The European League Against Rheumatism has issued its first guidelines on management of lupus nephritis, and they advise renal biopsy at the first sign of kidney involvement, unlike the guidance issued by the American College of Rheumatology, which leaves timing of that testing up to the clinician’s judgment.
Other bright spots in EULAR’s guidelines, which it issued jointly with the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) are their position that mycophenolic acid should be the first choice for immunosuppressive therapy, the precise recommendations for steroid dosage, stratification of treatment plans according to disease severity, and explicit advice on switching therapies after one drug has failed.
The European guidelines were published in the November issue of Annals of the Rheumatic Diseases (2012;71:1771-82) and are intended for rheumatologists, nephrologists, and internists managing adult and pediatric patients with lupus nephritis. The EULAR guidelines differ in several key ways from those issued by the American College of Rheumatology (ACR) in June (Arthritis Care Res. 2012;64:797-808).
The EULAR guidelines are unequivocal in their support for renal biopsy at any sign of renal involvement, including when unexplained renal insufficiency is accompanied by normal urinary findings. The ACR guidelines, by contrast, allow for more physician latitude in determining whether to biopsy.
"This can be an emotional issue because rheumatologists do not do biopsies and may try to avoid them," said the EULAR guidelines’ lead author, rheumatologist Dr. Dimitrios T. Boumpas, who is professor of medicine and director of internal medicine/rheumatology at the University of Crete in Heraklion, Greece, in an interview. "We felt that someone should make a position statement. Biopsy is simply best care. If you’re dealing with something severe like LN [lupus nephritis] and you avoid biopsy, that’s not good medicine."
Dr. Boumpas said the EULAR task force had also moved to put mycophenolic acid in the first position as an initial immunosuppressant treatment for most cases of class III-IV LN. Low-dose intravenous cyclophosphamide in combination with steroids is also recommended for this patient group.
There are no 5-year data for mycophenolic acid as there are for cyclophosphamide, Dr. Boumpas said. But the task force that developed the guidelines weighed data on safety and efficacy and found mycophenolic acid "as the clear first choice, while at the same time recognizing the limitations of the studies," he noted.
The ACR guidelines do not recommend use of azathioprine (AZA) as induction treatment. The EULAR recommendations acknowledge that AZA has been associated with a higher risk of renal flares, and call for its use in certain patients who have no adverse clinical or histological risk factors. Patients treated with AZA need close follow-up. "This is particularly important for countries without access to MPA [mycophenolic acid]," Dr. Boumpas said.
The EULAR guidelines also recommend switching to an alternative agent when patients fail to improve in 3-4 months or do not achieve partial response after 6-12 months, or a complete response after 2 years.
"This is based on evidence from both controlled trials and observational cohort studies, which highlight the fact that immunosuppressive agents, particularly cyclophosphamide, may take up to 2 years to achieve complete renal response," Dr. George K. Bertsias, also of the University of Crete in Heraklion and the first author of the guidelines, said in an interview. "On the other hand, lack of improvement at early time points (3-6 months) is associated with adverse prognosis and should evoke discussions for treatment intensification or switch."
This is a different timetable from that described in the ACR guidelines, which advocate switching after patients fail to respond after 6 months of treatment based on the treating physician’s clinical impression.
For patients not responding to mycophenolic acid or cyclophosphamide, treatment may be switched from mycophenolic acid to cyclophosphamide or from cyclophosphamide to mycophenolic acid, according to the guidelines.
If switching fails, rituximab, a biological agent, may be given either as an add-on treatment or as monotherapy. Although randomized controlled trials have failed to demonstrate the superiority of rituximab over standard treatment in lupus nephritis, "there is culminating evidence from several uncontrolled studies and several groups worldwide that rituximab works in about half of patients with nephritis refractory to conventional immunosuppressive therapy," Dr. Boumpas said. "Since rituximab does not have adverse effects on the gonads – a significant issue in the care of young women with lupus – the committee decided to recommend it as an additional treatment resource."
The EULAR guidelines, in contrast to the ACR guidelines, contain specific dosing advice on steroids, advocating pulse steroids (500-1,000 mg of methylprednisolone daily for three doses) in combination with initial immunosuppressive therapy, followed by daily oral glucocorticoids (0.5-1.0 mg/kg per day), afterward tapering to the minimal amount necessary to control disease.