The place of cyclical therapy for the treatment of membranous nephropathy in the era of rituximab

Primary membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults, due to a variety of autoantibodies, most frequently against phospholipase A2 receptor (PLA2R). In severe cases or when spontaneous remission is not achieved, immunosuppression is required. Cyclical therapy, based on glucocorticoids and cyclophosphamide on alternate months for 6 months, has proven effective to induce remission and reduce the risk of end-stage renal disease. Since the early 2000s, rituximab (RTX) has emerged as a key player in the management of MN, showing overall comparable effectiveness and likely better safety compared with the cyclical regimen, despite the lack of adequately powered trials comparing the two approaches head to head. For these reasons, RTX is now considered the agent of choice for most patients with MN. However, there are still uncertainties. Around 20-40% of patients are resistant to RTX, especially in the setting of high anti-PLA2R levels, and this drug remains relatively unexplored in patients with the most severe disease. In these scenarios, although the expanding therapeutic armamentarium is probably going to provide further options, the cyclical regimen still plays a key role as a safety net. The aim of this article is to illustrate the role of cyclical therapy in the RTX era.