Managing Lupus Nephritis: From Clinical and Economic Implications to Diagnosis and Treatment Advances

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), a chronic inflammatory and autoimmune disease that leads to tissue and organ damage.^1,2 In LN, persistent kidney inflammation can cause renal damage that drives chronic kidney disease (CKD), and it may eventually progress to end-stage renal disease (ESRD) and death.^3,4 ESRD is a serious and costly complication of LN, and greater disease severity is correlated with much greater health care costs than are milder forms with low disease activity.^4,5

Early diagnosis and initiation of effective treatment may help to promote preservation of kidney function and reduce health care costs.^4-6 FDA approval of 2 drugs indicated for the treatment of LN, belimumab (Benlysta; GlaxoSmithKline) and voclosporin (Lupkynis; Aurinia Pharmaceuticals), expands the list of available LN therapeutics.^7,8 This article provides a background of LN and a review of its associated clinical and economic burden, presentation and diagnosis, standard treatments, and the optimal use of available therapies to support managed care decision-making.

Disease Background

Prevalence

Limited and varying data make estimation of the prevalence of LN in the US population challenging. There were approximately 200,000 people with SLE in the United States in 2018.⁹ Between 12% and 69% of patients with SLE may either present with or develop LN.^10-12

Certain demographic groups are at higher risk of developing SLE and LN. The prevalence of SLE is 8 to 15 times greater among women than among men.^2,9 The highest prevalence of SLE across both genders was seen in populations with American Indian/Alaska Native, Black, or Hispanic race/ethnicity, according to results of a meta-analysis of 5 population-based SLE registries.⁹ Notably, among those with SLE, higher rates of LN can be seen in younger patients, men, and those of African, Asian, or Hispanic race/ethnicity.^10,11

Pathophysiology of LN

SLE is a chronic inflammatory and autoimmune disease.^1,2 Systemic autoimmunity can lead to damage to tissues and organs; commonly, the kidney is injured.^1,2 In patients with certain genetic polymorphisms (eg, those involved in DNA clearance, the complement pathway), exposure to specific environmental triggers can precipitate autovaccination against endogenous nuclear material and development of SLE.^1-3

A form of glomerulonephritis, LN can occur as a result of autoantibody-containing immune complex accumulation, local complement activation, leukocyte recruitment, and intrarenal cytokine signaling, which can lead to inflammation of the kidneys and contribute to glomerular and tubulointerstitial damage.^1-3,13 The location of immune complex accumulation and complement activation determines the type of glomerular cell that is preferentially injured, defining the different histopathological classes of lupus nephritis (please see page 5 of this publication).^3,13

Continued kidney inflammation can result in renal cell loss and nephron atrophy.³ Episodes of increased disease activity, called renal flares, typically result in irreversible nephron loss that severely shortens renal life span.^5,14 Nonimmune mechanisms of renal damage include disruption of cell-to-cell interactions,compromising the maintenance of nephron structures.¹³ Abnormal vascular function leads to tissue hypoxia and tubular atrophy, and renal fibrosis results from ischemia and hypertension.¹³ As nephron atrophy continues, compensatory hyperfiltration and other mechanisms in the remaining nephrons cause a rise in intraglomerular pressure and glomerular stress.^1,13 Independent of SLE disease activity, compensatory hyperfiltration and consequent increases in nephron loss may occur, driving progression of CKD.^1,13

Burden of Disease

LN is associated with considerable clinical and economic burdens in affected patients. Patients with incident LN (n = 72) had a mortality rate over 6 times greater than that seen in the general population in a population-based study of Minnesota residents identified between 1976 and 2018. Furthermore, the authors found no improvement in the mortality gap over the study period. The 3 most common causes of death among 19 patients with LN were infection, SLE disease activity, and cardiovascular disease. Generalizability of these results may be limited, as this study predominantly involved white patients.¹²

Even among patients with SLE, LN is associated with an increased risk for kidney failure (ie, ESRD) and death. In a Systemic Lupus International Collaborating Clinics (SLICC) inception cohort study of long-term outcomes in 1827 patients with SLE conducted between 1999 and 2012, patients with an LN diagnosis had nearly 45 times the risk of developing ESRD and approximately 3 times the risk of death when compared with those having SLE and no LN.¹¹ Generalizability of results may be limited, as data were derived from a disease inception cohort at academic medical centers focused on lupus; thus, patients were younger and disease duration was shorter than seen in prevalent cohorts of lupus cases, and data may not reflect community clinical practice.¹¹

At 10 years after diagnosis, approximately 10% of patients with LN develop ESRD.^11,12 In the Minnesota population study, after 10 years of follow-up, 39% of patients with LN had ESRD (ie, started dialysis or received a renal transplant) or died.¹² ESRD is associated with an increased risk of death.⁴ In a retrospective, observational analysis of 2007-2019 Optum medical and pharmacy claims data in 21,251 patients with LN (mean follow-up, 30.6 months), the death rate associated with ESRD (24.3%) was over twice that seen with periods of active disease (ie, flares or relapses) (11%) or low disease (10%).⁴ Limitations of this analysis included the inherent possibility of coding errors and omissions and the possible underestimation of medication use and consequent misclassification of low disease activity; further, the study did not measure treatment adherence or in-depth clinical data, such as disease severity.⁴

Progression of kidney disease also is associated with substantial increases in health care costs. In patients who have reached the point of kidney failure, the average annual cost of dialysis in the United States is around $100,000, and costs in the first year following a kidney transplant reach over $120,000 (2022 US$).⁶ Health care costs can increase considerably when any patients, especially private insurance enrollees, initiate dialysis.¹⁵ Additionally, commercial insurers may pay much higher rates for dialysis than do government insurers.^15,16 ESRD and dialysis are major contributors to the economic burden of LN.¹⁴ Preventing progression of kidney disease may help reduce health care resource use (HCRU) related to kidney failure.

Progression to ESRD in patients with SLE is associated with increased HCRU and costs. The mean number of all-cause HCRU visits (excluding pharmacy fills) increased from 61.6 visits at 5 years before ESRD diagnosis to 83.1 visits at 1 year before ESRD diagnosis in a retrospective observational study of IBM MarketScan data in 616 patients with SLE whodeveloped ESRD between 2012 and 2018.⁵ Over the same period, mean total health care costs per patient increased progressively from $34,890 to $73,236 (2019 US$). Limitations of this study included the possibility of misclassification or inaccuracies in diagnostic coding; thus, whether ESRD occurred consequent to LN or to other renal causes in this population could not be determined. In addition, generalizability of results was limited to those with insurance coverage. Finally, this study lacked comparators; thus, complete statistical analyses with other populations were not possible.⁵

In patients with LN, periods of active disease and ESRD are associated with higher health care costs than are periods of low disease activity, regardless of insurance coverage. Further results of the previously mentioned analysis of 2007-2019 Optum pharmacy and medical claims data showed that lower disease activity was associated with lower LN treatment use.⁴ Examination of HCRU and payer costs associated with periods of active disease, low disease activity, and ESRD found that medical and pharmacy costs were nearly twice as high during active disease periods than during low disease activity ($6612 vs $3584), and ESRD was associated with $21,844 in monthly health care costs (2020 US$). The study did not measure costs for medications or services; results may not be generalizable to the overall LN population, which included patients who were commercially insured or on Medicare with Part D coverage.⁴

Together, these results highlight both the clinical and economic incentives to prevent progression of renal disease in those with SLE. Early diagnosis of LN allows for swift initiation of effective treatment to promote achievement and maintenance of low disease activity, preservation of kidney function, and ultimately, reduction of medication use and overall health care costs ^4-6

Presentation and Diagnosis

Clinical presentation of LN is often heterogenous and subtle, with systemic signs of SLE appearing before renal involvement in most patients.^1,2,17 Clinical manifestations are often discovered via urine examination; signs of LN on urinalysis/sediment analysis may include excess protein (proteinuria; often measured via urine protein-to-creatinine ratio [UPCR]), presence of red blood cells or white blood cells, and detection of cellular casts; most patients show signs of renal insufficiency (often measured via increased UPCR or serum creatinine concentration or decreased estimated glomerular filtration rate [GFR]) and tubular abnormalities on biopsy.^1-3,18-20 Proteinuria serves as an important predictor of kidney function decline and long-term outcomes, such as risk of ESRD and mortality.^4,20

Recommendations from the European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) state that kidney biopsy should be considered in patients with SLE who exhibit signs of kidney involvement, including glomerular hematuria and/or cellular casts, proteinuria exceeding 0.5 g per 24 hours (or spot UPCR ≥ 0.5 g/g), and unexplained decrease in GFR.²⁰ However, LN may present with mild symptoms and minor or no laboratory changes.^2,19,20

The kidney biopsy is indispensable as a diagnostic and prognostic tool for identifying the nature and extent of renal involvement and tissue damage, and earlier use of biopsy may be associated with improved outcomes, regardless of histologic severity.^1,2,17,20,21 The histopathological classes of LN (per the 2003 International Society of Nephrology/Renal Pathology Society classification) are as follows^20,22:

• class I, minimal mesangial LN;
• class II, mesangial proliferative LN;
• class III, focal LN;
• class IV, diffuse LN;
• class V, membranous LN (may occur in combination with class III or IV LN); and
• class V, advanced sclerotic LN.

These classes inform the prognosis and management of LN. Class II LN is associated with low risk of CKD or ESRD, whereas class III and class IV LN indicate irreversible nephron loss that reduces kidney life span. Class III, IV, and V LN indicate the immediate risk of CKD progression, whereas class VI LN indicates kidney atrophy in ESRD.^1,3

Early identification of renal involvement is critical for identifying kidney damage, allowing prompt diagnosis and treatment of LN and promoting the best possible outcomes in patients with SLE.²³ Recommendations include monitoring patients with no previous history of or stable LN every 3 to 6 months; those at high risk of developing LN (eg, males, individuals with juvenile lupus onset, or patients who test positive for C1q and certain C-reactive proteins) should be tested at least every 3 months.^1,17,23 Surveillance should include regular urinalysis and sediment analysis; testing for antiphospholipid, anti-double stranded DNA, and anti-C1q autoantibodies; and tracking of C3 and C4 complement levels, blood pressure, and body weight.^17,20 In practice, LN screening rates among those with SLE and rates of kidney biopsy among those with LN may be lower than recommended.^17,24 Results of kidney biopsies are used to inform appropriate treatment decision-making.^1,3,17

Standard Therapies and Treatment Advances in Lupus Nephritis

Ultimately, the goals of LN management are to prevent progression to CKD or ESRD and include patient survival, long-term preservation of kidney function, prevention of renal flares and organ damage, management of comorbidities, and improvement of disease-related quality of life.^2,20 Improvement or preservation of kidney function may be accompanied by a reduction in proteinuria.²⁰ Treatment should aim for a complete clinical response, defined as a target UPCR of below 0.5 to 0.7 g/g at 12 months.²⁰ Accompanying milestones include a 25% reduction in proteinuria at 3 months and a 50% reduction at 6 months; however, EULAR/ERA-EDTA recommendations extend this timeline by 6 to 12 months in patients with nephrotic-range proteinuria (> 3.5 g/d) at baseline.^1,20

According to the 2020 EULAR/ERA-EDTA recommendations, initial treatment in patients with class III or IV LN (with or without class V LN) should consist of glucocorticoids given in combination with mycophenolate mofetil/mycophenolic acid (MMF/MPA), low-dose intravenous (IV) cyclophosphamide, or MMF/MPA plus a calcineurin inhibitor (CNI), especially in patients with nephrotic-range proteinuria.²⁰ In patients at high risk for kidney failure, high-dose cyclophosphamide therapy may be considered.²⁰ For initial glucocorticoid treatment, initial pulses of IV methylprednisolone followed by tapered oral prednisone is recommended, as medium- to long-term steroid use carries the risk of permanent organ damage.^20,23 Patients with pure class V LN should be treated with MMF/MPA given in combination with the above regimen of glucocorticoids; alternatives include CNIs or IV cyclophosphamide given alone or in combination with MMF/MPA.²⁰ If not contraindicated, hydroxychloroquine is recommended for use in all patients with LN to reduce the risk of renal flares, ESRD, and death.²⁰

In October of 2023, EULAR released new guidelines for the management of SLE, noting the important FDA approvals of belimumab and voclosporin for the treatment of active LN. According to the updated guidelines, in addition to use of glucocorticoids, mycophenolate or cyclophosphamide therapy in combination with belimumab, or mycophenolate therapy in combination with a CNI (especially voclosporin or tacrolimus) should be considered in all adult patients with active LN, regardless of disease class. The guidelines emphasize that the treating health care provider should determine the necessity and timing of early combination therapy, noting a lack of clarity on which patients would most benefit.²⁵

For subsequent treatment of LN after adequate response is achieved, EULAR/ERA-EDTA recommendations include continuing hydroxychloroquine in combination with MMF/MPA (especially in those who initiated treatment with MMF/MPA) or azathioprine. Keeping nephrotoxicity risks in mind, a high-dose CNI may be used in patients with class V LN. Discontinuation of glucocorticoids following gradual tapering may be possible depending on factors such as disease response and patient preferences.²⁰

In cases where treatment goals are not achieved, occurrence of nonresponding or refractory LN is possible. In patients with nonresponding/refractory disease, switching treatment to a different recommended therapy (mentioned above) is recommended, as is off-label use of a B-cell depleting therapy (eg, rituximab, belimumab).²⁰

Regular monitoring for response to treatment involves assessments similar to those used for surveillance and diagnosis of LN; additionally, repeated kidney biopsy may be warranted in patients whose disease is nonresponsive or relapsing to gather prognostic information and to identify other pathologies. In patients whose disease progresses to ESRD, all methods of kidney replacement treatments are recommended, although transplantation is associated with higher survival rates and, therefore, may be preferred.²⁰

Updated information is available in the 2023 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline, which also suggests the option of treatment initiation with belimumab in combination with MMF/MPA or low-dose IV cyclophosphamide in patients with class III or IV LN.²⁶ Departing from the EULAR/ERA-EDTA recommendations, a public review draft of the 2023 KDIGO guidelines (published in March of 2023) suggest maintenance treatment with MMF/MPA for individuals with class III or IV disease. In patients with class V LN, use of hydroxychloroquine in combination with renin-angiotensin system blockade, blood pressure control, and immunosuppressive treatment is recommended in the presence of low-level proteinuria; in patients with nephrotic syndrome, the addition of MMF/MPA, cyclophosphamide, rituximab, azathioprine, or a CNI is suggested. The KDIGO guidelines also note that in patients with class I or II LN, the immunosuppressive treatment given for nonrenal SLE is adequate; however, patients with nephrotic syndrome may benefit from maintenance therapy with a low-dose glucocorticoid given in combination with another immunosuppressive agent (MMF/MPA, azathioprine, or a CNI).²⁶

Supportive Evidence for Drugs Indicated in LN

Belimumab

Belimumab is a B-lymphocyte stimulator-specific inhibitor that is given IV or subcutaneously (SC); the drug is indicated to treat active SLE and active LN in patients 5 years or older who are receiving standard therapy.⁷ FDA approval of belimumab was first granted for the treatment of SLE; in 2020, it was extended to include LN based on the results of the 104-week BLISS-LN trial (NCT01639339) that evaluated the safety and efficacy of IV belimumab plus standard therapy (ie, MMF or cyclophosphamide with azathioprine) in 448 patients with active LN.^7,27,28 Results supported the efficacy and safety of belimumab used in combination with standard therapy.^27,29 Belimumab was the first therapy to be approved by the FDA to treat LN.²⁸

In the BLISS-LN study, higher proteinuria levels at baseline were associated with higher belimumab clearance, although clearance decreased as proteinuria decreased in response to treatment.²⁹ Belimumab was most effective in patients with low proteinuria at baseline (eg, UPCR < 2 g/g) in patients with all classes of LN and with standard treatment regimens used. Tapering of oral corticosteroids among patients with low proteinuria was greater in the belimumab arm than in the placebo arm; however, among patients with high proteinuria at baseline, there was no difference between study arms.²⁹ No formal studies on drug interactions with belimumab have been performed; in clinical trials, however, use of concomitant medications produced no evidence of a clinically meaningful effect on belimumab pharmacokinetics.⁷

Voclosporin

Voclosporin is a CNI indicated for oral administration to treat active LN in adult patients who are receiving background immunosuppressive therapy (ie, MMF and corticosteroids).⁸ Unlike other CNIs (eg, cyclosporine, tacrolimus), voclosporin does not require drug monitoring or affect concentrations of mycophenolic acid; additionally, voclosporin has a more favorable metabolic profile and demonstrates lower nephrotoxicity due to decreased off-target calcineurin inhibition.^30-32

Voclosporin is the first approved oral therapy for LN; in 2021, it received FDA-approval based on the randomized, controlled AURA-LV (NCT02141672) and AURORA 1 (NCT03021499) clinical trials in patients with class III, IV, or V LN.^31,33 Results from these international, double-blinded, placebo-controlled, multiethnic trials supported the efficacy and safety of voclosporin used in combination with MMF and tapered steroids.^30,31,34 An integrated analysis of results from the AURA-LV and AURORA 1 trials confirmed the efficacy of voclosporin over control regardless of the patient’s LN class or baseline UPCR.³⁵

Results from the recently published AURORA 2 extension study (NCT03597464) confirmed the long-term efficacy and safety of treatment with voclosporin over an additional 2 years of follow-up after the end of the 52-week AURORA 1 study.^30,32 Over 75% of patients in both arms maintained glucocorticoid tapering throughout the trial (≤ 2.5 mg/d of prednisone or equivalent).³²

Managed Care Considerations and Conclusions

Factors that can increase the risk of poor clinical outcomes in LN include low treatment adherence, certain genetic profiles, and prolonged glucocorticoid use.¹⁷ Goals of treatment include early diagnosis and rapid remission of active LN, prevention of disease progression, reduction of glucocorticoid use, and restriction of treatment-associated toxicity.^1,20 Ideal management involves collaboration between providers (eg, nephrologists, rheumatologists), communication with patients, and coordination with payers to optimize outcomes, promote shared decision-making, and balance treatment costs with long-term efficacy.^20,26

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