PO:16:233 | Efficacy of voclosporin on nephritis in patients with variable gain of function of TLR7 affected by lupus: clinical case

Veronica Spedicato¹, Laura Coladonato¹, Marco Fornaro¹, Marlea Lavista¹, Daniele Sabella¹, Marco Capodiferro¹, Maria Morrone¹, Crescenzio Scioscia¹, Giuseppe Lopalco¹, Florenzo Iannone¹ | ¹Unit of Rheumathology, Department of Precision and Regenerative Medicina, Area Jonica^J, University of Bari, Italy

Background. We present the case of a 45-year-old woman diagnosed with systemic lupus erythematosus (SLE) in 2022, following the identification of a hemizygous gain-of-function variant in the TLR7 gene, detected during family screening for type I interferonopathy. The family history revealed that her eldest daughter died in 2023 from severe type I interferonopathy with neurological, vasculitic, and intestinal involvement; her younger son is currently under follow-up for the same condition. The patient’s medical history includes facial photodermatitis during adolescence and idiopathic thrombocytopenia at age 24, treated with steroids. In 2022, concomitant with the genetic finding, laboratory results showed hypocomplementemia, hypergammaglobulinemia, ANA 1:160 (speckled pattern), borderline anti-dsDNA, and negative antiphospholipid antibodies. Treatment with mycophenolate mofetil and hydroxychloroquine was initiated. In 2023, she developed thrombosis of the right femoroiliac axis and femoral tripod, treated with embolectomy and anticoagulant therapy. Subsequently, she experienced recurrent pleural and pericardial effusions. In November 2023, the first evidence of proteinuria up to 6 g/24 h led to a renal biopsy showing focal endocapillary proliferative glomerulonephritis (consistent with class III lupus nephritis). Treatment with mycophenolate mofetil 2 g/day was continued. In April 2024, due to persistent proteinuria in the absence of other laboratory or clinical signs of disease activity, a repeat renal biopsy revealed membranous glomerulonephritis (stage I), consistent with class V lupus nephritis. Based on the histological findings and the limited efficacy of previous therapies, voclosporin was added to the treatment regimen. A few weeks after introducing voclosporin, a progressive reduction in proteinuria was observed, reaching values of approximately 900 mg/24 h (as shown in Figure 1), without significant side effects or deterioration in renal function.

Conclusions. This case highlights a favorable response to voclosporin in a patient with genetically determined SLE caused by a TLR7 gain-of-function variant. This mutation induces mesangial proliferative glomerular injury with immune deposits, resembling that seen in conventional lupus nephritis. Voclosporin, through modulation of T-cell activity and podocyte stabilization, proved effective in this setting as well. Although SLE is generally a polygenic autoimmune disease, the identification of monogenic lupus cases has provided valuable insights into its pathogenesis. TLR7 plays a pivotal role in lupus, and gain-of-function variants have been linked to lupus-like proliferative glomerulonephritis. The present case supports the use of voclosporin in combination with mycophenolate mofetil in patients with nephritis associated with a hemizygous TLR7 gain-of-function variant. Future studies will be needed to explore the efficacy of voclosporin in selected genetic subgroups, paving the way for targeted therapies based on immunogenetic profiles.