Successful Application of Canakinumab in a Patient with Undifferentiated Systemic Autoinflammatory Syndrome and Carrying a TNFRSF1A Gene Variant
Anja Kisić, Rada Mišković, Srđa Janković, Slađana AndrejevićIntroduction
Undifferentiated systemic autoinflammatory diseases (uSAID) are characterized by recurrent fever and systemic inflammation without a definitive molecular diagnosis. Increasing use of next-generation sequencing frequently identifies variants of uncertain significance (VUS), further complicating diagnosis. Therefore, the diagnosis of uSAID in clinical practice requires careful integration of the clinical phenotype, inflammatory biomarker dynamics, and therapeutic response.
Case Presentation
The male patient first developed symptoms at the age of 6, presenting with recurrent episodes of high fever (>40°C) lasting several days to weeks, with complete remission between episodes. Episodes were accompanied by severe joint pain, limiting movement, one episode of anterior uveitis, and mild nonspecific transitional rash. Detailed evaluation revealed no infectious or autoimmune cause. During febrile episodes, laboratory findings showed elevated C-reactive protein (CRP) (40–100 mg/L), erythrocyte sedimentation rate (ESR), mild anemia, and thrombocytopenia, but no leukocytosis. Imaging occasionally showed mild hepatosplenomegaly. Symptoms resolved quickly after a single dose of prednisone. Whole-exome sequencing identified a TNFRSF1A (c.434A>G) VUS. Over the last two years, attacks had become more frequent and severe, with arthralgia, weight loss, fatigue, and night sweats, and were resistant to lower corticosteroid doses. Elevated serum amyloid A levels were recorded, reaching a value of 971 mg/mL. Colchicine treatment was ineffective. Positron emission tomography/computed tomography (PET/CT) showed increased radiotracer uptake in cervical and mediastinal lymph nodes and hepatosplenomegaly. Hematologic evaluation excluded malignancy. Due to the high risk of secondary amyloidosis, targeted therapy was considered necessary, and treatment with canakinumab 150 mg subcutaneously once monthly was initiated, resulting in rapid and sustained remission and enabling complete corticosteroid withdrawal.
Conclusion
This case highlights the diagnostic challenges of uSAID, particularly regarding the interpretation of VUS. In the absence of a definitive molecular diagnosis, integration of the clinical phenotype, inflammatory biomarker dynamics, and therapeutic response may support the use of targeted IL-1 inhibition with canakinumab.