Introduction

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease in which interleukin-1β (IL-1β) is overexpressed owing to abnormalities in the NLRP3 gene [1-3]. The most severe type of CAPS is neonatal-onset multisystem inflammatory disease (NOMID) [1-3]. A 50-year-old woman with recurrent fever, conjunctival hyperaemia, and urticarial rash from early infancy was clinically diagnosed with NOMID. Whole-exome sequencing analysis of the NLRP3 gene was analysed and a point mutation was identified at the age of 44 years. After the administration of anti-IL-1β antibody (i.e., canakinumab), her severe symptoms disappeared, and acute-phase inflammatory marker levels improved, whereas arthralgia caused by cold exposure, dry mouth, sensorial deafness, and mild mental retardation remained. Herein, we present and discuss the first two sets of clinical manifestations, which have not been reported previously.

Methods

The patient had no family history of genetic abnormalities. At the age of 2 months, she developed pyrexia, conjunctival hyperemia, and urticarial rash, all of which were recurrent. Based on these symptoms, anterior uveitis and optic neuritis were diagnosed and symptomatic treatment was initiated. She subsequently complained of pain in multiple joints. Therefore, she was diagnosed with juvenile idiopathic arthritis. She received treatment with steroids and anti-inflammatory drugs. Although the treatment was continued and immunosuppressive agents were administered during exacerbation, her symptoms did not improve. Moreover, aseptic meningitis and abdominal pain recurred. She was repeatedly hospitalized for several days at that time. Mental developmental regression, sensorial deafness, and buttonhole and ulnar side deformities in both hands gradually progressed. At 22 years of age, she visited our hospital so that appropriate treatment could be determined.

Results

Blood tests showed marked increases in white blood cell counts and serum levels of C-reactive protein, amyloid A, and matrix metalloproteinase-3 (Table 1). Her serum antinuclear antibodies (ANA) have been positive for more than 20 years after visiting our hospital, and only the anticentromere antibody was positive in the ANA classification type. Scleroderma was suspected at the age of 40 years because of the development of dysphagia and anticentromere antibody positivity. However, scleroderma was not diagnosed because no sclerotic skin was observed, and normal esophageal findings were noted in the barium study and upper endoscopy. She complained of dry mouth in addition to dysphagia; therefore, a smear examination of her salivary sample from the mouth was performed. The smear examination results revealed high neutrophil counts. The salivary sample selectively collected from the parotid duct opening contained a mixture of mucus and serous fluid. The smear examination showed neutrophils without bacterial phagocytosis and some monocytes, but no bacteria were observed. In the bacterial culture tests, no pathogenic bacteria, other than some oral commensal bacteria, were isolated from the saliva sample. Saliva samples could not be collected from the duct openings of the submandibular and sublingual glands. Ultra sonographic findings showed several small, round, and hypoechoic areas with internal hyperechoic spots in the obscure heterogeneous structures of both parotid glands. Differentiating between the parotid glands and the surrounding tissues was difficult. Sjӧgren syndrome was not diagnosed because of both negative serum antiSS-A and anti-SS-B antibody test findings and the absence of dry eyes. These findings suggested that dysphagia was caused by a decrease in serous saliva production due to persistent inflammation of the parotid glands. Meanwhile, pain and swelling at the deformed joints of the index and middle fingers on both sides were observed during cold exposure. Therefore, magnetic resonance imaging (MRI) of the hands was conducted. Bone marrow edema (BME) was noted in the asymptomatic state (Figure 1a) and was exacerbated after cold stimulation (Figure 1b). No findings indicated arthritis. Based on these manifestations, NOMID was clinically diagnosed rather than autoimmune disease. Genetic testing results revealed a c.1060G>A point mutation (A352T) in the NLRP3 gene. The serum levels of interleukin-1β, interleukin-2, tumour necrosis factor-α, and interferon-γ in the acute phase were within the normal range. Treatment with canakinumab was initiated for the patient at the age of 44 years after discontinuing the administration of steroids and immunosuppressive agents.　Consequently, recurrent fever, conjunctival hyperemia, and the urticarial rash disappeared, and arthralgia and abdominal pain were alleviated. Six years after the start of treatment, laboratory tests were performed to evaluate the therapeutic effects. Blood test results showed normalized white blood cell counts and decreased levels of serum C-reactive protein, amyloid A, and matrix metalloproteinase-3 (Table 1). The serum ANA titer showed a four-fold increase compared to that before treatment, whereas no significant findings were obtained for the other autoantibodies. The patient continued to complain of pain in the index and middle fingers without swelling after cold exposure; however, no evidence of BME was found on MRI scans (Figures 1c and 1d). Avoiding cold exposure reduced arthralgia. The number of neutrophils in the parotid saliva did not decrease, although she no longer complained of dysphagia after frequent gargling, tooth-brushing, and gum-chewing. Her sensorineural deafness did not improve; however, she wore a hearing aid to resolve interference in daily life. Brain MRI findings showed moderate dilatation of the sulcus and lateral ventricles. These findings were not changed compared to those before treatment. She could become independent in daily life, although her mental retardation did not improve. The mild osteoporosis findings noted before treatment did not change after that. At present, treatment with canakinumab alone continues. No adverse effects have been observed and hospitalization is no longer required. Approval from the hospital ethics committee and consent from the patient and her family were obtained for publication of this report.

Table 1: Results of blood tests before and after treatment.

Figure 1: The T2-weighted fat-suppression images show high signals at the distal site of the right second metacarpal bone before the cold stimulation (a) and higher signals at the same site after the stimulation (b). The high signals disappear before (c) and after (d) the stimulation in a lull after treatment.