Sustained response and prevention of damage progression in patients with neonatal‐onset multisystem inflammatory disease treated with anakinra: A cohort study to determine three‐ and five‐year outcomes

Abstract

Objective Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. Methods We conducted a cohort study of 26 NOMID patients ages 0.80–42.17 years who were followed up at the NIH and treated with anakinra 1–5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. Results Sustained improvements in diary scores, parent’s/patient’s and physician’s global scores of disease activity, parent’s/patient’s pain scores, and inflammatory markers were observed (all P < 0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P = 0.0026 and P = 0.0076, respectively), albumin levels, and opening pressures (P = 0.0012 and P < 0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. Conclusion These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.

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).…”

“…However, mutations associated with FCAS are not observed in association with NOMID. Furthermore, MWS mutations are often associated with hearing loss, which presents later in life than in NOMID patients (18,21). Somatic mosaicism for NLRP3 mutations is observed in some sporadic cases of NOMID, as well as the closely related autoinflammatory disorder Schnitzler syndrome (22), but is rarely associated with the other milder phenotypes (23,24).…”

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

“…It is relevant to note that clinical experience with IL-1Ra in pediatric disease abounds, mainly because auto-inflammatory diseases such as familial Mediterranean fever, hyper-IgD syndrome, cryopyrin-associated periodic syndrome, and systemic juvenile idiopathic arthritis usually present in childhood. Neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of IL-1Ra (a loss-of-function mutation in il1rn) both present in early infancy and are successfully and safely treated with IL-1Ra (17)(18)(19)(20). Importantly, a study in 71 preterm infants identified a low-expression il1rn genotype to be strongly associated with an increased susceptibility to BPD (odds ratio 11.7 (16)).…”

“…Our rationale was that (i) IL-1α and IL-1β are already known to be important malefactors in BPD (6-9, 11, 13-15); (ii) tellingly, a low-bioactivity polymorphism of il1rn is strongly associated (odds ratio 11.7) with BPD (16); and (iii) IL-1Ra features a favorable safety profile that is well-established in a broad spectrum of diseases (17,18), including neonatal cases (19,20). We therefore embarked on the exploration of IL-1Ra as a candidate therapy for BPD using a clinically relevant mouse model.…”

Autoinflammatory diseases in Pediatrics

“…14,41,44 In certain cases, improvement is achieved, or at least CNS, visual and hearing damage is stabilized. 45 …”