New and emerging treatments for lupus nephritis

Abstract

The last decade has witnessed con-siderable progress in the thera-peutic approach to systemic lupus erythematosus (SLE), and particu-larly its renal manifestations. Advances in understanding the immunological basis of SLE, the development of increasingly specific and better tolerated pharmacologic agents, and an increased emphasis on rigor-ous clinical trial design have combined to produce validated treatment regimens with greater efficacy and less toxicity compared with the past.1

Despite these advances, there remains room for continued improvement. Lupus nephritis continues to carry substantial morbidity and mortality, affecting patients mostly in the prime of their youth.2, 3 Even with aggressive regimens, treatment-refrac-tory lupus nephritis may occur in a significant proportion of patients,4, 5 and disease relapses are both common and associated with worse prognosis.6-8 For these reasons, a large number of novel therapies are pres-ently in various stages of development and promise to provide further options for the treating physician. In this article, we sum-marize current therapeutic standards of care and review novel and emerging treatments for lupus nephritis.

While SLE may have a variety of presen-tations in the kidney, glomerulonephritis remains the most common and the most well studied.9 The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis provides a standardized, repro-ducible classification of disease that has essentially replaced the older World Health Organization classification.10 At present, the histologic pattern of disease as classified by ISN/RPS broadly determines the therapeutic approach, placed in the appro-priate context of an individual patient's clinical parameters.

In the setting of mild disease, repre-sented by ISN/RPS class I nephritis (nor-mal glomeruli by light microscopy with mesangial deposits on immunofluorescence or electron microscopy) and the majority of class II nephritis (pure mesangial hyper-cellularity by light microscopy with mesan-gial immune deposits), immunosuppressive treatment is not indicated. Most patients with these forms of disease will have good long-term renal outcomes. The cornerstone of therapy is control of blood pressure and suppression of proteinuria through block-ade of the renin-angiotensin-aldosterone system (RAAS) with either an angioten-sin-converting enzyme inhibitor (CEI) or angiotensin receptor blocker (ARB).

The rationale for this approach is based on extrapolation from human studies in other chronic proteinuric kidney diseases11 as well as an abundance of animal studies.12-14 Additional support has been provided by a recent report from the lupus in minorities: nature versus nurture (LUMINA) cohort.15 In this cohort, 80 of 378 patients (21%) were CEI users. CEI use was associated with higher probability of renal involve-ment-free survival at 10 years (88.1% vs. 75.4% for non-users, P = 0.01), a delay in the development of renal involvement (haz-ard ratio [HR] 0.27; 95% CI 0.09, 0.78), and a decreased risk of disease activity (HR 0.56; 95% CI 0.34, 0.94).

Focal or diffuse proliferative lupus nephritis are classified respectively in the ISN/RPS schema as classes III and IV. They are each subclassified based on the presence of active lesions (A), chronic inactive or sclerosed lesions (C), or a com-bination of the two (A/C). These prolifera-tive forms of lupus nephritis, particularly with active lesions, confer a high risk for progressive loss of kidney function that mandates more aggressive immunosup-pressive treatment. It has become standard practice to separate treatment into two phases: induction, during which aggres-sive immunosuppression is used to achieve complete or partial disease remission over a period of months, and maintenance, during which lower doses of immunosuppression are used to keep the autoimmune process in check.

Many novel immunomodulatory agents are currently in various stages of development or study for the treatment of lupus nephritis. At present, 20 studies are registered at on the government's clinical trials website (www.clinicaltrials.gov) that are actively recruiting lupus nephritis patients. In general, the novel agents promise a more specific target of action with the hope of limiting the toxicities seen with current therapy.

The treatment of lupus nephritis has become increasingly sophisticated since the turn of the millennium, with an increase in high-quality clinical trials and a wider arsenal of therapeutic agents from which the clinician may choose. However, cur-rent regimens leave a substantial propor-tion of patients with uncontrolled or only partially controlled disease, and safety and toxicity profiles still leave much to be desired. Active research along a number of different therapeutic avenues promises continued improvement and refinement of our treatment of lupus nephritis.