Lupus nephritis (LN) affects approximately 50–70% and accounts for the highest morbidity and mortality among lupus patients. Established treatment protocols for LN typically include immunosuppressive therapy in combination with glucocorticoids. Although the survival of LN patients has improved over the last 2 decades due to earlier recognition and more aggressive intervention, about a quarter of patients continue to progress to end stage renal disease (ESRD).¹

There is considerable diversity in the definition of ‘refractory lupus nephritis’ depending on the treatment protocol, physician’s subspecialty, and histopathologic findings. Molecular biomarkers further show potential as surrogates to kidney biopsies in predicting renal outcomes and long-term prognosis.² The factor of drug adherence, however, may draw the fine distinction between refractory (or resistant) and relapsing LN, with the latter substantially more common than the former.³ Nearly half of patients with proliferative LN who initially achieve a complete response to immunosuppressive therapy will have a relapse or renal flare following cessation or reduction of immunosuppression. Other risk factors for refractoriness include genetics and comorbidities like hypertension, diabetic nephropathy and antiphospholipid antibodies, each of which must be effectively addressed in the overall management of these patients.

Treatment options for refractory LN include switching or multitargeted therapy with immunosuppressives cyclophosphamide, mycophenolate derivatives and calcineurin inhibitors (cyclosporine A, tacrolimus, and recently voclosporin).⁴ Literature abounds with the use of rituximab in refractory LN including trials exploring the sequential use of rituximab plus cyclophosphamide followed by belimumab.⁵ Other modalities such as extracorporeal treatment (plasma exchange or immunoadsorption) and stem cell transplantation may be tried in special situations. Novel insights of LN pathogenesis have led to the development of new or re-purposed drugs including obinutuzumab, itolizumab, and iguratimod which can significantly prevent progression to ESRD. Finally, the timely, aggressive and highly individualised management of LN which reinforces strict patient adherence is key to enhanced outcomes.

Learning Objectives

• Define refractory and/or relapsing LN

• Identify risk factors for refractoriness among LN patients

• Describe the management approach to refractory LN

• Describe advances in drug development for LN

References

1. Weidenbusch M, Bai Y, Eder J, et al. Refractory lupus nephritis: a survey. Lupus 2019;28(4):455–64.

2. Parodis I, Tamirou F, Houssiau FA. Prediction of prognosis and renal outcome in lupus nephritis. Lupus Sci Med 2020;7(1).

3. Kronbichler A, Brezina B, Gauckler P, et al. Refractory lupus nephritis: When, why and how to treat. Autoimmun Rev 2019;18(5):510–18.

4. Yo JH, Barbour TD, Nicholls K. Management of refractory lupus nephritis: challenges and solutions. Open Access Rheumatol 2019;11:179–88.

5. Zhong Z, Li H, Zhong H, et al. Clinical efficacy and safety of rituximab in lupus nephritis. Drug Des Devel Ther 2019;13:845–56.