A case of Takayasu arteritis with advanced macrovascular lesions due to 6 years from onset to diagnosis

Takayasu arteritis (TAK) is a large-vessel vasculitis with the highest prevalence among women aged 20–40 years with uncommon incidence in children. TAK diagnosis is based on systemic symptoms: fever and left–right differences in blood pressure and imaging findings: thickening, stenosis, and aortic dilation after excluding other diseases.1 Recently, positron emission tomography-computed tomography (PET-CT) has been used for TAK diagnosis and evaluating disease activity. Herein, we report a case of TAK with idiopathic fever that developed at 10 months of age and was misdiagnosed as incomplete Kawasaki disease (KD) and Castleman disease (CD) until 6 years of age. An 11-month-old girl was admitted to our hospital with persistent fever. Due to the presence of right coronary artery lesions, suspecting incomplete KD, three rounds of immunoglobulin therapy and cyclosporine were administered, following which the fever resolved (Figure 1a). During her clinical course, both erythema and strawberry tongue were also observed, leading to an incomplete KD diagnosis. Follow-up cardiac catheterization and contrast-enhanced CT revealed coronary artery lesion resolution. However, slight dilatation of the ascending aorta and brachiocephalic artery was observed (Figure 1b,c). At 21 months of age, the patient was readmitted to the hospital due to persistent fever for more than a week. On admission, her vital signs were: body temperature, 38.2°C; blood pressure, 86/58 mmHg without discrepancy. Blood test results revealed inflammation (C-reactive protein, 10.2 mg/dL; white blood cell count, 12,600/μL). There was no increase in the IgG4, antinuclear antibody, or antineutrophil cytoplasmic antibody-related antibody levels. The patient was negative for human leukocyte antigen-B 52. Cytokine profile analysis revealed elevated interleukin-6 levels. PET-CT showed accumulation in the axillary and inguinal lymph nodes but no accumulation in the large vessels (Figure 1d). Bone marrow aspiration revealed no abnormalities. Histological analysis of the inguinal lymph node biopsy showed no specific findings. However, CD was highly suspected due to enlarged lymph nodes and the negative results for various infections, autoimmune diseases, and malignant diseases. Thus, treatment with prednisolone (PSL; 2 mg/kg/day) was started. Subsequently, the patient's fever subsided but recurred during the dose reduction of PSL, accompanied by increases in inflammatory response. Intravenous administration of tocilizumab (8 mg/kg every 2 weeks) at 2 years and 3 months of age resulted in fever resolution. PSL was discontinued at the age of 2 years and 10 months. Although a slight increase in C-reactive protein was observed with interval extension, this improved with administration interval adjustment. Owing to the absence of recurrent fever, tocilizumab was gradually administered every 6 weeks until 6 years of age. Routine ultrasonography revealed no progression of coronary artery dilation during the disease course. However, at 6 years and 5 months of age, contrast-enhanced CT revealed tortuosity and dilatation of the aortic arch, bifurcation, and descending aorta (Figure 1e), leading to TAK diagnosis. The dosing schedule for tocilizumab was changed to a subcutaneous injection of 165 mg every 2 weeks, covered under insurance. This was intended to minimize hospital visits, taking into consideration the proposal by the Japan Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis.2 Imaging studies were re-performed at the age of 7 years and 5 months, without showing progression of tortuosity or dilation of the great vessels. TAK diagnosis in childhood, particularly in patients aged <5 years, may be delayed.3 Although KD is the most likely cause of coronary artery aneurysms, coronary lesions are common in patients with TAK.4 Our patient was initially diagnosed with incomplete KD because of fever and right coronary artery dilatation. The clinical course of TAK is divided into three phases: pre-pulseless, pulseless, and fibrotic. TAK progresses through repeated remissions and relapses of inflammation.5 In our case, the inadequate interval of tocilizumab administration after PSL discontinuation might have resulted in the progression of the vascular lesion. Tocilizumab might mask clinical and laboratory findings of inflammation including fever in patients with suspected Takayasu arteritis; therefore, whole-vessel imaging is essential. Additionally, PET-CT has a sensitivity of 84% and 87% and a specificity of 84% and 73% for TAK diagnosis and evaluation of disease severity, respectively.6 The absence of TAK findings on PET/CT in this case also contributed to the delayed diagnosis. Although PET/CT may be a suitable modality for diagnosing TAK, the diagnosis should not be excluded based on PET/CT findings alone. In conclusion, TAK should be considered a differential diagnosis of idiopathic fever of unknown origin in infancy. Coronary artery dilatation or slight vasodilation of large vessels can be a clue for TAK diagnosis. Y.T. and Y.K. designed the study; Y.T. drafted the initial manuscript and prepared the figure; Y.K. performed the modifications. J.S., R.M., A.O., and K.S. critically reviewed the manuscript and supervised the entire study. All the authors have read and approved the final version of the manuscript. Informed consent was obtained from the patient's family for publication of the case. We would like to thank the Scientific English Editing Section of Fukushima Medical University for the English language editing. The authors declare no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.