Updated EULAR Recommendations Revamp Treatment Targets for Lupus Nephritis
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Treatment goals for lupus nephritis should include complete response by 12 months, according to updated recommendations published by EULAR, along with the European Renal Association–European Dialysis and Transplant Association, in the Annals of the Rheumatic Diseases.
The 2019 update, which includes overarching principles and recommendations for the management of lupus nephritis, also cover the glucocorticoids and calcineurin inhibitors and management of end-stage kidney disease.
“Up to 40% of patients with systemic lupus erythematosus (SLE) develop kidney disease, which represents a major cause of morbidity,” Antonis Fanouriakis, MD, of Attikon University Hospital in Greece, and colleagues wrote. “In 2012, the European League Against Rheumatism–European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) developed joint recommendations for lupus nephritis (LN), involving a panel of rheumatologists, nephrologists, renal pathologists and pediatricians.”
“Since then, new evidence has emerged, which includes the use of calcineurin inhibitors (CNIs) and ‘multitarget’ therapy, disease monitoring and treatment targets,” they added. “We therefore sought to update the recommendations for the management of LN.”
To update the 2012 recommendations for the management of lupus nephritis, officials from the three European organizations assembled a multidisciplinary panel of 11 rheumatologists, 11 nephrologists, one nephropathologist, one pediatric rheumatologist, one pediatric nephrologist, one allied health professional and two patient representatives. The group drafted 15 questions for a systemic literature review, performed by Fanouriakis and colleagues. The researchers included all English-language articles published between January 2012 and December 2018.
The panel later met in May 2019 to present and discuss the results of the literature search. The members then reappraised the previous recommendations and considered levels of evidence and grading for the update. Each member was asked to rate their level of agreement for each statement on a scale of 0-10. During the final vote, members were given the opportunity to voice their disagreement with any individual statement.
The members drafted and approved four overarching principles and more than 40 specific recommendations. The overarching principles are:
- Kidney involvement in SLE is best managed through interdisciplinary care with shared patient–physician decisions;
- Vigilance for symptoms and signs suggesting kidney involvement, histological assessment by nephropathologists, and input from specialized centers ensure best outcomes;
- Treatment goals should include patient survival, long-term preservation of kidney function, prevention of disease flares, prevention of organ damage, management of comorbidities and improvement in disease-related quality of life; and
- Management of active of lupus nephritis should involve an initial period of intense immunosuppressive therapy to control disease activity, followed by a longer period of typically less intensive treatment to consolidate response and prevent relapses.
Recommendation topics include the assessment of patients with suspected lupus nephritis, pathological assessment of kidney biopsy, immunosuppressive treatment indications, adult treatment, adjunct treatment, monitoring and prognosis, end-stage kidney disease management, antiphospholipid syndrome, pregnancy and pediatric patients.
New additions to the recommendations include treatment targets, the use of glucocorticoids and calcineurin inhibitors, and the management of end-stage kidney disease. According to the update, the target of therapy is complete response — defined as proteinuria less than 0.5 g to 0.7 g per 24hours with normal or near-normal glomerular filtration rate — by 12 months. However, this deadline can be extended in patients with baseline nephrotic-range proteinuria. Further, the panel recommended hydroxychloroquine with regular ophthalmological monitoring.
“These recommendations intend to inform rheumatologists, nephrologists, patients, national professional societies, hospital officials, social security agencies and regulators about the treatment of LN based on most recent evidence, to ensure optimal outcomes with existing therapies,” Fanouriakis and colleagues wrote. “In addition to the quality of evidence for risks and benefits, considerations were also given to the availability and costs of treatments.”
“The development of new classification criteria for SLE with increased weighting for kidney disease will facilitate the inclusion of more patients in LN trials,” they added. “New drugs in development for LN, including novel CNI, B-cell inhibiting and depleting agents, kinase inhibitors, inhibitors of co-stimulation, inhibitors of complement activation, in combination with improved trial designs, may provide additional agents in the near future.” – by Jason Laday
Disclosures: Fanouriakis reports personal fees from AbbVie, Amgen, Enorasis, Genesis Pharma, GlaxoSmithKline and Roche. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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Mark E. Pearson, MD, FACR
The 2019 update from EULAR/European Renal Association–European Dialysis and Transplant Association with regard to management of lupus nephritis is welcome for several reasons. Most importantly, it reinforces other reviews with regard to the appropriate medication options for initial treatment.
For induction, mycophenolate mofetil (MMF) continues to be a first-line agent, especially in biopsy-proven proliferative glomerulonephritis — low-dose IV cyclophosphamide continues to be an alternative. The trend towards using lower doses of steroids (IV pulse followed by oral) than in the past, as well as the addition of relatively safer therapy in the form of hydroxychloroquine, are now accepted.
Also helpful for rheumatologists is the new recommendation to add a calcineurin inhibitor, such as tacrolimus, to MMF in patients with nephrotic range proteinuria, refractory disease or those with other poor prognostic factors. A Chinese randomized trial has demonstrated superiority in this group compared to cyclophosphamide; however, toxicities in the combination group are enough to temper enthusiasm for first-line treatment.
We, as rheumatologists, are fairly united in the use of MMF as first-line therapy, along with steroids, for proliferative glomerulonephritis. IV cyclophosphamide has also been used for decades. We become uncomfortable in patients without a great or complete response. The paper mentions proteinuria <0.5-0.7 grams protein/24 hour and near normal GFR by 12 months as goals. However, we are not united behind the next line of therapy for these patients. Multiple options have been studied but as of now, no definite regimen has become universally accepted.
It’s helpful when a large, respected group such as EULAR/ERA-EDTA come out and make a new recommendation for these patients. As always, future studies will be helpful, especially with so many new therapeutic options — including B cell inhibitors — that appear to be on the way.
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