Review: Treatment for Lupus Nephritis

Among lupus patients, lupus nephritis can be one of the most common and most severe disease manifestations - affecting 40% of lupus patients. For nearly 50 years, though, treatments have advanced, and lupus nephritis outcomes have improved.

Now, a new literature review study reveals those therapeutic steps forward have stalled. The plateau began in 2000. In fact, the risk of developing lupus nephritis-related end stage renal disease (ESRD) at 5, 10, and 15 years has stagnated at 11%, 17%, and 22% for the past decade.

According to study authors from Brigham and Women’s Hospital in Boston, this freeze isn’t related to ongoing work.

“The lack of progress in lupus nephritis outcomes is not due to lack of effort,” they wrote. “In fact, alongside government funding, private agencies have emerged as important drivers of lupus nephritis research through their own investigations and funding mechanisms.”

Still, the reasons for the stymied progress remain unclear. Researchers hypothesize poor healthcare access for some groups, limited efficacy of current treatments, and adverse effects of those treatments might be to blame.

To shed more light on this problem, the study authors reviewed existing literature. They analyzed existing incidence and outcomes data, reviewed diagnosis and treatment guidelines, and evaluated the role rheumatologists play in the therapeutic process.

Prevalence

While lupus nephritis impacts 40% of lupus patients, it is far more common in nonwhite populations and affects women more than men. According to data from a 2000-2004 Medicaid study, lupus nephritis is 3.8 times more likely in blacks, 3.7 times more in Asians, 2.3 times more in Native Americans, and 1.9 times more in Hispanics.

The incidence of lupus nephritis is also greater among patients who experience lupus onset in childhood versus as an adult – 37% versus 20%, respectively.

Barriers to Care

Regardless of ethnicity, however, existing research points to socioeconomic status as a significant contributing factor to increase lupus nephritis incidence. Based on findings from a 2010 Journal of Rheumatology study, patients in poor urban areas are less likely to have insurance, and they use emergency department services more.

In addition, these patients usually live more than 200 miles away from a rheumatologist, or immunosuppressive medications might be unavailable or cost-prohibitive. In some cases, available care could simply be substandard.

Treatment Recommendations

Overall, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) and the European Dialysis & Transplant Association (ERA-EDTA) recommend lupus patients be closely monitored from lupus nephritis outset through routine screenings and kidney biopsies.

Authors Paul Hoover, M.D., and Karen Costenbrader, M.D., highlighted six additional, official recommendations designed to maximize lupus nephritis treatment outcomes:

1.      All lupus nephritis patients should receive adjunctive medication, including hydroxycholorquine (HCQ) that reduces systemic lupus relapses and may be associated with slowing renal damage, thrombosis, hyperglycemia, and hyperlipidemia, as well as a reno-protective agent and a lipid-lowering statin. Any woman considering pregnancy should be counseled about the effects of therapy on a fetus.

2.      EULAR/ERA-EDTA endorses low-to-moderate oral glucocorticoid doses, plus azathioprine for individuals with proteinuria >1g/day or urinary acanthocytes.

3.      Patients with Class III or IV proliferation glomerulonephritis induction therapy should receive induction therapy with moderate oral glucocorticoid doses, plus intravenous cyclophosphamide or mycophenolate mofetil (MMF) or without initial pulses of intravenous methylprednisolone.

4.      For maintenance therapy, it’s recommended that MMF or azathioprine be used with or without low-dose glucocorticoids.

5.      EULAR/ERA-EDTA recommends treatment of “active lesions” only.

6.      EULAR/ERA-EDTA recommends the continuing maintenance therapy for two years after complete remission (proteinuria <0.5mg/day – near normal glomerular filtration rates).

Poor Outcomes Due to Treatment

Historically, adherence to lupus and lupus nephritis treatment has been low with less than 25% of lupus patients having adherence rates of more than 80% over two years. This often leads to lupus relapse, kidney problems, and hospitalizations.

Existing literature shows, though, that some providers are turning to serial serum HCQ level measurements to determine whether patients are adhering to treatment regimens. HCQ levels between 500-to-2,000 ng/ml are associated with modestly-improved lupus disease activity. This type of measurement could point to treatment adherence. Behavioral therapy and patient education could also be effective, though they haven’t been tested with lupus nephritis patients yet.

Adherence isn’t the only factor that determines outcomes, however.

Recent research suggests that genetics might play a role, as well. Over the past decade, investigations have identified more than 50 lupus risk loci. Many of these focus on lupus nephritis: BLK, STAT4, TNFS4, IKZFI, IRF5, TLR9, TNFAIP3, TNIP3, ACE, KLK, FCGR2A, FCGR3A, and ITGAM. For example, APOLI1 risk alleles associated with ESRD are 60-times more likely in blacks than whites, more than doubling their risk of developing ESRD and shortening their time to developing the disease by two years.

Most participants were European and Asian, however, so it’s unclear if this data is accurate across ethnicities.

However, there are treatment-related factors that contribute to poor outcomes, investigators said. In fact, Hoover said, the research review revealed a surprising finding. Glucocorticoids and long-term immunosuppression – despite effectively controlling lupus activity – have significant side effects, such as infections.

Traditionally, glucocorticoid use induces successful remission within six months. However, in one Medicaid study of 33,000 lupus patients – 7,100 of which had lupus nephritis – the incidence rate of serious infection is more than 2-fold higher for lupus nephritis patients than those with lupus alone. However, the highest risk rate was among those treated with glucocorticoids followed by those treated with immunosuppressive drugs.

It is possible to minimize bad outcomes by following vaccination guidelines before beginning immunosuppressive treatment for lupus and lupus nephritis patients. Only killed infections, such as influenza, pneumococcus, hepatitis B, and HPV, are used – live vaccines are avoided.

But, in the long term, glucocorticoid use presents significant challenges to lupus nephritis treatment. Over time, continued use can cause osteoporotic fractures, avascular necrosis, diabetes mellitus, cataracts, glaucoma, and premature death.

Because of these negative effects, ACR has issued recommendations for all patients treated with glucocorticoids. Before patients begin a regimen, providers should: evaluate all patients for fall risk, counsel them on smoking cessation, encourage reduced alcohol consumption, promote modest weight loss and exercise, and encourage patients to get enough calcium and Vitamin D.

The ACR also recommends anti-osteoporotic medication for patients with prior fragility fractures. However, selecting the best anti-osteoporotic medication can be difficult. Among patients with renal insufficiency or ESRD, bisphosphonates are contraindicated for use. And, there’s no general consensus on whether these drugs can be used with women of child-bearing years.

Treatment Possibilities

Given the negative impacts of prolonged glucocorticoid usage among lupus nephritis patients, the authors wrote, the use of low-dose or glucocorticoid-free treatments are under investigation.

Although previous research with rituximab, the monoclonal antibody that targets the B-cell surface protein CD20, showed no statistical improvement in outcomes for patients who received MMF and glucocorticoids, a recent study is showing more promise. Of 50 lupus nephritis patients treated without oral glucocorticoids, 52% achieved complete renal remission at 1 year. Participants received two pulses of methylprednisolone and two 1-gram doses of rituximab, separated by two weeks, as well as MMF.

This study, the authors wrote, is setting the foundation for similar ones to determine whether lupus nephritis patients can be successfully treatment without glucocorticoids or with lower doses.

The Future

As treatment for lupus nephritis moves forward, the authors wrote, changes must be made to encourage and ensure that lower-income and nonwhite patients receive better therapies and experience improved outcomes.

Alongside creating modified therapies that change dosing levels for glucocorticoids, implementing behavioral interventions that address treatment adherence rates could be effective. Additionally, exploring personalized medicine as a method to target individuals who are genetically pre-disposed to poor outcomes can move the needle for most positive outcomes.

Ultimately, the authors said, additional steps must be taken to improve access to care overall because any delay in diagnosis and treatment inevitably leads to negative impacts on a patient’s kidneys.

References:

Feldman CH, Hiraki LT, Liu J, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000–2004. Arthritis Rheum. 2013;65:753–763.

Ward MM. Access to care and the incidence of endstage renal disease due to systemic lupus erythematosus. J Rheumatol. 2010;37:1158–1163.

Feldman CH, Hiraki LT, Winkelmayer WC, et al. Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis Rheumatol. 2015;67:1577–1585.

Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids.

Ann Rheum Dis. 2013;72:1280–1286.