Successful resolution of stromal keratitis and uveitis using canakinumab in a patient with chronic infantile neurologic, cutaneous, and articular syndrome: a case study
© Hirano et al. 2015
Received: 27 August 2015
Accepted: 13 November 2015
Published: 21 November 2015
Cryopyrin-associated periodic syndrome (CAPS) is a group of rare autoinflammatory diseases, and of these, chronic infantile neurologic, cutaneous, and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID) syndrome has the most severe phenotype. Canakinumab, a monoclonal antibody that targets interleukin-1β, has been shown to be an effective treatment for resolving systemic inflammation. However, its efficacy for treating ophthalmic symptoms of this disorder remains unclear.
A 64-year-old female reported episodes of nonpruritic urticaria, fever, aseptic meningitis, and bilateral sensorineural deafness. Her son had experienced similar symptoms. She was initially referred for ophthalmologic treatment for an infectious corneal ulcer. Examination of her right eye by slit lamp biomicroscopy showed diffuse conjunctival injection, corneal infiltrates, a corneal ulcer, and hypopyon. She was therefore treated aggressively with topical and systemic antibiotics in addition to antifungal medications. However, this was ineffective. Genetic analysis detected the heterozygous germline p.Asp303Asn mutation in the NLRP3 gene in both our patient and her son. She was therefore diagnosed with CINCA/NOMID syndrome based on her clinical manifestations. All of the patient’s physical and ophthalmic symptoms were resolved within a few days after the initiation of canakinumab treatment. During an 18-month follow-up period, no adverse events or severe infections were observed.
Our case report indicates that canakinumab is effective not only for the treatment of systemic inflammation but also for treating ophthalmic involvement, such as recurrent stromal keratitis and anterior uveitis.
KeywordsCryopyrin-associated periodic syndrome Chronic infantile neurologic Cutaneous and articular/neonatal-onset multisystem inflammatory disease syndrome Canakinumab Stromal keratitis Uveitis
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disorder caused by heterozygous mutations in the NLRP3 gene and include three distinct conditions, namely familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, and articular (also known as neonatal-onset multisystem inflammatory disease) (chronic infantile neurologic, cutaneous, and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID)) syndrome [1–5]. Gain-of-function mutations in NLRP3 result in the excessive production of the potent proinflammatory cytokine interleukin-1β (IL-1β), thereby evoking the autoinflammatory manifestations of CAPS [6–8]. CINCA/NOMID syndrome is the most severe CAPS phenotype [9, 10]. The eye manifestations are pleiotropic in patients with CINCA/NOMID syndrome, with inflammation involving the cornea, sclera, anterior chamber, vitreous, retina, and optic disc . Canakinumab, a fully humanized monoclonal antibody that selectively blocks IL-1β, has been shown to be an effective treatment for CINCA/NOMID syndrome [12–14]. However, the efficacy of canakinumab in treating its ophthalmic manifestations remains unclear.
Here, we describe a case of an adult female with CINCA/NOMID syndrome-related stromal keratitis and uveitis, which was successfully treated with canakinumab.
A 64-year-old female was referred to our department for the treatment of an infectious corneal ulcer. She reported experiencing daily episodes of urticaria-like rashes, fevers, and arthralgia since birth. She also had a history of meningitis, which showed no evidence of infection and did not respond to antibiotic treatment, and bilateral sensorineural deafness since high school. The patient had been evaluated for collagen diseases many times at other hospitals, but no disease-specific autoantibodies had been detected. Her detailed ophthalmic history was unclear. Her family history was significant in that her son had displayed similar symptoms from birth that had been treated with corticosteroids and immunosuppressants.
The presence of the urticaria-like rash, fever, arthralgia, and both her past history and her family history led us to consider a CAPS diagnosis. Therefore, a genetic analysis was carried out, and this detected a heterozygous, germline p.Asp303Asn mutation in the NLRP3 gene in both the patient and her son, confirming a diagnosis of CAPS. Based on her severe physical and ophthalmic manifestations, including chronic meningitis and posterior segment involvement in the left eye, a diagnosis of CINCA/NOMID syndrome was made. The patient was therefore started on a course of 150 mg canakinumab (Ilaris; Novartis Pharma AG, Basel, Switzerland) given subcutaneously once every 6 weeks. All of the patient’s physical symptoms (rash, arthralgia, aseptic meningitis, and fever) and ophthalmic symptoms (conjunctival injection, ulcerative keratitis, anterior chamber inflammation, and hypopyon) resolved within a few days. In addition, the patient’s CRP level normalized and stabilized (Fig. 2).
In this report, we have described a case of CINCA/NOMID syndrome-related stromal keratitis and uveitis in an adult female, which was successfully treated with canakinumab. To the best of our knowledge, this is the first report of CINCA/NOMID syndrome, which describes the ophthalmic findings before and after the canakinumab treatment in detail. In most of the previous reports describing the efficacy of canakinumab in patients with CAPS, conjunctivitis has been the only end point used to assess ocular manifestations [13, 15]. Therefore, the efficacy of canakinumab for a variety of ophthalmic symptoms had remained unclear. In the patient we have described in this report, we found that canakinumab therapy led to a marked improvement, not only in systemic inflammation but also in ophthalmic manifestations such as recurrent stromal keratitis and anterior uveitis. We were surprised that the subcutaneous injection of canakinumab resolved the ophthalmic inflammation so dramatically, in spite of the presence of blood-retina and blood-aqueous barriers in the eye. Canakinumab has been reported to induce adverse events, such as nasopharyngitis, upper respiratory infections, and gastroenteritis, presumably due to the effects of blocking the actions of the proinflammatory cytokine IL-1β [13, 15]. However, no side effects were observed during the follow-up period in this case. Further observation will be needed to check the long-term efficacy of canakinumab.
This case indicates that it is important to make a diagnosis and start treatment with canakinumab as early as possible to prevent irreversible ocular complications. In our patient, the visual acuity of the right eye did not completely recover, as the delay in diagnosis resulted in post-inflammatory optic disc atrophy and stromal opacification. It has been only 13 years since the mutation of CIAS1 was discovered in CAPS patient. Although the discovery has made much progress in pathophysiologic and therapeutic understanding of CAPS, clear diagnostic criteria have not been yet established. In addition, CAPS is a very rare disease; for example, CINCA/NOMID syndrome has a prevalence of 1/4,000,000 in Japan . These conditions can cause our lack of awareness of the disease, resulting in delayed diagnosis and treatment. We think it is important to consider CAPS including CINCA/NOMID syndrome in the differential diagnosis for patients who present with periodic fever, urticaria-like rashes, meningitis, articular manifestations, and ocular inflammation.
In conclusion, our case report indicates canakinumab is effective in CINCANOMID syndrome, not only for systemic inflammation but also for ophthalmic involvement, such as recurrent stromal keratitis and anterior uveitis. Further prospective studies will be required to determine the efficacy of canakinumab, including as many patients as possible with this rare disease.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
cryopyrin-associated periodic syndrome
chronic infantile neurologic, cutaneous and articular
neonatal-onset multisystem inflammatory disease
The authors have no support from a funding body.
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