Cryopyrin-associated periodic syndromes (CAPS) have been proposed to describe cryopyrin-related diseases with heterogenous phenotype severity. The mildest condition is the familial cold auto-inflammatory syndrome, patients with Muckle–Wells syndrome have an intermediate phenotype, the chronic infantile neurological cutaneous and articular syndrome (CINCA) also known as neonatal onset multisystem inflammatory disease (NOMID) is the most severe disease in this spectrum [1, 2]. The patients are presenting urticaria and life-like skin rash from early in life, variable articular involvement (arthralgia/arthritis is associated in 30% of cases with hypertrophic arthropathies), chronic aseptic meningitis, and neurosensorial involvement associated with biologic markers of neutrophil-driven inflammation. Broad ophthalmologic abnormalities have been described in CINCA/NOMID. An international collaborative study based on a questionnaire including 31 patients described the optic disc changes as the most common feature (83%), including optic disc edema, pseudopapilledema, and optic atrophy. Anterior segment manifestations varying from mild to severe (42%); chronic anterior uveitis (55%) [3]. CAPS are all caused by dominantly inherited or de novo mutations in CIAS1, a gene that encode for NLRP3 (also known as cryopyrin/NALP3/PYPAF1) [4, 5]. NLRP3 is a component of interleukin-1 (IL-1) inflammasome that regulates IL-1β production, a strong pro-inflammatory cytokine. Mutations of CIAS1 associated with CAPS result in a gain-of-function effect. Thanks to substantial advances in understanding genetic basis and mechanisms of these disorders, new therapeutics targeting the IL-1 pathway could be proposed as recombinant nonglycosylated homolog of human interleukin-1 receptor antagonist (IL-1Ra), anakinra that competitively inhibits binding of IL-1α and IL-1β to IL-1 receptor. Previous studies showed remarkable efficacy of anakinra in patients suffering from CIAS1-associated diseases [6].
In the presenting case of CINCA/NOMID successfully treated by anakinra, we report and document normalization of ophthalmologic involvement undertreatment.
Case report
The patient, an 8-year-old Caucasian girl, was referred to the Pediatric Immuno-hematology and Rheumatology Department for diagnosis and treatment of CINCA/NOMID syndrome. Diagnosis was suspected based on medical history of the child. She was born preterm at 30.5 weeks of gestational age with normal weight and height for age (2,010 g and 41.5 cm). She was issued from a twin pregnancy. Because the twin child was diagnosed with trisomy 13, in utero reduction was performed. Prematurity might be related to this procedure rather than to the disease. She presented with daily urticaria-like rash associated with fever since 1 week of age. Arthralgia and transient haunch swelling revealed with nonsteroidal anti-inflammatory drugs were reported at the age of 3 years. Since the age of two, she also complained of recurrent episodes of headaches. Diagnosis of CAPS was genetically confirmed (after the parents provided written informed consent according to the recommendations of the Declaration of Helsinki) and revealed a previously reported mutation, D303N, in the CIAS1 gene. Extensive baseline evaluation was performed before starting treatment with IL1-Ra, anakinra. Clinical examination confirmed the rash. Height and weight were 1.3 m and 24.8 kg, respectively. Biologic inflammatory markers were increased [C-reactive protein 40 mg/dl (normal <5)], white blood cell count 11,800 cells/mm3, and neutrophil count 7,860 cells/mm3). Bone X-Ray confirmed the absence of arthropathy. Lumbar puncture was performed and cerebrospinal fluid (CSF) examination revealed pleocytosis (25 cells/μl with 90% neutrophils), increased proteinorachia (protein level 0.71 mg/l), and high open pressure (21 H20 cm). Brain MRI (with FLAIR imaging and contrast injection) was normal (absence of abnormalities of small vessels of the basal ganglia and periventricular white matter lesions). Cognitive performances were normal. Audiographic examination showed mild bilateral sensorineural deafness (−20 dB). Vision was preserved in both eyes (20/25 Snellen visual acuity). The Goldmann visual field illustrated a mild blind spot enlargement. Slit lamp biomicroscopy revealed bilateral anterior, nummular, stromal keratitis, and absence of anterior uveitis (Fig. 1). On fundus examination and photographs of both eyes, we observed a bilateral papilledema without vitritis. Diagnosis of CINCA/NOMID was performed.
The patient did not receive any steroids or immunosuppressive treatment before initiation of anakinra treatment. Follow-up period is 30 months; initial dose of 2 mg/kg/day in subcutaneous injection has been maintained. All symptoms related to the diseases (rash, headaches, arthralgia, and chronic fatigue) ceased durably in few days. Biologic inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)], white blood cells, and neutrophil numerations rapidly decrease 1 month after initiation of the anti-IL-1 treatment. Inflammation markers rates were normalized and stabilized during the follow-up (Fig. 2). The velocity of growth was restarted and the height and weight increased progressively during the treatment. Audiogram remained stable overtime.
Six months after the introduction of anakinra, the corneal infiltrates disappeared. On fundus examination and photographs of both eyes, we observed a pale optic disc corresponding to the resolution of the papilledema (Fig. 3). The campimetry was not modified by the treatment and the blind spot enlargement was stable between the different exams. No adverse events and severe infection occurred. Treatment was well tolerated.
