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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arthritis Rheum. Author manuscript; available in PMC 2013 July 1.
Published in final edited form as:
PMCID: PMC3474541
NIHMSID: NIHMS408789

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.

Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular syndrome) (MIM 607115) is the most severe clinical phenotype of a spectrum of autoinflammatory disorders caused by autosomal dominant mutations in CIAS1 or NLRP3 (also called NALP3 or PYPAF1), termed cryopyrin-associated periodic syndromes (CAPS) (1,2). Most patients with milder forms of CAPS (familial cold autoinflammatory syndrome and Muckle-Wells syndrome [MWS]) and NOMID patients present around birth with systemic inflammation, including fever and elevation of acute-phase reactants, conjunctivitis, and an urticaria-like rash. Hearing loss is seen in MWS patients but presents later in life than in NOMID patients. The severe organ-specific manifestations involving the eye, the severe manifestations in the central nervous system (CNS), with aseptic meningitis and ventriculomegaly, and the damage in the bone, with benign, tumor-like lesions, are seen only in NOMID patients (3). Before interleukin-1 (IL-1)–blocking therapy, disease-related progressive organ damage and treatment-related complications resulted in progressive hearing and vision loss, cognitive impairment, physical disability, and infections in NOMID patients and an estimated mortality of up to 20% before adulthood (4).

The discovery that NLRP3 is a critical component of an IL-1–activating and secreting complex termed the NLRP3 inflammasome (57) suggested IL-1 as a therapeutic target. The pivotal role of IL-1 in causing the clinical manifestations of CAPS was indeed confirmed by clinical studies, initially using the short-acting IL-1 receptor antagonist anakinra (810) and, more recently, with 2 long-acting IL-1 inhibitors (1113).

While the short-term effects of IL-1–blocking agents on clinical symptoms and measures of systemic inflammation in the milder forms of CAPS are established, data on the effects of long-term IL-1 suppression on sustained clinical responses with regard to the organ-specific manifestations in NOMID are only recently emerging (14). In this open-label, long-term followup study, we evaluated the efficacy and safety of 36 and 60 months of IL-1–blocking therapy with the IL-1 receptor antagonist anakinra in controlling systemic and organ-specific inflammation and in preventing the progression of organ damage.

PATIENTS AND METHODS

Patients

Of 43 patients who met the criteria for NOMID and were enrolled at the NIH Clinical Center between September 2003 and April 2010 in an ongoing study (NCT00069329), 26 had completed at least 36 months of treatment at the time of this analysis. Of these 26 patients, 20 had completed 60 months of treatment. All 26 patients were included in the analysis (see Supplementary Figure 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131). Enrolled patients had at least 2 of the following clinical manifestations: urticaria-like rash, CNS involvement (papilledema, cerebrospinal fluid [CSF] pleocytosis, or sensorineural hearing loss), or epiphyseal and/or patellar overgrowth on radiographs. All patients had evidence of current or prior CNS disease and all had active disease, as defined by the presence of daily symptoms assessed in a diary and elevated acute-phase reactant levels at baseline. Three of the patients had previously been treated with tumor necrosis factor inhibitors. At treatment initiation, patients had a mean ± SEM age of 11.5 ±9.1 years (range 10 months to 42.2 years). Anakinra therapy was initiated in 4 children younger than 2 years (between 10 months and 20 months old). The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Institutional Review Board (IRB). Written informed consent was obtained from all patients or their legal guardians.

Study design and treatment

Anakinra therapy was started at 1 mg/kg by daily subcutaneous injection. Stepwise dose increases of 0.5–1 mg/kg per injection were made as frequently as every 2 weeks to achieve laboratory and organ inflammation remission (as described below under Laboratory outcomes and Organ-specific outcomes). The IRB-approved maximal anakinra dosage, initially 2 mg/kg/day, was increased to 3 mg/kg/day in December 2004 and to 5 mg/kg/day in May 2007, allowing for higher dosages of medication later in the course of the study. Clinical assessments were performed at the NIH at baseline and at 6, 12, 18, 24, 30, and 36 months in 26 patients. An additional assessment was performed at 60 months in 20 of the patients.

Assessment of clinical end points

Clinical outcomes

A NOMID-specific daily diary was kept by the patient or parent at home (10) and was filled out an average of 70.80% of days during the treatment period. The Childhood Health Assessment Questionnaire (C-HAQ) (15) and a visual analog scale for pain and overall disease activity were completed by the parent or patient and by the physician at each NIH visit.

Laboratory outcomes

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level were analyzed at the NIH Clinical Center laboratory. Serum amyloid A (SAA) was measured as previously described (16). Systemic inflammatory remission was defined as a normal CRP level (≤0.5 mg/dl). Normal ESR values were defined as ≤25 mm/hour, and normal SAA values were defined as ≤10 mg/liter.

Organ-specific outcomes

Magnetic resonance imaging (MRI) with gadolinium-enhanced fluid-attenuated inversion recovery (FLAIR) sequences and fast imaging employing steady-state acquisition were performed yearly to obtain images of the brain and inner ear. Cochlear enhancement on FLAIR MRI was graded on a scale of 0–3, where 0 = no signal, 1 = signal barely detectable above noise, 2 = signal comparable to brain parenchymal signal, and 3 = signal comparable to T2 signal of fluid. The images were graded by a single investigator (JAB) who was blinded with regard to the sequence of the radiographs.

Organ inflammation and damage were assessed at baseline and during treatment. Absence of organ inflammation was defined in the CNS as a normal CSF white blood cell (WBC) count (≤5 cells per microliter) and the absence of leptomeningeal enhancement on MRI, and in the eyes as the absence of eye inflammation on examination. After 2006, the presence of cochlear enhancement on inner ear MRI was also defined as organ inflammation in the inner ear and resulted in dose increases. CNS, hearing, vision, and bone end points are described in the supplementary text available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131.

Other end points included corticosteroid dose and drug safety parameters. Adverse events were recorded as clinically described and were coded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 after study completion. Those occurring at lower anakinra dosages (≤2.5 mg/kg/day) and higher dosages were summarized to assess a dose effect on adverse events. Pharmacokinetic studies of anakinra dosages up to 4.5 mg/kg/day were performed (see supplementary text available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131).

Statistical analysis

Descriptive statistics were used to summarize demographic and baseline characteristics. All analyses were performed using Stata, version 10 (StataCorp). Data at 12, 24, 36, and 60 months were compared to baseline values using paired t-tests or Wilcoxon’s signed rank tests. The chi-square test was used for unpaired dichotomous proportional end points and McNemar’s test was used for paired data. The mean ± SEM and 95% confidence intervals were calculated from all data points available for the respective time point. Only data available at both time points were included for paired statistical analyses. Mixed model analyses to account for the correlation of paired organs were used to assess audiology and vision outcomes. All P values are 2 sided and were not adjusted for multiple comparisons.

The percentage of patients whose disease was in systemic inflammatory remission, and the mean scores of MRI cochlear enhancement following 6 months of treatment in each patient were calculated (see supplementary text available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131).

RESULTS

Patient demographics and baseline patient characteristics

All 26 patients had active disease at baseline as defined by diary scores and elevated levels of inflammatory markers (Figures 1A and B). The majority of the patients (21 of 26) had mutations in CIAS1. Reliable results of lumbar punctures performed within 3 months of baseline were obtained in 24 of the 26 patients (see supplementary text available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131). Increased intracranial pressure was seen in the great majority of these patients (21 of 24), and aseptic meningitis was present in 19 of the 24 patients. All patients had historically proven aseptic meningitis by lumbar puncture prior to the baseline visit. Growth retardation below the 3rd percentile (in 16 of the 26 patients) and body weight below the 3rd percentile (in 15 of the 26 patients) were frequent. Specific organ damage present at baseline was recorded (Table 1).

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 ...
Table 1
Baseline demographic characteristics and organ-specific disease damage in the 26 NOMID patients*

Primary outcome of clinical and laboratory response

A clinical and laboratory response to anakinra was achieved and sustained in all patients. Scores for daily diaries, parent’s and physician’s global assessment of disease activity, parent’s assessment of pain, and C-HAQ decreased significantly from baseline to 36 months (P = 0.0016 for C-HAQ and P <0.001 for all other assessments). Between 36 months and 60 months these parameters did not change significantly (Figure 1A). Similarly robust decreases in inflammatory markers (CRP level, ESR, and SAA) were seen from baseline to 12 months and from baseline to 36 months (all P <0.001) with stable values from 36 months to 60 months (Figure 1B). Systemic inflammatory remission was achieved in all patients; however, remission and relapse occurred often in patients with infections or stress. At 12 months, systemic inflammatory remission had been achieved in 46% of the patients compared to 50% at 24 months, 58% at 36 months, and 65% at 60 months.

Patients with growth below the 3rd percentile at baseline showed the largest percentile increases, indicating catch up growth at 36 months and 60 months (P = 0.018 and P = 0.021, respectively, versus baseline). This was also observed for weight gain (P = 0.001 at 36 months and 60 months, versus baseline). Among the 16 patients taking corticosteroids at baseline, the mean daily prednisone equivalent dosage decreased from 0.80 mg/kg/day at baseline to 0.054 mg/kg/day at 36 months (P = 0.0052) and 0.033 mg/kg/day at 60 months (P = 0.021). Anakinra dosages ranged from 2 mg/kg/day to 4.5 mg/kg/day at 36 months, and from 2 mg/kg/day to 5 mg/kg/day at 60 months, with a slightly lower time of exposure at low dosages (defined as ≤2.5 mg/kg/day) (69.21 patient-years) compared to high dosages (defined as >2.5 mg/kg/day) (78.89 patient-years).

Secondary outcomes

CNS outcomes

At baseline, CNS organ damage and/or cognitive disabilities were seen in 18 of 24 patients. Four patients had prior strokes, 5 had seizures, and 10 had cognitive impairment (IQ <80). MRI evidence of permanent CNS organ damage in 17 patients included ventriculomegaly, ventriculoperitoneal shunts, brain atrophy, and arachnoid adhesions (Table 1).

Indicators of active CNS inflammation, including CSF leukocyte count and elevated opening pressure, decreased significantly at the study end points 36 and 60 months compared to baseline (P = 0.0026 and P = 0.0076, respectively, for CSF WBC count and P = 0.0012 and P < 0.001, respectively, for opening pressure) (Figure 2A). Abnormal CSF leukocyte and opening pressure values were frequently seen in the setting of normal blood inflammatory marker values. Of the 11 patients (of 25 assessed) with elevated CSF leukocyte count at 36 months, 7 had normal CRP values, and of the 12 patients (of 24 assessed) with elevated opening pressure at 36 months, 4 had normal serum CRP values. Of the 21 patients (88% of the 24 assessed) with elevated intracranial pressure at baseline, all but 3 showed decreases at both 36 and 60 months. Mean CSF protein levels also decreased significantly, from 45.5 mg/dl at baseline to 35.9 mg/dl at 36 months (P = 0.026) and 41.2 mg/dl at 60 months (P = 0.80).

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. ...

No further significant decreases were seen in mean CSF leukocyte count, opening pressure, or protein level from 36 months to 60 months. The majority of the patients with abnormal CSF leukocyte count or opening pressure underwent dose escalation. Seven of 9 patients with elevated CSF leukocyte count at 36 months and 9 of 10 patients with elevated opening pressure at 36 months improved at 60 months. Of the 5 patients with elevated CSF leukocyte count at 60 months, 3 were receiving the maximum IRB-approved anakinra dosage of 5 mg/kg daily. Despite significant decreases in opening pressure with treatment, acetazolamide treatment was still required in 13 of the 26 patients at 36 months and in 9 of the 20 patients at 60 months.

Leptomeningeal enhancement on FLAIR MRI (Figure 2B) was present in 10 of the 26 patients at baseline but was less sensitive in indicating CNS inflammation than the CNS WBC count, which was elevated in all patients at baseline. The number of patients with leptomeningeal enhancement decreased to 3 of 26 patients at 36 months (P = 0.039) and 1 of 20 patients at 60 months (P = 0.016). Patients with leptomeningeal enhancement at baseline had significantly higher CSF albumin levels compared to patients without enhancement (P = 0.039). The improvements in leptomeningeal enhancement, albumin, and albumin quotient without changes in the IgG index (data not shown) at 36 months and 60 months suggest improvement of the blood–brain barrier leak with treatment (P = 0.0044 and P = 0.016, respectively). Mean IQ levels did not significantly change from baseline to either 36 months or 60 months.

Hearing outcomes

The majority of the patients, 18 of 26, had at least mild hearing loss in 1 ear at baseline (Table 1). Hearing loss correlated with older age (Spearman’s ρ = 0.52, P = 0.021) and was most pronounced at higher frequencies (4,000 Hz and 8,000 Hz). However, hearing loss was observed at all frequencies (see Supplementary Figures 2A and B, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131).

Improvement in hearing occurred in 30% of ears, and progression of hearing loss was halted in the majority of the patients. In ears with progressive hearing loss (9 of 44) at 36 months, hearing loss was present at baseline and the progression occurred mostly during the first 3 years of treatment. Between 36 months and 60 months, hearing worsened in 4 additional ears (Figure 3A). Patients with worsened hearing had a higher mean CRP level over the first 36 months of the study (P = 0.017). One patient with severe hearing loss at baseline and progressive hearing loss during the study successfully received a cochlear implant at month 50.

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 ...

Cochlear enhancement on gadolinium-enhanced MRI (Figure 3B) was seen in 22 of 25 patients at baseline, indicating an inflammatory origin of the hearing loss. Cochlear enhancement persisted in 14 of 25 patients at 36 months (P = 0.0078) and in 10 of 19 patients at 60 months (P = 0.031). However, the mean cochlear enhancement scores improved significantly (see Supplementary Figure 2C, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131). Interestingly, mean cochlear enhancement scores were predictive of hearing loss, with higher scores observed for ears with progressive hearing loss compared to those ears with stable or improved hearing (Figure 3C). Mean cochlear enhancement scores were significantly correlated with the degree of hearing loss (see Supplementary Figure 2D, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/ (ISSN)1529–0131).

All 4 very young children who were younger than 20 months of age at enrollment had inner ear enhancement at baseline and normal hearing at their last recorded followup visit: 1 child at 48 months and 3 children at 60 months (Figure 3A, green dots) with 3 of the 4 showing resolution of inner ear enhancement on MRI at 36 months and 60 months.

Vision outcomes

At baseline, decreased visual acuity was present in at least 1 eye in 8 of the 26 patients, and 5 eyes of 3 patients were legally blind. Peripheral vision abnormalities were seen in 12 of the 18 patients able to perform testing, and 3 had severely reduced visual fields at baseline (Table 1). Nine patients had optic nerve atrophy. Of the 9 patients with optic pallor at baseline, 1 had trace, 5 had mild to moderate, and 3 had severe optic nerve atrophy. Other forms of eye damage were seen in 15 of the 26 patients (Table 1).

Inflammatory eye manifestations included conjunctivitis (in 25 of 26 patients), anterior uveitis (in 11 of 26 patients), posterior uveitis (in 2 of 26 patients), and papilledema (in 22 of 26 patients). Of the 4 patients without papilledema on baseline examination, 2 patients had severe optic nerve atrophy and did not have sufficient nerve fiber mass to mount papilledema, and 1 patient had posterior uveitis, which interfered with an adequate visual assessment of the optic nerve. Patient diary scores for conjunctivitis and papilledema scores on eye examination significantly decreased from baseline to 36 months and remained low at 60 months (Figure 4A). Papilledema resolved in all but 2 of 26 patients at 36 months and in all but 1 of 20 patients at 60 months, and at 60 months the affected patient had only mild papilledema. Anterior and posterior uveitis resolved in all patients; 1 patient with posterior uveitis was left with retinal scaring and blindness in the affected eye.

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 ...

Visual acuity and peripheral vision improved or stabilized in most patients over 5 years. One patient had worsening of visual acuity, and 2 other patients had worsening of peripheral vision in the absence of clinically detectable intraocular inflammation. All 3 of these patients had severely atrophic nerves at baseline. Both patients with worsening of peripheral vision presented with significant nerve fiber loss at baseline, suggesting that nerve fiber loss is an indicator of continued functional loss. Reduced peripheral vision correlated with reduced optic nerve thickness with an optic nerve fiber mass of <80μ on optical coherence tomography (OCT), showing a linear correlation with peripheral vision loss (Figure 4B). The 4 children who were younger than 20 months of age at enrollment had normal OCT measurements when measurements could first be obtained, suggesting that optic nerve fiber mass was preserved in patients receiving treatment who did not have optic nerve fiber loss at baseline.

Bone outcomes

Bony overgrowth was present in 10 of 26 patients; some patients had joint contractures and limb length discrepancy (Table 1). Despite anakinra therapy, the volume of the bony lesions increased significantly. In 4 patients with open growth plates and paired MRIs, the mean lesion volume increased at 3 months, at 12 months, and at 36 months (P <0.05 for all analyses). In patients with unilateral bone lesions with a contra-lateral unaffected bone, the longitudinal growth of the affected bone was less than the growth of the unaffected bone, leading to limb length discrepancies. No new bone lesions developed in patients while they were receiving anakinra therapy.

Outcomes in mutation-positive versus mutation-negative patients

The distinction of mutation-positive versus mutation-negative is dependent on the method of sequencing. By the Sanger method of sequencing, 21 patients were mutation positive, and 5 were mutation negative. Subsequent analysis with deep sequencing and subcloning techniques showed that 4 of the 5 mutation-negative patients had evidence of mosaicism (17). No differences were observed between patients who were mutation positive and those who were mutation negative, as determined by Sanger method, at 36 months or 60 months in terms of anakinra dose requirements or response to treatment as measured by inflammatory markers (CRP level, SAA, and ESR), global measures of disease activity, CSF leukocyte count and opening pressure, visual field mean deviation scores, or 4-frequency pure-tone average (4F-PTA) measurements of hearing loss.

Medication dosing, pharmacokinetics, and safety

Over the study period, the anakinra dosages that were required to maintain clinical remission ranged from 2 mg/kg/day to 5 mg/kg/day. The maximum dosage was required in 4 of 20 patients at 60 months. Drug exposure (area under the plasma concentration curve) increased linearly in proportion to the anakinra dose.

Over the 148.1 patient-year study period, no dose-limiting toxicity was observed; however, viral upper respiratory infections, gastroenteritis, otitis media, and urinary tract infections were frequent (Table 2). The infection rate did not show a dose-dependent difference in patients treated with anakinra ≤2.5 mg/kg/day compared to patients treated with anakinra >2.5 mg/kg/day. Five episodes of suspected viral pneumonia occurred in 3 patients receiving higher dosages, a finding that warrants followup. Injection site reactions occurred frequently. No malignancies were observed, and no patient discontinued the study drug. The mean ± SEM glomerular filtration rate did not change from 0 months to 36 months to 60 months, with values of 120.7 ± 44.6, 123.7 ± 46.8, and 115 ± 33.1, respectively.

Table 2
Cumulative adverse event summary*

Six serious adverse events were thought to be possibly related to the study drug. These included 2 wound infections, an episode of macrophage activation syndrome (MAS), posttraumatic hypopyon, vertigo, and gastroenteritis. Anakinra was not discontinued in any patient or during infections. The patient who developed MAS had 2 episodes of MAS before starting anakinra and 2 episodes while receiving anakinra.

DISCUSSION

NOMID is a systemic autoinflammatory disease caused by gain-of-function mutations in NLRP3 that illustrates the effects of increased IL-1 levels on organ inflammation and damage in human disease. The life-changing impact of treatment with IL-1–blocking therapies confirms the important role of IL-1β in the pathogenesis of not only NOMID and the clinically milder forms of CAPS (813), but also other IL-1–mediated diseases, including gout (1820) and Still’s disease (21,22).

Herein, we present data indicating that 36 months or 60 months of IL-1–blocking therapy leads to sustained improvement of symptoms and serum markers of inflammation, reduction in manifestations due to organ inflammation, and stabilization of organ function in patients with NOMID. We suggest that anakinra doses need aggressive, individual adjustments to achieve control of inflammation and describe modalities to monitor CNS, inner ear, and eye disease in NOMID patients with severe disease.

The irreversible organ damage that develops in patients with untreated NOMID, which is largely absent in patients with the milder forms of CAPS, is a consequence of chronic organ inflammation. In most patients in our study, the progression of organ damage was halted, and organ function (hearing, vision, and cognition) was preserved. A small subset of patients had further hearing loss and vision impairment and, notably, progression in bone lesion size was seen in all patients who had nonossified lesions at study enrollment.

Although hearing improvement was seen in 30% of ears early in the course of treatment, patients with severe hearing loss at baseline typically did not show improvement, likely due to irreversible cochlear damage from prior inflammation. Cochlear enhancement as visualized on MRI at baseline and during the study was most pronounced in patients with severe hearing loss at baseline and in ears with progressive hearing loss, suggesting that inner ear enhancement on MRI may be predictive of further hearing loss. Higher CSF leukocyte values at baseline were associated with the development of hearing loss (data not shown). However, since hearing loss and cochlear enhancement are often asymmetric, local factors at the tissue level must also be important.

Visual acuity and peripheral vision were preserved in most patients. Improvements in visual acuity from baseline were judged to be due to resolution of papilledema and a possible learning factor in testing. Progressive optic nerve atrophy, a known consequence of chronically increased intracranial pressure (23), is the main cause of vision loss in patients with NOMID. Other, rare causes include scarring from posterior uveitis and corneal clouding. We observed progressive vision loss in 2 patients receiving treatment. Both of these patients had severely reduced optic nerve fiber mass at baseline and no evidence of ocular inflammation during the study. Optic nerve thickness measurements obtained before the initiation of anakinra treatment may thus identify patients at risk of vision loss, and may be useful in monitoring the optic nerve during treatment.

Headaches and CSF leukocytosis improved dramatically during anakinra treatment, but low-grade CNS inflammation persisted in some patients without headaches and in the presence of normal serum CRP values. Although the consequences of low-grade CNS inflammation over time are not known, we have observed reduction in WBC counts and opening pressure with further anakinra dose escalation. Given that dose-dependent increases in anakinra concentration in the CNS have been measured in nonhuman primates (24), we advocate increasing doses of IL-1–blocking agents to attempt to achieve remission of CNS inflammation. At this point we do not know whether persistently elevated opening pressure in the absence of measureable CNS inflammation would respond to further increases in anakinra; this will be addressed in future studies.

Bone lesions present at baseline continue to grow during therapy. Biopsy specimens of these lesions are void of inflammatory cells, and cells from these lesions have an osteoblast progenitor cell phenotype that is also seen in fibroblastoid tumors, with IL-1–independent proliferation (25).

Anakinra dose escalation was necessary to control inflammation. The criteria of dose escalation evolved during the study from initial dose increases for clinical symptoms and elevated CRP levels to increases based on persistent organ inflammation of the eyes, inner ear, and CNS, given evidence of organ inflammation in patients who at the time of examination had no symptoms and normal acute-phase reactant levels. We have used CRP levels rather than SAA levels to define systemic inflammatory remission since they are highly correlated (data not shown) and reliable SAA measurements were unavailable after June 2009.

Whether the rapid response to anakinra can also be attributed to its ability to block both IL-1α and IL-1β is currently not known; however, CAPS patients respond to treatment with specific IL-1β blockade (13). There are a number of triggers, including IL-1α, lipopolysaccharide, ATP, and monosodium urate monohydrate released by dying cells, that are potential stimulators of the inflammasome in vivo, but we have no data at this point regarding their relative contribution to promoting the exaggerated inflammasome activation in patients with NLRP3 mutations. Interestingly, temporary dose increases during active infections or surgery are frequently necessary since patients can develop flares while receiving anakinra in these situations, suggesting that the exaggerated IL-1 response in the context of infections and other stressors remains in treated patients.

Limitations of this study include the open-label treatment study design, which is ethically necessary given the proven efficacy of IL-1 inhibition for the severe clinical manifestations of NOMID. As such, the rates of organ damage progression in untreated patients were not measured, but historical data and our organ damage assessment at the initiation of the study provide cross-sectional data on hearing, vision, and cognitive impairment. Optimal doses of anakinra to control inflammation in patients with NOMID were unknown at the initiation of the study. Therefore, anakinra dose escalation occurred more slowly in the initially enrolled patients until IRB approval was obtained for doses of up to 5 mg/kg. Given the progression of hearing loss in some patients with inner ear inflammation in the first 3 years of the study when the anakinra doses were still lower, we favor a rapid dose-escalation schedule with titration to control systemic as well as organ-specific inflammation, with the goal of achieving systemic inflammatory remission and the absence of organ inflammation.

Our data, including the absence of any hearing or vision loss in the 4 youngest children who began treatment before the age of 2 years, raise the hope that organ damage can be prevented with the initiation of treatment at early time points (before the development of organ damage). Our findings emphasize the importance of early diagnosis and aggressive treatment in patients with severe disease.

Dysregulation of IL-1 contributes to the pathology of genetically complex disorders such as gout (18), Behçet’s disease (26,27), diabetes mellitus (28), Alzheimer’s disease (29), and atherosclerosis (30,31). Insight gained through the study of patients with NOMID may not only help in elucidating the inflammatory pathogenesis of these disorders and other eye and hearing conditions but may also guide rational therapeutic approaches in these conditions.

Supplementary Material

Supplemental figure 1

Supplemental figure 2

Supplementary Data

Acknowledgments

The authors would like to thank Dr. Phil Hawkins for measurements of the serum amyloid A levels, Hang Pham for sample management, and Bahar Afshar for help with data collection. The authors would also like to thank the following referring physicians for their ongoing support and collaboration in this study: Dr. Barbara Adams, Dr. Laurie Beitz, Dr. Susan Boyer, Dr. Ruy Carrasco, Dr. Peter Dent, Dr. Robert Fuhlbrigge, Dr. Amnon Goodman, Dr. Brandt Groh, Dr. William Hannon, Dr. Hal Hoffman, Dr. James Jarvis, Dr. Phillip Khan, Dr. Raju Khubhchandani, Dr. Daniel Kingsbury, Dr. Thomas Klausmeier, Dr. Ronald Laxer, Dr. Robert Listernick, Dr. Diana Milojevic, Dr. Terry Moore, Dr. Laura Schanberg, Dr. Rayfel Schneider, Dr. Bracha Shaham, Dr. Michael Shishov, Dr. Leonard Stein, Dr. Richard Vehe, Dr. Maria Vitoria Quintero, Dr. Robert Warren, and Dr. Elivette Zambrana. Last, but not least, the authors thank the parents and their families for their longstanding participation in this study.

Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. Portions of the work were supported in part by the Intramural Research Programs of the National Cancer Institute, the National Institute on Deafness and Other Communication Disorders, the National Eye Institute, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the NIH Clinical Center.

Dr. Goldbach-Mansky has received grant support from Regeneron, Novartis, and Swedish Orphan Biovitrum AB.

Footnotes

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Goldbach-Mansky had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Wiggs, Brewer, Zalewski, Kim, Paul, Pucino, Wesley, Goldbach-Mansky.

Acquisition of data. Sibley, Plass, Snow, Wiggs, Brewer, King, Zalewski, Kim, Bishop, Hill, Paul, Kicker, Phillips, Dolan, Stone, Chapelle, Butman, Goldbach-Mansky.

Analysis and interpretation of data. Sibley, Plass, Snow, Brewer, King, Zalewski, Kim, Bishop, Paul, Kicker, Widemann, Jayaprakash, Pucino, Chapelle, Snyder, Butman, Wesley, Goldbach-Mansky.

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