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.
- Prieur AM (2001) A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 19(1):103–106, ReviewPubMedGoogle Scholar
- Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint BG (2002) Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71(1):198–203PubMedPubMed CentralView ArticleGoogle Scholar
- Dollfus H, Häfner R, Hofmann HM, Russo RA, Denda L, Gonzales LD, DeCunto C, Premoli J, Melo-Gomez J, Jorge JP, Vesely R, Stubna M, Dufier JL, Prieur AM (2000) Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol 118(10):1386–1392PubMedView ArticleGoogle Scholar
- Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 29(3):301–305PubMedPubMed CentralView ArticleGoogle Scholar
- Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 46(12):3340–3348PubMedPubMed CentralView ArticleGoogle Scholar
- Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P (2010) Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 62(1):258–267PubMedView ArticleGoogle Scholar
- Granowitz EV, Porat R, Mier JW et al (1992) Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 4:353–360PubMedView ArticleGoogle Scholar
- Rivier C, Rivest S (1993) Mechanisms mediating the effects of cytokines on neuroendocrine functions in the rat. Ciba Found Symp 172:204PubMedGoogle Scholar
- Boissier MC, Assier E, Falgarone G et al (2008) Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine 75:373–375PubMedView ArticleGoogle Scholar
- Rigante D, Stabile A, Minnella A, Avallone L, Ziccardi L, Bersani G, Stifano G, Compagnone A, Falsini B (2010) Post-inflammatory retinal dystrophy in CINCA syndrome. Rheumatol Int 30(3):389–393PubMedView ArticleGoogle Scholar
- Adán A, Solé M, Corcostegui B, Navarro R, Burés A (2007) Cytological vitreous findings in a patient with infantile neurological cutaneous and articular (CINCA) syndrome. Br J Ophthalmol 91(1):121–122PubMedPubMed CentralView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited.