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

Abstract

Objective. Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin-1 (IL-1) processing. Anakinra, an IL-1 receptor antagonist, has been shown to be an effective treatment; however, data on long-term efficacy and safety have been sparse. This study was undertaken to assess the long-term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.Methods. We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.Results. There were 10 patients with NOMID/ CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26-42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection-site reactions.Conclusion. The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…5). Some studies have indeed reported efficacy of anakinra for stabilizing or reversing hearing loss in a subset of CAPS patients treated with anakinra (18,21,44). Our observations are consistent with the concept of a therapeutic window of opportunity preceding or occurring soon after the onset of hearing loss since it appears to be irreversible at later ages (18,44).…”

“…Some studies have indeed reported efficacy of anakinra for stabilizing or reversing hearing loss in a subset of CAPS patients treated with anakinra (18,21,44). Our observations are consistent with the concept of a therapeutic window of opportunity preceding or occurring soon after the onset of hearing loss since it appears to be irreversible at later ages (18,44). Hearing loss in our 59-y-old subject 1236 might have been irreversible due to its long duration, but we cannot exclude the possibility that anakinra treatment was insufficient in duration or dosage.…”

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

“…Osteopenia/ osteoporosis is common, and patients are at increased risk for the development of amyloidosis, which has a higher prevalence in Europe, where the incidence can be as high as 25% in cases of MWS [11]. Although amyloidosis was also seen in NOMID/CINCA patients in France and elsewhere in Europe [9,12], we have thus far not seen amyloidosis in any of the approximately 40 patients with NOMID in the United States. This is in line with epidemiologic studies suggesting that environmental factors in old world countries may significantly contribute to the risk of developing amyloidosis [13].…”

“…MRI enhancement of the cochlea can improve with treatment, which suggested an inflammatory-induced hearing loss. Interestingly, damage to the neuroepithelial Corti hair cells was found in necrobiopsy of the inner ears of MWS patients [12]. Inner ear inflammation leads to hearing loss that can initially improve on treatment in some patients [8], however persistent and chronic, longstanding and severe hearing loss is irreversible.…”

Successful Management of Cryopyrin-Associated Periodic Syndrome With Canakinumab in Infancy

“…22 The massive secretion of active IL-1b observed in CAPS suggested that anti-IL-1b could represent an effective therapy. A number of studies have pointed to the efficacy and safety of anti-IL-1b-receptor MoAb (anakinra) [6][7][8][23][24][25] as well as to the IL-1 blockers rilonacept 9,10 and canakinumab. The prolonged half-life of canakinumab allows the 8-weekly dosing scheme and makes it well tolerated by the pediatric population.…”