Neonatal-onset multisystem inflammatory disease (NOMID), which in Europe is called chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome), is a severe and hitherto poorly treatable autoinflammatory disease. It is caused by mutations in the gene known as NALP3 or CIAS1, which encodes a member of the pyrin superfamily of death domain fold proteins that are involved in inflammation and apoptosis (1–3). Manifestations of NOMID/CINCA syndrome include arthropathy, conjunctivitis, an urticaria-appearing skin rash, chronic sterile meningitis, progressive visual and severe auditory defects, and abnormal growth and neurologic development (1). Patients typically have an intense acute-phase response, and some develop AA amyloidosis. The disease responds only modestly to high-dose corticosteroids and other antiinflammatory and immunosuppressive therapies. Herein we describe a patient with NOMID/CINCA syndrome associated with G571R, a de novo variant of NALP3, whose inflammatory disease remitted rapidly and completely following treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra) (anakinra).
The patient was a 32-year-old British woman who had developed a generalized erythematous/urticarial rash and conjunctivitis at birth. These symptoms persisted virtually constantly except during brief periods when she received high doses of corticosteroids. She had marked arthralgia most of her life, affecting her ankles, knees, wrists, and elbows, and had mild frontal bossing of the skull and flattening of the nasal bridge characteristic of NOMID/CINCA syndrome. Her growth was restricted, and exogenous estrogen treatment was needed to stimulate secondary sexual development. Hearing difficulties had been evident since she was pre–school age, and she had become profoundly deaf over the last 5 years. Longstanding neurologic features included irritability, headaches, papilledema, and progressive loss of vision consistent with chronic elevated intracranial pressure. She reported severe fatigue and the need for an aftenoon nap most days. Numerous blood tests throughout her life had revealed persistent massive neutrophilia, normocyctic anemia, and an intense acute-phase response. Renal and liver function were preserved, and AA amyloidosis was excluded by serum amyloid P component scintigraphy. Prior to the institution of anakinra treatment, she was being treated with prednisone 5 mg on alternate days and azathioprine 50 mg daily, with little evidence of benefit.
Sequencing of the NALP3 gene revealed that the patient was heterozygous for a point mutation encoding the NALP3 variant G571R, which was not present in either parent, consistent with the reported high frequency of de novo mutations underlying NOMID/CINCA syndrome (1). Mutations in this gene were originally found to be responsible for the ostensibly distinct inherited periodic fever syndromes familial cold urticaria/familial cold autoinflammatory syndrome and Muckle-Wells syndrome (4), and we have shown that the latter is highly responsive to treatment with anakinra (5, 6). The patient consented to undergo a therapeutic trial of anakinra (Kineret; Amgen) at 100 mg daily (the dosage licensed for treatment of rheumatoid arthritis).
Investigations performed immediately before anakinra was instituted revealed a hemoglobin level of 10.1 gm/dl, a white blood cell (WBC) count of 29 × 109/liter (mainly neutrophils), a platelet count of 899 × 109/liter, reactive polyclonal hyperglobulinemia, and plasma serum amyloid A protein (SAA) and C-reactive protein (CRP) concentrations of 284 mg/liter and 109 mg/liter, respectively (normal <5 for both). Within 24 hours of the initiation of this treatment the rash, conjunctivitis, and arthralgia had disappeared, and the patient reported a steady and dramatic improvement in general well-being thereafter. Her headaches and fatigue ceased, and the intense acute-phase response resolved completely within 5 days of the first injection of anakinra. At review 1 month later, her hemoglobin level was 12.4 gm/dl, the WBC count was 10.7 × 109/liter, and the platelet count was 366 × 109/liter. During the next 6 months, the dosage of anakinra was tapered to 33 mg daily, and her other antiinflammatory therapy was discontinued without any recrudescence of the inflammatory disease activity. The median plasma SAA and CRP concentrations, measured every 2 weeks, decreased from 281 mg/liter and 121 mg/liter, respectively, during the 2 months before institution of anakinra treatment to 3.7 mg/liter and 5.5 mg/liter during the 7 months of therapy. Her deafness and visual acuity have not changed.
NALP3 is a member of the recently characterized pyrin superfamily of death domain fold proteins which contain a characteristic 6–alpha helix death domain–related structure; now known as the pyrin domain, originally identified as the product of the gene responsible for familial Mediterranean fever (7). The NALP3 gene is expressed in peripheral blood leukocytes and chondrocytes, and the pyrin domain of NALP3 is thought to interact with ASC, leading to signaling of NF-κB and increased IL-1β production (1, 3). Up-regulation of IL-1β has been observed in unstimulated monocytes obtained from a patient with NOMID/CINCA syndrome (3), and the rapid and complete clinical and serologic responses to rIL-1Ra in the patient described herein and in Muckle-Wells syndrome patients we have treated (5, 6) confirm that IL-1β has a fundamental role in the pathogenesis of the inflammatory disorders associated with mutations in the NALP3 gene. Interestingly, the dramatic rate of decline in this patient's plasma SAA concentration following anakinra therapy indicates that SAA must have a circulating half-life of <13 hours, reinforcing its status as the most sensitive and dynamic marker of the acute-phase response.
It is notable that as a child, this patient had been thought to have a severe sporadic form of Muckle-Wells syndrome, long before the genetic basis of the disease or its relationship with NOMID/CINCA syndrome were known. It has recently become clear that NOMID/CINCA syndrome, Muckle-Wells syndrome, and familial cold urticaria represent a spectrum of overlapping phenotypes that correlate inconsistently with particular mutations among the ∼20 allelic variants of NALP3 thus far identified. Our findings strongly indicate that trials of anakinra therapy are warranted in patients with all of these disorders and offer hope that early and prolonged treatment with rIL-1Ra might prevent the deafness and abnormal neurologic and skeletal development that occur in children with NOMID/CINCA syndrome.