ABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Cryopyrin-Associated Periodic Syndromes/drug therapy , Interleukin-1beta/antagonists & inhibitors , Adolescent , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , C-Reactive Protein/metabolism , Cerebrospinal Fluid/cytology , Child , Cryopyrin-Associated Periodic Syndromes/complications , Cryopyrin-Associated Periodic Syndromes/metabolism , Female , Headache/drug therapy , Headache/etiology , Humans , Leukocyte Count , Male , Remission Induction , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Antirheumatic Agents/therapeutic use , Cryopyrin-Associated Periodic Syndromes/drug therapy , Disease Progression , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Adolescent , Adult , Antirheumatic Agents/administration & dosage , C-Reactive Protein , Child , Child, Preschool , Cryopyrin-Associated Periodic Syndromes/pathology , Female , Humans , Infant , Infant, Newborn , Inflammation/drug therapy , Inflammation/pathology , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Male , Surveys and Questionnaires , Treatment OutcomeABSTRACT
BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Autoimmune Diseases/genetics , Inflammation/immunology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Interleukin-1/antagonists & inhibitors , Autoimmune Diseases/drug therapy , Base Sequence , Child , Female , Genes, Recessive , Homozygote , Humans , Infant , Infant, Newborn , Inflammation/drug therapy , Inflammation/genetics , Interleukin 1 Receptor Antagonist Protein/deficiency , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-1/genetics , Interleukin-1/physiology , Interleukin-1beta/antagonists & inhibitors , Male , Mutation , Pedigree , RNA, Messenger/metabolismABSTRACT
BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.
Subject(s)
Azetidines/therapeutic use , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/immunology , Inflammation/drug therapy , Inflammation/immunology , Interferons/antagonists & inhibitors , Interferons/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Adolescent , Azetidines/administration & dosage , Azetidines/adverse effects , Child , Child, Preschool , Cohort Studies , Compassionate Use Trials , Female , Hereditary Autoinflammatory Diseases/enzymology , Humans , Infant , Inflammation/enzymology , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Male , Prospective Studies , Purines , Pyrazoles , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID.
ABSTRACT
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.
Subject(s)
Blood-Brain Barrier/metabolism , Cryopyrin-Associated Periodic Syndromes/cerebrospinal fluid , Cytokines/metabolism , Meningitis, Aseptic/cerebrospinal fluid , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antirheumatic Agents/therapeutic use , Biomarkers/cerebrospinal fluid , Child, Preschool , Cryopyrin-Associated Periodic Syndromes/drug therapy , Cytokines/cerebrospinal fluid , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Meningitis, Aseptic/drug therapy , Treatment OutcomeABSTRACT
Autosomal recessive mutations in proteasome subunit ß 8 (PSMB8), which encodes the inducible proteasome subunit ß5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes ß7), PSMB9 (encodes ß1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.
Subject(s)
Hereditary Autoinflammatory Diseases/genetics , Interferon Type I/biosynthesis , Lipodystrophy/genetics , Mutation , Proteasome Endopeptidase Complex/genetics , Amino Acid Sequence , Cells, Cultured , Fibroblasts , Gene Expression Regulation , Genotype , Hereditary Autoinflammatory Diseases/immunology , Hereditary Autoinflammatory Diseases/metabolism , Humans , Interferon Type I/genetics , Lipodystrophy/immunology , Lipodystrophy/metabolism , Models, Molecular , Molecular Chaperones/genetics , Molecular Sequence Data , Mutation, Missense , Pedigree , Phenotype , Protein Conformation , Protein Subunits , RNA Interference , RNA, Small Interfering/genetics , Sequence Alignment , Sequence Deletion , Sequence Homology, Amino Acid , Syndrome , Transcription, GeneticABSTRACT
Objective: To describe the pregnancy course and outcome, and use of anakinra, a recombinant selective IL-1 receptor blocker, during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multi-system inflammatory disease (NOMID). Methods: Women currently enrolled in natural history protocols (NCT00059748, and/or NCT00069329 under IND) who have been pregnant were included. Subjects underwent a structured, standardized interview with regards to maternal health, pregnancy and fetal outcomes. Medical records were reviewed. Results: Nine women (four with FCAS, one with MWS and four with NOMID) reported one to four pregnancies, each resulting in a total of fifteen FCAS, three MWS, and six NOMID pregnancies. Six births from FCAS mothers and three births from NOMID mothers occurred while patients were receiving anakinra. If a woman became pregnant while taking anakinra, the pre-pregnancy anakinra dose was continued. Anakinra dose was increased during one twin pregnancy. No preterm births or serious complications of pregnancy were observed. One fetus of the twin pregnancy had renal agenesis and suffered fetal demise. Genetic testing showed the deceased twin carried the same NLRP3 c.785T>C, p.V262A mutation as the mother. The other twin is healthy and mutation negative. Conclusions: Anakinra was continued during pregnancy in women with CAPS and provided significant, persistent CAPS symptom relief while continuing to prevent the long-term sequelae of CAPS. Anakinra was well tolerated. Although a causal relation between anakinra and renal agenesis seems unlikely, further safety data are needed.
Subject(s)
Antirheumatic Agents/therapeutic use , Cryopyrin-Associated Periodic Syndromes/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Adult , Antirheumatic Agents/adverse effects , Clinical Protocols , Congenital Abnormalities , Female , Fetal Diseases/chemically induced , Humans , Interleukin 1 Receptor Antagonist Protein/adverse effects , Interviews as Topic , Kidney/abnormalities , Kidney Diseases/chemically induced , Kidney Diseases/congenital , Pregnancy , Pregnancy Outcome , Young AdultABSTRACT
Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1ß and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1ß oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1ß and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.