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Ocular modifications in a young girl with cryopyrin-associated periodic syndromes responding to interleukin-1 receptor antagonist anakinra
© The Author(s) 2011
Received: 26 October 2010
Accepted: 29 December 2010
Published: 9 April 2011
An 8-year-old patient with genetically confirmed chronic infantile neurological cutaneous and articular syndrome was treated with interleukin-1 receptor antagonist, anakinra. She initially presented with recurrent episodes of fever, rash, chronic fatigue, frequent headaches, ocular involvement (corneal infiltrate and papillary edema), and permanent increased biologic inflammatory markers. Following treatment with anakinra, all symptoms and inflammation resolved. Ophthalmologic signs normalized. This ophthalmologic description (optic nerve and cornea) has never been illustrated, even if ocular affections are classic in the cryopyrin-associated periodic syndromes.
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%) . 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 .
In the presenting case of CINCA/NOMID successfully treated by anakinra, we report and document normalization of ophthalmologic involvement undertreatment.
Here we report a case of CINCA/NOMID with chronic inflammation and neurosensorial involvement but without hypertrophic arthropathy successfully treated with IL-1Ra, anakinra. The recombinant form of the naturally occurring IL-1Ra is called anakinra (rmetHuIL-1Ra), and differs from the native human protein that is not glycosylated and has an additional N-terminal methionine . Anakinra competitively inhibits binding of large number of IL-1 receptors, as these receptors are expressed on all cells except red blood cells. IL-1 is a major inflammatory mediator and induces fever, anorexia, hypotension, leucopenia, and thrombocytopenia. IL-1 stimulates production of IL-6, fibrinogen, and complement components. IL-1 also stimulates the hypothalamic–pituitary–adrenal axis  and promotes Th17 differentiation. Th17 is involved in autoimmunity and Th17 cells are pivotal in autoimmune uveitis . Eye involvement in our patient was characterized by papillary edema and cornea infiltrate. Ophthalmologic involvement in CAPS are pleiotropic as episclera, anterior chamber, vitreous, and optic disc can be affected [10, 11]. To the best of our knowledge, corneal infiltrates were not previously reported. The explanation proposed regarding reversal nummular infiltrates included  cellular inflammatory infiltration in the stroma or  reversal amyloid deposits. The first hypothesis seems to be more rational because in this case, systemic amyloidosis was not present. Papilledema is related to chronic intracranial hypertension due to chronic CSF inflammation. Anakinra was dramatically efficient to treat systemic inflammation, articular pain and recurrent headaches were also relieved. Ophthalmologic improvement was also remarkable as shown in Fig. 3: papilledema resolved in 6 months as corneal infiltrates. Unfortunately, visual field does not improve because of papilledema duration before anti-IL-1Ra treatment and alteration of the optic nerve fibers.
The auto fluorescence fundus photographs did not show hyper signal resulting in auto fluorescent material accumulation (not shown). Unfortunately, visual field does not improve because of papilledema duration and alteration of the optic nerve fibers.
We confirmed improvement in fundus examination and regulation of CSF white cell counts with IL-1 receptor antagonism in the treatment of auto-inflammatory conditions. Also, we suggest, early in the course of the disease, the use of IL-1 receptor antagonist as a therapeutic option to chronic papilledema in order to prevent irreversible consequence of chronic excessive intracranial pressure and final optic atrophy.
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