C3 Glomerulopathy with Autoimmune-like Features: A 12-Year Course and Rationale for Iptacopan Therapy

C3 glomerulopathy (C3G) is a rare glomerular disorder characterized by the activation of the alternative complement pathway, leading to C3 deposition. Its presentation may mimic autoimmune diseases, including systemic lupus erythematosus (SLE), with features such as arthralgia, rash, and hypocomplementemia. We present the case of a young woman initially suspected of having SLE, who was ultimately diagnosed with C3G with multiple complement and immunoregulatory gene variants, highlighting a 12-year disease course and the rationale for complement inhibition therapy

A 13-year-old girl presented with migratory arthralgia, erythematous rash, and cervical lymphadenopathy. The antinuclear antibody test was positive at 1:160 titer, while the anti-double-stranded DNA antibody test was negative. Hypocomplementemia with low C3 and total hemolytic complement (CH50) levels but normal C4 levels indicated alternative pathway activation. 

At year 3 (age 16), prednisolone (PSL 50 mg/day) and methotrexate were initiated, followed by tacrolimus. Methotrexate was changed to mycophenolate mofetil (MMF) in year 4 (age 17) for relapsing arthralgia and proteinuria. Tacrolimus was discontinued in year 4 following herpes zoster infection. Microscopic hematuria persisted from admission, and proteinuria (0.2–0.5 g/gCr) developed at year 4 (age 17). Over five years, proteinuria stabilized at 0.3 g/gCr while C3 and CH50 levels remained low. 

Kidney biopsy at year 9 (age 22) showed a membranoproliferative pattern with C3-dominant granular deposits and absence of immunoglobulins by immunofluorescence. Electron microscopy revealed mesangial, subepithelial, and intramembranous electron-dense deposits, confirming the diagnosis of C3G. Exome sequencing identified heterozygous variants in CFH, THBD, C3, C7, MBL2, CR2, and CTLA4. Hydroxychloroquine (HCQ) was administered at year 7 (age 20) for skin and joint manifestations. At years 9-10 (ages 22-23), belimumab was initiated for arthralgia resulting in partial remission. During years 10-11 (ages 23-24), baricitinib was introduced after belimumab withdrawal but was discontinued at year 12 (age 25) owing to limited efficacy and infection risk. During PSL tapering to 5 mg/day at year 11 (age 24), disease relapse occurred (proteinuria 1.56 g/gCr), but remission was achieved six months later after increasing PSL to 10 mg/day, with stable renal function. C3 levels remained low (62 mg/dL) despite treatment with MMF, PSL, and HCQ. In view of ongoing alternative pathway activation refractory to standard immunosuppression, oral iptacopan, a factor B inhibitor, is planned as a rational steroid‑sparing therapy. In line with the recent phase 3 APPEAR-C3G trial, iptacopan demonstrated 40% reduction in proteinuria and complement normalization after 12 months. Preliminary post-iptacopan findings will be presented at WCN’26.

This case illustrates C3G with autoimmune-like features mimicking an SLE phenotype, showing isolated C3/CH50 reduction despite normal C4, reflecting persistent alternative pathway activation over a 12‑year course. Despite multi-agent immunosuppression, the patient remained steroid‑dependent, indicating complement‑driven disease activity. Iptacopan, an oral factor B inhibitor, offers a rational steroid‑sparing option for complement-driven C3G activation unresponsive to conventional therapy.