Introduction: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease where anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IIF) is a cornerstone of diagnosis, making the diagnosis of ANA-negative SLE challenging.Complete androgen insensitivity syndrome (CAIS) is a 46,XY disorder of sex development resulting in a female phenotype due to reduced functional androgen receptors.While androgens are known to have protective, anti-inflammatory effects in SLE, the clinical consequence of their abrupt withdrawal in a CAIS patient has not been described.We report the first case of a patient with CAIS and ANA-negative SLE who developed a severe lupus nephritis flare following gonadectomy.Methods: A 56-year-old Japanese woman with congenital amenorrhea and a 10-year history of pancytopenia presented to nephrology with proteinuria and microscopic hematuria.A bone marrow examination ruled out bone marrow disease, and chromosome analysis incidentally revealed that she had an XY karyotype.She was diagnosed with CAIS and underwent prophylactic gonadectomy for malignancy five months before presentation.She developed progressive hypoalbuminemia post operatively, which led to the discovery of proteinuria and microscopic hematuria.Physical examination revealed conjunctival pallor, circular depigmentation on both cheeks, and pitting edema and purpura on both lower legs.Repeated ANA by IIF were consistently negative.However, complement levels of C3 and C4 were decreased, and anti-ds-DNA antibodies were positive.Renal biopsy showed an increase in mesangial matrix and proliferation of mesangial cells, with focal cellular crescents.Immunofluorescence microscopy revealed no significant deposition of immunoglobulins, while granular depositions of C1q and C3 along glomerular tufts were observed.Electron microscopy revealed widespread electron-dense deposits in the paramesangial area, subepithelial, intramembranous, and subendothelial regions, leading to a diagnosis of lupus nephritis type IV + V. Treatment with glucocorticoids, including pulse therapy, hydroxychloroquine, and mycophenolate mofetil led to decrease in urine protein and anti-ds-DNA antibody titers, increase in serum complement levels, and improvement of pancytopenia.Results: Sex differences in the incidence of SLE are attributed to factors such as X chromosome dose, the pro-inflammatory effects of estrogen, and the anti-inflammatory effects of androgens.In this case, the loss of the anti-inflammatory effects of androgens after gonadectomy may contribute to the exacerbation of lupus nephritis although the X chromosome dose and effects of estrogen were likely smaller compared to XX females.It can be hypothesized that, despite a complete female phenotype, a minor degree of androgen function persisted, which had been suppressing inflammation.Conclusion: This case highlights that a lupus nephritis flare can be triggered by the abrupt loss of endogenous androgens following prophylactic gonadectomy in a patient with CAIS.The diagnosis was particularly complex, underscored by the patient's negative ANA status and atypical pauci-immune immunofluorescence findings on renal biopsy.Therefore, SLE should be a key differential diagnosis in CAIS patients who develop renal abnormalities post-gonadectomy, necessitating close collaborative management and a comprehensive diagnostic approach that is not solely reliant on ANA positivity.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
TANSECO et al. (Wed,) studied this question.