Corticosteroids in Lupus Nephritis and Central Nervous System Lupus




Corticosteroids are a mainstay of therapy for severe organ-threatening systemic lupus erythematosus. Lupus nephritis and central nervous system (CNS) lupus remain two of the most debilitating and potentially life-threatening manifestations of lupus. The dose and duration of corticosteroids required for control of lupus nephritis and CNS lupus have never been tested in a randomized trial design, so current recommendations are based on observation and expert opinion. As more targeted individualized therapeutic approaches are developed for lupus nephritis and CNS lupus, reliance on long-term corticosteroids will decrease, as will the long-term damage and early mortality associated with their use.


Key points








  • The current standard of care for active proliferative lupus nephritis and severe central nervous system (CNS) lupus includes corticosteroids in high doses for immunosuppression.



  • Despite the potential to be lifesaving in cases of lupus nephritis and CNS lupus, corticosteroids are also associated with long-term damage and early mortality.



  • The goal of lupus therapy remains elimination of corticosteroids when possible.






Introduction


Corticosteroids, often in high doses and typically in combination with other immunosuppressive treatments, are a mainstay of therapy for severe organ-threatening systemic lupus erythematosus (SLE; lupus). The antiinflammatory effects of corticosteroids are pervasive and complex and depend on the timing, dose, and route of administration. Corticosteroids act on multiple immune cell types to inhibit the production of inflammatory mediators and stimulate the production of antiinflammatory proteins through both genomic and nongenomic pathways.


Until recently, the standard design of treatment trials for active lupus allowed, or even mandated, the use of corticosteroids for more immediate control of active disease while awaiting the anticipated benefits of the experimental intervention. It is only recently that interventional trials for active lupus have been designed with minimal use of corticosteroids. Given the known dose-related and duration-related adverse effects of corticosteroids, the potential of treating active lupus with minimal to no corticosteroids is appealing. However, the value and lifesaving potential of high doses of corticosteroids for uncontrolled severe lupus is undeniable.


This article reviews the evidence for, and against, the efficacy of corticosteroids in the clinical setting of active lupus nephritis and/or active central nervous system (CNS) lupus. The adverse effects of corticosteroids in patients with lupus nephritis and CNS lupus are also reviewed.




Introduction


Corticosteroids, often in high doses and typically in combination with other immunosuppressive treatments, are a mainstay of therapy for severe organ-threatening systemic lupus erythematosus (SLE; lupus). The antiinflammatory effects of corticosteroids are pervasive and complex and depend on the timing, dose, and route of administration. Corticosteroids act on multiple immune cell types to inhibit the production of inflammatory mediators and stimulate the production of antiinflammatory proteins through both genomic and nongenomic pathways.


Until recently, the standard design of treatment trials for active lupus allowed, or even mandated, the use of corticosteroids for more immediate control of active disease while awaiting the anticipated benefits of the experimental intervention. It is only recently that interventional trials for active lupus have been designed with minimal use of corticosteroids. Given the known dose-related and duration-related adverse effects of corticosteroids, the potential of treating active lupus with minimal to no corticosteroids is appealing. However, the value and lifesaving potential of high doses of corticosteroids for uncontrolled severe lupus is undeniable.


This article reviews the evidence for, and against, the efficacy of corticosteroids in the clinical setting of active lupus nephritis and/or active central nervous system (CNS) lupus. The adverse effects of corticosteroids in patients with lupus nephritis and CNS lupus are also reviewed.




Epidemiology of lupus nephritis


Lupus nephritis remains one of the most debilitating and potentially life-threatening manifestations of lupus, occurring in 40% to 60% of adults and up to 80% of children with lupus. The susceptibility and burden of lupus are substantially higher among black women compared with other groups, with black people having 3 times the incidence rate compared with whites and women having 9 to 10 times the prevalence compared with men. Peak age of incidence for both lupus and lupus nephritis is also younger among black women. The disparities in lupus-related risk are most striking when examining renal involvement, with black patients and Hispanic patients having more frequent and more severe lupus nephritis compared with other groups.


The prognosis of lupus nephritis is related to the degree of active renal inflammation and chronic damage, which is reflected in the renal histologic class on kidney biopsy as well as the associated clinical and laboratory features. Ultimately, 10% to 20% of patients with lupus nephritis require renal-replacement therapy for end-stage renal disease, most commonly with hemodialysis, and early mortality remains unacceptably high.




Evaluation of lupus nephritis


Renal biopsy histology helps not only confirm the diagnosis but also helps guide therapy for lupus nephritis. Proliferative lupus nephritis is the most common form, often presenting as proteinuria, microscopic hematuria, urinary casts, hypertension, and potentially including renal insufficiency. Membranous lupus nephritis is also frequently seen histologically either alone or in conjunction with proliferative nephritis, often presenting as nephrotic syndrome with edema, wasting, and hypercoagulability.




Treatment goals for lupus nephritis


Prevention of end-stage renal disease and reducing the risks of chronic kidney disease with associated comorbidities are primary goals of lupus nephritis therapy. Typical immunosuppression for lupus nephritis consists of induction with corticosteroids combined with a cytotoxic medication to achieve a rapid response, followed by a maintenance period of continued but less potent immunosuppression.


In practice, evidence supporting certain treatment regimens for specific clinical and histologic situations is considered in conjunction with other patient-specific variables. These variables influencing therapeutic decisions include patient ethnicity, age, comorbidities, pregnancy plans, fear of certain adverse effects, and any doubts about compliance, which results in a shift away from one-size-fits-all protocols toward more highly individualized treatment regimens.




Proliferative lupus nephritis induction therapy


A shift occurred in the 1970s and 1980s from using corticosteroids alone to using them in combination with cytotoxic medications to treat lupus nephritis, based on clinical trial evidence supporting combination therapy. At present, the 3 most widely accepted induction regimens for proliferative lupus nephritis are corticosteroids plus either monthly high-dose intravenous (IV) cyclophosphamide (the National Institutes of Health Regimen), low-dose IV cyclophosphamide every 2 weeks (the Euro-Lupus Regimen), or daily oral mycophenolate mofetil (MMF).


The American College of Rheumatology (ACR) published guidelines for treating lupus nephritis recommending the use of pulse-dose corticosteroids for the first 3 days of induction, followed by 0.5 to 1 mg/kg/d prednisone tapered to the lowest effective dose by the first 3 to 6 months ( Table 1 ). Similarly, the National Kidney Foundation’s KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend an initial prednisone dose of 1 mg/kg/d, with a slow taper over 6 to 12 months.



Table 1

Definitions and indications for common corticosteroid regimens used in the treatment of lupus
































Corticosteroid Regimen Formulation, Dose, and Timing Indication in Lupus Nephritis and/or CNS Lupus
Pulse-dose corticosteroids 0.5–1.0 g IV methylprednisolone per day for 1–3 d


  • Life-threatening or organ-threatening complications



  • Active lupus refractory to high-dose corticosteroids

Very-high-dose corticosteroids >100 mg IV or oral prednisone equivalent per day


  • Life-threatening or organ-threatening complications

High-dose corticosteroids >30 and ≤100 mg IV or oral prednisone equivalent per day


  • Proliferative lupus nephritis



  • Severe flares of lupus

Moderate-dose corticosteroids >7.5 and ≤30 mg IV or oral prednisone equivalent per day


  • Moderate flares of lupus



  • Used in conjunction with pulse dose for severe lupus

Low-dose corticosteroids ≤7.5 mg oral prednisone equivalent per day


  • Mild flares of lupus



  • Maintenance therapy

Alternate-day corticosteroids Oral prednisone equivalent taken every other day


  • Treatment of membranous lupus nephritis



  • Tapering from daily dosing


Doses are based on a 60-kg patient.

Adapted from Kirou KA, Boumpas DT. Systemic glucocorticoid therapy in SLE. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 8th edition. Philadelphia: Elsevier; 2013. p. 595; with permission.


Although a patient with lupus nephritis on induction therapy with pulse-dose corticosteroids and cyclophosphamide or MMF may start to respond clinically within the first 2 weeks, lupus nephritis biomarkers (particularly proteinuria) may take longer than 6 weeks for improvement. Patient demographics influence the response to induction therapy as well, with MMF, when adequately dosed, leading to better renal responses compared with cyclophosphamide among the subgroup of black and Hispanic patients.




Proliferative lupus nephritis maintenance therapy


Following induction, the use of maintenance therapy decreases the risk of nephritis relapses and reduces cumulative corticosteroid exposure in the long term. From the results of the ALMS (Aspreva Lupus Management Study) and MAINTAIN trials in proliferative lupus nephritis, it was learned that both mycophenolate mofetil and azathioprine can be used as long-term maintenance therapy.


The KDIGO guidelines recommend using low-dose to moderate-dose prednisone (≤10 mg/d) for maintenance therapy (see Table 1 ). For relapse of active nephritis, reinitiating the same dose of prednisone that was effective in inducing the original remission is recommended.




Challenging current corticosteroid practices


The dose and duration of corticosteroids required for control of lupus nephritis have never been tested in a randomized trial design, so current recommendations are based on observation and expert opinion.


The presumption that oral corticosteroids are a required adjunctive therapy for lupus nephritis has been called into question recently. An uncontrolled trial of 2 doses of 1000 mg of IV rituximab combined with 2 doses of 500 mg of IV methylprednisolone followed by MMF in 50 patients with lupus nephritis found that most subjects achieved complete renal remission without any oral corticosteroids. Of the 50 trial participants, 72% achieved complete renal remission by a median time of 36 weeks and an additional 18% achieved persistent partial renal remission by a median time of 32 weeks. These early results suggest that early initiation of a targeted biologic agent may be a safe and effective substitute for maintenance corticosteroids. A randomized controlled trial for patients with active lupus nephritis testing this hypothesis is underway.




Tapering of corticosteroids


It is important to use other immunosuppressive medications as steroid-sparing agents to help allow the safe tapering of corticosteroids among patients with lupus nephritis. When tapering, the initial step is consolidation of the regimen into a once-a-day morning dose of corticosteroids. The daily dose should then be slowly decreased with the rate dependent on the patient’s history of sensitivity to changes in dose, duration of corticosteroid therapy, and provider preference. There is high variability in steroid-tapering regimens between different physician practices. Standard practice in some European centers is to continue low-dose prednisone long term. In our experience, tapering to less than or equal to 10 mg/d within 4 to 6 months is a reasonable goal, with subsequent tapering by 2.5 mg decrements every 2 weeks until the patient has tapered off prednisone. Patients who have been on corticosteroids longer than 6 months may require tapering less than 10 mg/d to be in decrements of 1 mg rather than 2.5 mg every 2 weeks.

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Corticosteroids in Lupus Nephritis and Central Nervous System Lupus
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