A 36-year-old French Canadian male presented with a 3-week history of left knee arthritis. Blood work revealed leukocytosis with predominance of neutrophils at 23 × 109/L, microcytic anemia with hemoglobin at 95 g/L, and markedly elevated C-reactive protein (CRP) at 321 mg/L. Left knee radiograph revealed significant joint effusion. Synovial fluid analysis was abnormal with 161 500 white blood cells/ml (91% neutrophils) and low glucose level at 0.8 mmol/L, consistent with septic arthritis. The patient was treated accordingly, with no clinical or biochemical improvement. Extensive microbiological investigations were negative. An underlying inflammatory disorder was therefore suspected. High dose oral prednisone was started, leading to marked clinical improvement and decrease in CRP from 271 to 106 mg/L within forty-eight hours. Work-up for autoimmune diseases revealed positive HLA-B27 antigen and rheumatoid factor at 160 IU/mL; antinuclear antibodies, extractable nuclear antibodies, anti-double stranded DNA, antineutrophil cytoplasmic antibodies and anti-cyclic citrullinated peptides were negative, while complement levels were normal.
One week later, the patient complained of chest pain, with concomitant increase in inflammatory markers. Imaging revealed a right loculated pleural effusion. Fluid analysis revealed the presence of a non-purulent exudate with markedly low pH, undetectable glucose level, and negative gram stain. Although pleural white blood cells were increased at 7300/uL, differential count was not available. Antibiotics were resumed for suspected complicated parapneumonic effusion. The dose of prednisone was halved to 25 mg daily. Chest tube drainage was unsuccessful. Pleural thrombolysis was therefore attempted and led to massive hemothorax with respiratory distress requiring urgent thoracotomy and decortication. Pleural bacterial, fungal, and mycobacterial cultures were negative. A 4-week course of antibiotics was administered, while moderate dose prednisone was maintained. Upon discharge, knee synovitis and pleural effusion had resolved, but CRP remained elevated at 111 mg/L.
Given the uncertainty of the underlying inflammatory disorder, immunology was consulted. Family history was found to be unremarkable, with no consanguinity. Personal history revealed first admission at 2 years old for aseptic meningitis. Sensorineural hearing loss, macrocephaly, and global developmental delay were concurrently diagnosed in the setting of elevated inflammatory markers, namely leukocytosis with eosinophilia. The latter was persistently superior to 1500/mm3, despite the absence of atopic manifestations including urticaria, negative allergy tests, and normal immunoglobulin E level. A maculopapular rash was, however, noted on the patient’s abdomen on a few occasions between 7 and 8 years, with no recurrence afterwards. Cerebral CT scan revealed diffuse atrophy. A few years later, recurrent episodes of hyperthermia and lower extremity arthralgia led to a diagnosis of juvenile idiopathic arthritis. Aspirin was administered, with transient improvement in symptoms. In light of persistent inflammation and failure to thrive, upper and lower gastrointestinal endoscopies were performed revealing eosinophilic enterocolitis. Prednisone was given for several months, which partially reversed growth retardation in spite of persistent elevation in inflammatory markers. Pericarditis, with hemodynamically significant pericardial effusion requiring drainage, as well as unilateral pleural effusion, left elbow arthritis, and fever developed at 6 years old. Microbiologic work-up was negative. Aspirin was resumed, with improvement of symptoms.
During the following years, global developmental delay persisted. Pseudopapilledema was diagnosed during adolescence. Repeat cerebral CT scan revealed diffuse brain atrophy with cortical calcifications (Fig. 1). The patient developed alternating buttock pain relieved by non-steroid anti-inflammatory drugs (NSAIDS). Radiographs showed sclerosis and possible erosion of the right and left sacroiliac joints, respectively. In light of positive HLA-B27 status, spondyloarthritis was diagnosed and treated with NSAIDS as needed. During adulthood, the patient continued to suffer from intermittent arthralgia. He was treated twice for suspected septic arthritis of the right wrist, despite negative microbiologic work-up and absence of crystals on joint aspiration.
In light of the long-standing history of sensorineural hearing loss, physical and mental developmental delay, intermittent serositis, and elevated inflammatory markers, NLRP3-AID was suspected. DNA analysis by next-generation sequencing of 36 genes implicated in autoinflammatory diseases was normal, except for a heterozygous class 4 mutation in exon 3 of the NLRP3 gene, c.1991T > C (p.Met662Thr) [3]. No NLRP3 mutation was detected in the patient’s parents. The mutation had previously been described in two cases of severe NLRP3-AID [45]. Canakinumab was started at a dose of 150 mg every 2 months, then increased to 300 mg every month. Prednisone was initially maintained at 20 mg daily, then tapered over a few months. Although inflammatory markers almost normalized, visual deterioration prompted a switch to anakinra 100 mg daily after 6 months. The latter allowed clinical stabilisation with resolution of pseudopapilledema within a few months. Unfortunately, intellectual disability and deafness persisted. He has now been treated with anakinra for over 4 years, with no disease recurrence. Clinical evolution is summarized in Fig. 2.
