Guideline Update: KDIGO 2024 Management of Lupus Nephritis Includes Belimumab for Triple Therapy

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The update includes a recommended triple therapy with belimumab as a first line treatment for class III or IV lupus nephritis following the approvals of belimumab and voclosporin.

Experts from the Kidney Disease: Improving Global Outcome group updated the clinical practice guidelines for the management of lupus nephritis (LN). The update includes a recommended triple therapy with belimumab (Benlysta; GSK) as a first line treatment for class III or IV LN, according to the guidelines.1,2

Kidney disease concept. | Image Credit: Rasi - stock.adobe.com

Rasi - stock.adobe.com

According to the authors, the most significant update includes the recommendation “that patients with active class III or IV LN, with or without a membranous component, be treated initially with glucocorticoids plus any one of the following: i. mycophenolic acid analogs (MPAA) (1B); or ii. low-dose intravenous cyclophosphamide (1B); or iii. belimumab and either MPAA or low-dose intravenous cyclophosphamide (1B); or iv. MPAA and a calcineurin inhibitor (CNI) when kidney function is not severely impaired (i.e., estimated glomerular filtration rate [eGFR] ≤45 ml/min per 1.73 m2) (1B).”1,2

According to the executive summary, since the 2021 guidelines, belimumab and voclosporin (Lupkynis; Aurinia) were both approved by the FDA and the European Medicines Agency as add-on therapies to standard of care treatment of LN.1 When choosing between the 2 medications, the guidelines suggest physicians consider kidney function, kidney histology, proteinuria, risk of disease flare, background immunosuppression, need for parenteral therapy, significant extrarenal lupus, and safety.1

3 Key Takeaways

  1. The updated Kidney Disease: Improving Global Outcome (KDIGO) guidelines recommend a triple therapy approach with belimumab as a first-line treatment for class III or IV LN. This includes the use of glucocorticoids in combination with mycophenolic acid analogs (MPAA), low-dose intravenous cyclophosphamide, or a combination of belimumab with either MPAA or low-dose intravenous cyclophosphamide.
  2. The guidelines highlight the approval of belimumab and voclosporin as add-on therapies for LN. The choice between the two medications should consider various factors, including kidney function, histology, proteinuria, risk of disease flare, background immunosuppression, need for parenteral therapy, presence of extrarenal lupus, and safety considerations.
  3. The guidelines emphasize the importance of managing LN to slow or stop chronic kidney disease (CKD) progression, with a focus on blood pressure control, renin-angiotensin-aldosterone system blockade, flare prevention, and nephrotoxin avoidance.

For the triple therapy, the guideline authors compiled suggestions for physicians to help decide between belimumab and a CNI. According to the authors, belimumab is preferred if patients are at higher risk of LN flare or for those who have advanced chronic kidney disease (CKD). It has been shown to decrease flares and have a slower decline in kidney function. CNI could be considered for patients with relatively good kidney function and heavy proteinuria due to podocyte injury, according to the executive summary.1

The authors defined 1B as a strong recommendation due to moderate evidence and based on randomize controlled trials. The downgrade of “moderate evidence” was due to the limitations of trials, which included small study size or event numbers, risk of other biases, and lack of blinding.1

The authors reviewed that initial therapy is based on cost, local availability of therapeutics, local health care resources, likelihood of adherence, prior immunosuppression, and the presence and severity of CKD, and is typically not related to disease manifestation of LN. Although there is evidence that shows safety of triple therapy has similar safety and better efficacy compared to dual therapy, the guideline acknowledged that cost and accessibility are factors to consider when determining how to treat patients.1

Further, they also acknowledged that not all patients need triple therapy, but they said that identifying these patients is not yet possible given current information. Additionally, the revised guidelines indicated that treatment with a triple therapy containing belimumab or a CNI could remain on the triple therapy for an extended period of time based on clinical trial results of both sets of drugs.1

Beyond belimumab and voclosporin for class III and IV, the recommendation did not update class V LN, which remains without definitive recommendation, only suggested practice points. The authors suggested the management of disease with glucocorticoid plus MPAA, CNI, or cyclophosphamide. However, they also suggested that clinical trials should focus more on class V LN. Further, the guidelines have been updated for the consideration or reducing cumulative glucocorticoid dosing by using methylprednisolone pulses at the start of treatment. The authors stated that this could reduce dosing and more rapid tapering of glucocorticoids, according to the executive summary.1

A new section was also included for CKD progression in LN, stating that “management of patients with LN must include not only immunosuppression for acute treatment of active LN, but also measures to slow or stop CKD progression.” Currently, the section is small and limited to blood pressure control, renin-angiotensin-aldosterone system blockade, flare prevention, and nephrotoxin avoidance. The authors said it is likely to expand as future data becomes available. Finally, the guidelines acknowledge several additional therapies that are being evaluated in phase 2 and 3 trials. They added that they will update the guidelines when the trials are completed, dependent on success of those drugs.1

Reference

  1. Rovin BH, Ayoub IM, Chan TM, Liu Z, et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis. Kidney Int. 2024;105(1):31-34. doi:10.1016/j.kint.2023.09.001
  2. Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis. Kidney Int. 2024;105(1S):S1–S69. doi:10.1016/j.kint.2023.09.002
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