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.

Trial registration: ClinicalTrials.gov NCT00069329.

Figure 1

Systemic manifestations in patients with neonatal-onset multisystem inflammatory disease treated with anakinra. A, Patient diary score, Childhood Health Assessment Questionnaire (C-HAQ) score, parent’s/patient’s global score of overall disease activity, and parent’s/patient’s pain ratings at baseline and after 1, 2, 3, and 5 years of anakinra treatment. B, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and serum amyloid A (SAA) level at baseline and after 1, 2, 3, and 5 years of anakinra treatment. Bars show the mean ± SEM. * = P < 0.05; ** = P < 0.001, versus baseline.

Figure 2

Central nervous system outcomes in patients with neonatal-onset multisystem inflammatory disease treated with anakinra. Lumbar punctures were obtained in 24 of 26 patients at baseline, 24 of 26 patients at 36 months, and 18 of 20 patients at 60 months. Two patients were unable to undergo a lumbar puncture (1 due to spinal lipomatosis and 1 due to technical difficulties). A, Cerebrospinal fluid (CSF) leukocyte (white blood cell [WBC]) count, albumin level, and opening pressure at baseline and after 1, 2, 3, and 5 years of anakinra treatment. Decreases were seen at all time points. Bars show the mean ± SEM. * = P < 0.05; ** = P < 0.001, versus baseline. B, Example of leptomeningeal enhancement seen on the gadolinium-enhanced magnetic resonance image (MRI) obtained at baseline and no longer detected on MRIs obtained at the 3-year and 5-year followup examinations.

Figure 3

Audiology outcomes in patients with neonatal-onset multisystem inflammatory disease treated with anakinra. A, Comparison of mean bone 4-frequency pure-tone averages (4F-PTAs) (at 0.5k Hz, 1k Hz, 2k Hz, and 4k Hz) at baseline (x-axis) and at the 3-year and 5-year followup examinations (y-axis). The broken line indicates the estimated mean 4F-PTA. Red circles indicate ears with worsening of hearing with a mean change in 4F-PTA of ≥10 dB, and purple circles indicate ears with worsening of hearing with a mean change in 4F-PTA between 5 dB and 10 dB. Green circles indicate hearing in 4 patients (8 ears) who were younger than 20 months of age at enrollment. In these 4 patients, hearing was first assessable by 4F-PTA between 2.5 and 3 years of age, which was used as the baseline, and the last hearing assessment was conducted at 60 months for 3 patients and at 48 months for 1 patient. Upper case letters represent individual patients; r and l indicate the right and left ears, respectively. B, Cochlear enhancement pre– and post–gadolinium contrast on fluid-attenuated inversion recovery magnetic resonance imaging. Arrows indicate the cochlea; arrowheads indicate the vestibule. The enhancement seen on the postcontrast images at baseline had subsided on the images obtained after 3 years of treatment. C, Significantly higher cochlear enhancement scores in ears with hearing loss progression compared to those without hearing loss progression. Bars show the mean ± SEM. * = P < 0.05 versus ears without hearing loss progression.

Figure 4

Ophthalmology outcomes in patients with neonatal-onset multisystem inflammatory disease treated with anakinra. A, Significant decreases in conjunctivitis and papilledema scores throughout the study. Bars show the mean ± SEM. ** = P < 0.001 versus baseline. B, Significant correlation of low optic nerve thickness, measured by optical coherence tomography, with visual field loss. A near linear correlation was observed for optic nerve thickness of less than ~80μ.