RESUMEN
OBJECTIVE: To identify commonalities in gene expression data across all antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) tissues thus far characterized. METHODS: Gene expression data were collected from the 3 AAV tissues thus far characterized (orbit, peripheral leukocytes, and sinus brushings). These data were analyzed to identify commonly expressed genes and disease pathways. The pathways data were adjusted for multiple comparisons using a combined local false discovery rate, which estimates the probability of a false discovery of a given pathway in all 3 tissues analyzed. RESULTS: Only 4 genes were upregulated in all 3 tissues - IL1RN, TLR2, SLC11A1, and MMP9. After multiple comparison adjustments, the network pathway analysis revealed 28 pathways associated with all 3 tissues. The most strongly associated pathway for all 3 tissues was the neutrophil degranulation pathway [multidimensional local false discovery (md-locfdr) = 1.05 × 10-12], followed by the osteoclast differentiation (md-locfdr = 3.8 × 10-05), cell surface interactions at the vascular wall (md-locfdr = 4.2 × 10-04), signaling by interleukins (md-locfdr = 6.1 × 10-04), and phagosome (md-locfdr = 0.003) pathways. There were no downregulated genes or pathways common to all 3 tissues. CONCLUSION: This analysis identified individual genes and pathways of disease common to all AAV tissues thus far characterized. The use of a network pathway analysis allowed us to identify pathologic mechanisms that were not readily apparent in the commonly expressed genes alone. Many of these pathways are consistent with current theories about infectious drivers and the crossroads of innate and adaptive immune mechanisms. In addition, this analysis highlights novel pathways, such as vessel wall interactions and platelet activation, which require further investigation.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Regulación de la Expresión Génica , Regulación hacia Arriba , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Humanos , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismoRESUMEN
Importance: Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies. Objective: To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups. Design, Setting, and Participants: In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017. Main Outcomes and Measures: The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis. Results: Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores. Conclusions and Relevance: Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.
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Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Enfermedades del Aparato Lagrimal/genética , Aparato Lagrimal/metabolismo , Seudotumor Orbitario/genética , ARN/genética , Adulto , Biopsia , Femenino , Marcadores Genéticos/genética , Humanos , Aparato Lagrimal/patología , Enfermedades del Aparato Lagrimal/etiología , Enfermedades del Aparato Lagrimal/patología , Masculino , Seudotumor Orbitario/complicaciones , Seudotumor Orbitario/patología , Estudios Retrospectivos , Análisis de Matrices Tisulares/métodosRESUMEN
BACKGROUND: The effect of IL-1 blocking therapy on mucocutaneous manifestations of Behçet's disease is incompletely understood. METHODS: Six patients with Behçet's disease and ongoing oral/genital ulcers for ≥1 month were enrolled into an adaptive, two-phase clinical trial and included in the analysis. Study duration was 6 months with extension up to 16 months. All were treated non-blinded with anakinra 100 mg subcutaneous daily with the option to escalate the dose to 200 mg in partial responders after 1 month and 300 mg after 6 months. Patients recorded the number and severity of ulcers in daily diaries. The primary outcome was remission defined as no ulcers on physical exam for two consecutive monthly visits between months 3 and 6. Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores. RESULTS: Two of six patients achieved the primary outcome. Five of six patients had improvement in the number and severity of ulcers. Non-statistically significant improvements were seen in secondary outcomes. Over the entire study, patients reported ≥1 oral and ≥1 genital ulcer on 665 (66%) and 139 (14%) days, respectively. On anakinra 200 mg vs 100 mg, patients reported fewer days with oral ulcers (65% vs 74% of days, p = 0.01) and genital ulcers (10% vs 22% of days, p < 0.001) and milder oral ulcer severity (p < 0.001). Increase of anakinra to 300 mg did not result in further improvements. Adverse events were notable for mild infections. CONCLUSION: Anakinra at an optimal dose of 200 mg daily had an acceptable safety profile and was partially effective in the treatment of resistant oral and genital ulcers in Behçet's disease. TRIAL REGISTRATION: Clinicaltrials.gov. NCT01441076 . Registered on 24 September 2011.
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Antirreumáticos/uso terapéutico , Síndrome de Behçet/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Úlcera/tratamiento farmacológico , Adulto , Síndrome de Behçet/complicaciones , Femenino , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Enfermedades de los Genitales Femeninos/etiología , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Enfermedades de los Genitales Masculinos/etiología , Humanos , Masculino , Persona de Mediana Edad , Úlceras Bucales/tratamiento farmacológico , Úlceras Bucales/etiología , Proyectos Piloto , Úlcera/etiología , Adulto JovenRESUMEN
OBJECTIVE: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers-anakinra and canakinumab. METHODS: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3-5-year follow-up visits and compared them to samples from healthy controls. RESULTS: CSF levels of IL-6, interferon-γ-inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood-brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. CONCLUSION: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood-brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.
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Barrera Hematoencefálica/metabolismo , Síndromes Periódicos Asociados a Criopirina/líquido cefalorraquídeo , Citocinas/metabolismo , Meningitis Aséptica/líquido cefalorraquídeo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antirreumáticos/uso terapéutico , Biomarcadores/líquido cefalorraquídeo , Preescolar , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Citocinas/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Masculino , Meningitis Aséptica/tratamiento farmacológico , Resultado del TratamientoRESUMEN
HLA-B27 associated disorders comprise a group of inflammatory conditions which have in common an association with the HLA class I molecule, HLA-B27. Given this association, these diseases are classically considered disorders of adaptive immunity. However, mounting data are challenging this assumption and confirming that innate immunity plays a more prominent role in pathogenesis than previously suspected. In this review, the concept of autoinflammation is discussed and evidence is presented from human and animal models to support a key role for innate immunity in HLA-B27 associated disorders.
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Presentación de Antígeno/inmunología , Antígeno HLA-B27/sangre , Inmunidad Innata/fisiología , Espondiloartritis/inmunología , Uveítis Anterior/inmunología , HumanosRESUMEN
PURPOSE OF REVIEW: Ophthalmologists and rheumatologists frequently have a miscommunication among themselves, and as a result differ in their opinion for patients consulting them with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent studies on this diagnosis. RECENT FINDINGS: The genetic basis of some rare forms of retinal vascular disease has recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; Behçet's disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; retinal imaging, including fluorescein angiography and other newer imaging modalities, has proven crucial to the identification and characterization of retinal vasculitis and its complications; although monoclonal antibodies to interleukin-17A or interleukin-1 beta failed in trials for Behçet's disease, antibodies to TNF-alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B-cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. SUMMARY: Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behçet's disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of noninfectious retinal vasculitis may require alternate therapeutic management.
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Manejo de la Enfermedad , Terapia de Inmunosupresión/métodos , Vasculitis Retiniana , Vasos Retinianos/diagnóstico por imagen , Enfermedades Reumáticas/complicaciones , Angiografía con Fluoresceína , Fondo de Ojo , Humanos , Vasculitis Retiniana/diagnóstico , Vasculitis Retiniana/etiología , Vasculitis Retiniana/terapiaRESUMEN
The effort to subdivide diseases and to individualize therapies based on characteristics of the patient has been labeled precision medicine. Jameson and Longo define precision medicine as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations" (Jameson and Longo, 2015). We illustrate how molecular diagnosis can be applied to orbital inflammatory disease to achieve the goals of precision medicine.
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Técnicas de Diagnóstico Molecular/métodos , Enfermedades Orbitales/diagnóstico , Biopsia , Diagnóstico Diferencial , Perfilación de la Expresión Génica/métodos , Humanos , Oftalmología/métodos , Medicina de Precisión/métodosRESUMEN
Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n=20) and patients with GPA (n=6), NSOI (n=25), sarcoidosis (n=7), or thyroid eye disease (TED) (n=20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays. Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>1.5-fold difference, false discovery rate adjusted p<0.05). The immunoglobulin family of genes had the most dramatic increase in expression. Although gene expression in GPA could be readily distinguished from gene expression in TED, sarcoidosis, or controls, a comparison of gene expression in GPA versus NSOI found no statistically significant differences. Thus, forms of orbital inflammation can be distinguished based on gene expression. NSOI/pseudotumor is heterogeneous but often may be an unrecognized, localized form of GPA.
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Biomarcadores/metabolismo , Perfilación de la Expresión Génica , Granulomatosis con Poliangitis/genética , Oftalmopatía de Graves/genética , Inflamación/genética , Seudotumor Orbitario/genética , Sarcoidosis/genética , Adulto , Estudios de Casos y Controles , Femenino , Granulomatosis con Poliangitis/patología , Oftalmopatía de Graves/patología , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Seudotumor Orbitario/patología , Sarcoidosis/patologíaRESUMEN
IMPORTANCE: Sarcoidosis is a major cause of ocular or periocular inflammation. The pathogenesis of sarcoidosis is incompletely understood and diagnosis often requires a biopsy. OBJECTIVE: To determine how gene expression in either orbital adipose tissue or the lacrimal gland affected by sarcoidosis compares with gene expression in other causes of orbital disease and how gene expression in tissue affected by sarcoidosis compares with gene expression in peripheral blood samples obtained from patients with sarcoidosis. DESIGN, SETTING, AND PARTICIPANTS: In a multicenter, international, observational study, gene expression profiling of formalin-fixed biopsy specimens, using GeneChipp U133 Plus 2 microarrays (Affymetrix), was conducted between October 2012 and January 2014 on tissues biopsied from January 2000 through June 2013. Participants included 12 patients with orbital sarcoidosis (7 in adipose tissue; 5 affecting the lacrimal gland) as well as comparable tissue from 6 healthy individuals serving as controls or patients with thyroid eye disease, nonspecific orbital inflammation, or granulomatosis with polyangiitis. In addition, results were compared with gene expression in peripheral blood samples obtained from 12 historical individuals with sarcoidosis. MAIN OUTCOMES AND MEASURES: Significantly differentially expressed transcripts defined as a minimum of a 1.5-fold increase or a comparable decrease and a false discovery rate of P < .05. RESULTS: Signals from 2449 probe sets (transcripts from approximately 1522 genes) were significantly increased in the orbital adipose tissue from patients with sarcoidosis. Signals from 4050 probe sets (approximately 2619 genes) were significantly decreased. Signals from 3069 probe sets (approximately 2001 genes) were significantly higher and 3320 (approximately 2283 genes) were significantly lower in the lacrimal gland for patients with sarcoidosis. Ninety-two probe sets (approximately 69 genes) had significantly elevated signals and 67 probe sets (approximately 56 genes) had significantly lower signals in both orbital tissues and in peripheral blood from patients with sarcoidosis. The transcription factors, interferon-response factor 1, interferon-response factor 2, and nuclear factor κB, were strongly implicated in the expression of messenger RNA upregulated in common in the 3 tissues. CONCLUSIONS AND RELEVANCE: Gene expression in sarcoidosis involving the orbit or lacrimal gland can be distinguished from gene expression patterns in control tissue and overlaps with many transcripts upregulated or downregulated in the peripheral blood of patients with sarcoidosis. These observations suggest that common pathogenic mechanisms contribute to sarcoidosis in different sites. The observations support the hypothesis that a pattern of gene expression profiles could provide diagnostic information in patients with sarcoidosis.
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Oftalmopatías/diagnóstico , Oftalmopatías/genética , Perfilación de la Expresión Génica/métodos , Sarcoidosis/diagnóstico , Sarcoidosis/genética , Tejido Adiposo/patología , Adulto , Anciano , Biopsia con Aguja , Estudios de Casos y Controles , Oftalmopatías/sangre , Femenino , Regulación de la Expresión Génica , Humanos , Internacionalidad , Aparato Lagrimal/patología , Masculino , Persona de Mediana Edad , Órbita , ARN Mensajero/genética , Valores de Referencia , Sarcoidosis/sangre , Sarcoidosis/patología , Sensibilidad y Especificidad , Regulación hacia ArribaRESUMEN
Orbital inflammatory diseases include thyroid eye disease (TED), granulomatosis with polyangiitis (GPA), sarcoidosis, and nonspecific orbital inflammation (NSOI). Histopathological diagnosis usually relies on the clinical context and is not always definitive. Gene expression profiling provides diagnostic and therapeutic information in several malignancies, but its role in evaluating nonmalignant disease is relatively untested. We hypothesized that gene expression profiling could provide diagnostic information for NSOI. We collected formalin-fixed, paraffin-embedded orbital biopsies from 10 institutions and 83 subjects including 25 with thyroid eye disease, 25 nonspecific orbital inflammation, 20 healthy controls, 6 with granulomatosis with polyangiitis, and 7 with sarcoidosis. Tissues were divided into discovery and validation sets. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays. A random forest statistical algorithm based on data from 39 probe sets identified controls, GPA, or TED with an average accuracy of 76% (p=0.02). Random forest analysis indicated that 52% of tissues from patients with nonspecific inflammation were consistent with a diagnosis of GPA. Molecular diagnosis by gene expression profiling will augment clinical data and histopathology in differentiating forms of orbital inflammatory disease.
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Granulomatosis con Poliangitis/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Seudotumor Orbitario/diagnóstico , Sarcoidosis/diagnóstico , Perfilación de la Expresión Génica , Granulomatosis con Poliangitis/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Órbita/patología , Seudotumor Orbitario/genética , Sarcoidosis/genéticaRESUMEN
Cryoglobulins are immunoglobulins that precipitate at temperatures less than 37°C. They occur secondary to infectious, autoimmune, and malignant processes. In the Brouet classification, type I cryoglobulinemia is caused by hyperviscosity, whereas type II and III manifestations are caused by vasculitis in target organs (primarily skin, peripheral nerves, and kidney). New classification criteria were recently proposed that may help with study and treatment of cryoglobulinemic vasculitis (CryoVas). Hepatitis C virus is the most common cause of CryoVas and treatment with antivirals can be curative in mild cases, whereas rituximab is highly effective in treating active vasculitis in more severe cases.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antirreumáticos/uso terapéutico , Crioglobulinemia/tratamiento farmacológico , Crioglobulinemia/diagnóstico , Crioglobulinemia/etiología , Hepatitis C/complicaciones , Humanos , RituximabRESUMEN
OBJECTIVE: To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1ß monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID). METHODS: 6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150â mg (or 2â mg/kg in patients ≤40â kg) or 300â mg (or 4â mg/kg) with escalation up to 600â mg (or 8â mg/kg) every 4â weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6. RESULTS: All patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred. CONCLUSIONS: Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed. CLINICALTRIALSGOV IDENTIFIER: NCT00770601.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Interleucina-1beta/antagonistas & inhibidores , Adolescente , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Proteína C-Reactiva/metabolismo , Líquido Cefalorraquídeo/citología , Niño , Síndromes Periódicos Asociados a Criopirina/complicaciones , Síndromes Periódicos Asociados a Criopirina/metabolismo , Femenino , Cefalea/tratamiento farmacológico , Cefalea/etiología , Humanos , Recuento de Leucocitos , Masculino , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
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.