New ACR lupus nephritis guidelines reflect ‘conceptual shift’ in treatment

Twelve years is a long time by most measures, but in a field has rapidly changing as lupus nephritis research, it may as well be an eternity.

Responding to a dozen years of emerging research, and a handful of new FDA approvals, the American College of Rheumatology recently released its 2024 Guideline for the Screening, Treatment, and Management of Lupus Nephritis. According to the document’s lead author, Lisa Sammaritano, MD, the new guidelines reflect a “conceptual shift” that has occurred in lupus nephritis treatment over the past decade.

“The ACR last published a lupus nephritis clinical practice guideline in 2012,” she said. “Those recommendations called for induction therapy with high dose glucocorticoids plus mycophenolate mofetil or cyclophosphamide, and endorsed mycophenolate for maintenance therapy.

“Since then, belimumab and voclosporin have been approved by the FDA for lupus nephritis treatment, prompting a conceptual shift from induction/initial and maintenance/subsequent therapy, to one of ongoing combination therapy targeting different arms of the immune system,” she added. “Evidence on the relative effectiveness and toxicity of systemic glucocorticoids has also evolved over this time, favoring pulse IV followed by low-moderate dose oral glucocorticoid with a more rapid taper.”

The new guidelines feature 41 recommendations and good practice statements, all geared toward the aim of preserving kidney function and reducing morbidity and mortality.

Two of the strong recommendations pertain to monitoring protein in the urine, while the key conditional recommendations champion a immunosuppressive regimen using triple therapy for patients with active Class III, IV and V disease. That regimen includes glucocorticoids alongside either mycophenolate (CellCept, Genentech) plus belimumab (Benlysta, GlaxoSmithKline), mycophenolate plus a calcineurin inhibitor, or low-dose cyclophosphamide plus belimumab.

Healio sat down with Sammaritano, who is also a professor of clinical medicine at Weill Cornell Medicine and an attending physician for the Hospital for Special Surgery division of rheumatology, to discuss the guideline development process, updates from the 2012 version, and what the future holds for lupus nephritis treatment.

Healio: What were some of the key data sets that you reviewed for these recommendations? I am sure there are too many trials to recount, but what overall trends impacted the process and impetus to update the recommendations?

Sammaritano: Our systematic literature review initially pulled more than 10,000 records that were screened for relevance, and some were set aside for our now ongoing general systemic lupus erythematosus treatment guideline.

Ultimately, lupus nephritis treatment data were analyzed from 105 publications deemed appropriate for review. All of these played an important role in helping the voting panel to formulate the current treatment recommendations, but several recent studies stand out. These include the BLISS LN and the AURORA trials, which looked at safety and efficacy of the addition of belimumab and voclosporin, respectively, to standard lupus nephritis therapy — glucocorticoid plus either mycophenolate or cyclophosphamide.

Healio: What are some of the key changes from the last ACR guideline on lupus nephritis? Why they are important?

Sammaritano: In this new guideline we propose treatment with a triple therapy as the most desirable therapy for Class III/IV and Class V lupus nephritis. Triple therapy for Class III/IV includes glucocorticoid and one of three combination immunosuppressive regimens: mycophenolate plus belimumab, mycophenolate plus calcineurin inhibitor therapy, and low dose cyclophosphamide plus belimumab.

For pure Class V lupus nephritis with proteinuria greater than 1 gram daily, we propose treatment with glucocorticoids plus mycophenolate and calcineurin inhibitor therapy. In addition, we propose a lower dose glucocorticoid regimen — after initial intravenous pulse therapy — to minimize medication-related toxicity, with a prednisone goal of 5 mg/day by 6 months of therapy.

In the highlighted studies, addition of a third immunosuppressive agent improved complete responses, compared with the standard therapy, and, importantly, these benefits were seen without an increase in adverse events. This improved efficacy with a stable side effect profile allows more patients and clinicians to consider these combination therapies.

The final decision regarding treatment will depend on specific clinical details, the physician’s assessment of these in conjunction with the risks and benefits of available therapies, and the patient’s values and preferences.

Healio: What were the strong recommendations in the new document?

Sammaritano: Our strong recommendations rely on a combination of evidence, clinical expertise, and patient panel input. They are important in preventing serious adverse outcomes and are applicable to almost all people with lupus nephritis.

Strong recommendations include screening at least every 6 to 12 months for proteinuria in people with SLE without known kidney disease, or when experiencing extra-renal flares, as well as quantifying proteinuria at least every 3 months in those with lupus nephritis who have not achieved complete renal response, and every 3 to 6 months in those with sustained complete renal response.

For those with active lupus nephritis who are not already on hydroxychloroquine, we strongly recommend initiation and continuation of hydroxychloroquine therapy to manage and prevent lupus clinical manifestations, unless contraindicated.

In people with lupus nephritis who have progressive refractory disease and are approaching kidney failure, we strongly recommend kidney transplantation over dialysis.

Finally, in those who are on current dialysis or who have had a kidney transplant, we strongly recommend regular follow up with a rheumatologist in addition to the nephrologist.

Healio: What do these recommendations mean for patient care? What impact do you expect them to have?

Sammaritano: Lupus nephritis manifests in close to half of people with SLE, and 10% to 22% of impacted patients develop end-stage kidney disease. We hope these new recommendations, which incorporate the most recently published treatment trials, enable clinicians and patients to have the best discussion possible regarding therapy, one that is based on the most recent data and clinical expertise.

We recognize that there are many variables involved in treatment decisions, including clinical presentation and patient preferences, and that treatment may be limited by access to specialists, procedures and medications.

As a result, this guideline does not preclude using available traditional therapies. We hope, however, that it expands the possibilities for improved outcomes for more people who are living with lupus nephritis.

Kidney function declines in everyone over time, but in people with lupus nephritis it occurs at an accelerated rate for as long as the inflammatory process is present. In addition, even after inflammation is controlled, a later recurrence of active lupus nephritis imposes further loss in kidney function.

Even with the preferred triple therapy, the complete response rates reported in studies were still only in the 40% to 50% range.

As a result, an important overall message is to diagnose and treat lupus nephritis as promptly and effectively as possible to minimize risk of long-term damage and preserve kidney function.

Healio: Were there topics you hoped to cover, or recommendations you were hoping to make, but were unable to for any reason? What are the shortcomings of this document?

Sammaritano: We compiled a research agenda based on those topics that are promising and/or relevant, but for which we do not have enough data or experience to formulate recommendations at this time. They include optimal timing of repeat kidney biopsy, most effective treatment for less common lupus nephritis subsets — for example, lupus podocytopathy and others — the potential use of non-immunosuppressive medications for other chronic kidney disease — such as sodium-glucose cotransporter-2 (SGLT2) inhibitors — and the use of serum and urinary biomarkers to better reflect disease activity.

Healio: Looking ahead, what ground do you expect to cover for the next iteration of lupus nephritis recommendations? Pending FDA approvals, new mechanisms of action, or other advances in the field?

Sammaritano: We are excited about the promise of new agents for the treatment of lupus nephritis that are in various phases of development. For example, data suggesting benefits from obinutuzumab (Gazyva, Genentech) treatment have been recently reported, although not yet formally published, and so were not considered for this current guideline.

We plan to revise this lupus nephritis guideline regularly, including when important new data are published. Assuming the evidence, voting panel discussion, and patient panel preference all support inclusion of newly approved agents, these would potentially be incorporated as recommended therapy in a revised, updated guideline.

References:

Furie R, et al. NEJM. 2020;doi:10.1056/NEJMoa2001180.

Rovin BH, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00578-X.