutuzumab or before B-cell recovery occurs.

CONCLUSION ― Addition of the IV CD20-directed monoclonal antibody obinutuzumab (Gazyva) to standard treatment improved renal response rates in patients with active proliferative lupus nephritis. Obinutuzumab has not been directly compared with other drugs approved for this indication, but the interval between maintenance doses is much longer with obinutuzumab (6 months) than with voclosporin (Lupkynis) or belimumab (Benlysta).

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