Dr. Lovell has received honoraria or consulting fees of less than $10,000 from Amgen, Inc. Dr. Solinger has stock ownership or stock options in Amgen, Inc.
Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease
Version of Record online: 7 APR 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 4, pages 1283–1286, April 2005
How to Cite
Lovell, D. J., Bowyer, S. L. and Solinger, A. M. (2005), Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease. Arthritis & Rheumatism, 52: 1283–1286. doi: 10.1002/art.20953
- Issue online: 7 APR 2005
- Version of Record online: 7 APR 2005
- Manuscript Accepted: 21 DEC 2004
- Manuscript Received: 28 JUL 2004
Neonatal-onset multisystem inflammatory disease (NOMID) is a rare, childhood-onset disease that is characterized by chronic, systemic inflammation. The purpose of this report is to describe the effects of interleukin-1 (IL-1) blockade on the clinical symptoms of 2 patients with NOMID. At the time of this report, the patients had been treated with anakinra (Kineret), a recombinant human IL-1 receptor antagonist, for 1.5 and 2 years, respectively. Both patients demonstrated rapid improvement in clinical symptoms and laboratory markers of inflammation. The use of anakinra in these patients seemed to be effective, without any safety concerns. These observations suggest that IL-1 plays a critical role in the pathogenesis of this inflammatory disease, and that blockade with anakinra should be further studied as a treatment for patients with NOMID and related disorders.
Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular syndrome) is a rare pediatric disease that represents the most severe form of a spectrum of autoinflammatory disorders. Other milder clinical syndromes include familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (1). Recent reports suggest that interleukin-1 (IL-1) may play an important role in the pathogenesis of NOMID. Mutations in CIAS1, the gene encoding the cryopyrin protein, which is a product of immune cells that is involved in processing of the proinflammatory cytokine IL-1β (2), have been documented in many (but not all) patients with NOMID, FCAS, and Muckle-Wells syndrome (2, 3), suggesting an etiologic role for CIAS1-related proteins in some cases. Blockade of IL-1β by the recombinant IL-1 receptor antagonist anakinra has been shown to rapidly and completely resolve the inflammatory symptoms in patients with Muckle-Wells syndrome (4, 5) and patients with NOMID (6). We now report sustained responses to anakinra in 2 patients with NOMID.
Patient 1, a 14-year-old boy, experienced chronic rash, daily intermittent fevers, generalized lymphadenopathy, moderate hepatomegaly (the liver edge was palpable 4 cm below the costal margin), significant splenomegaly (ultrasound demonstrated an enlarged spleen pushing down on the kidney), chronic aseptic meningitis, anemia, and an increase in the white blood cell (WBC) count and levels of acute-phase reactants, starting in the neonatal period. Moderate conductive hearing loss (bilateral) requiring use of hearing aids, developmental delay, hydrocephalus, cerebral atrophy, and poor growth also began in infancy. Loss of developmental milestones, chorea, ataxia, increased hearing loss (moderate to severe, requiring ongoing use of hearing aids bilaterally), and extreme emotional lability began at age 6 years. Persistent aseptic meningitis with increased intracranial pressure was also documented at this time. The duration of the increased intracranial pressure was unclear, because opening pressures had not been performed in prior lumbar punctures.
Ventriculoperitoneal shunting was performed at age 11 years. Serial magnetic resonance imaging (MRI) showed progressive loss of cerebral cortex. Treatment included use of nonsteroidal antiinflammatory drugs (NSAIDs), oral and intermittent intravenous steroids, methotrexate (MTX), etanercept, and infliximab. No improvement was observed with any of these antiinflammatory agents. Anakinra (1 mg/kg/day) was added to the regimen of prednisone (0.5 mg/kg/day), indomethacin (2.5 mg/kg/day), and MTX (0.7 mg/kg/day). The daily intermittent fevers and persistent rash that had been present since the neonatal period resolved completely within the first week of treatment with anakinra and have not returned. After 4 weeks of treatment with anakinra, obvious improvements in speech, attention span, and emotional lability were noted. During the next 9 months, serial MRI testing demonstrated no additional loss of cerebral cortex. During this 9-month period, the hearing loss, generalized lymphadenopathy, and hepatosplenomegaly gradually resolved completely. Over this period of time the MTX therapy was discontinued, and the prednisone dosage was reduced to 0.3 mg/kg/day. At the last visit, the patient had been receiving anakinra for 24 months, and the dosage at that visit was 1.5 mg/kg/day. The patient was tolerating the treatment without problems, and the dosage of prednisone had been tapered to 0.2 mg/kg/day without recurrence of rash, fever, joint pain, lymphadenopathy, hepatosplenomegaly, or hearing loss. This patient had been included in a prior study examining CIAS1 genetic sequences in patients with NOMID, and no mutations were found (7).
Patient 2, a 9-year-old girl, had experienced fevers, rash, lymphadenopathy, hepatosplenomegaly, and chronic aseptic meningitis since the neonatal period. Decreased vision with retinal cystoid macular edema was noted at age 3 years. She had experienced progressive sensorineural hearing loss. Progressive joint symptoms started before age 5 years, resulting in massive bilateral enlargement of the patellae. Previous medications included NSAIDs, colchicine, hydroxychloroquine sulfate, MTX, etanercept, infliximab, and steroid therapy continuously since elementary school. Reductions in the steroid dosages resulted in worsening of bone pain and headaches. With etanercept therapy, bone pain improved, and the steroid dosage was decreased to 5 mg/day, but etanercept was discontinued due to the presumed onset of septic arthritis. Severe serum sickness occurred with infliximab therapy. Anakinra therapy (1.5 mg/kg/day) was initiated at age 17 years and resulted in immediate resolution (within 1 week) of bone pain and rash. Eye inflammation and headaches resolved within 1 month. The prednisone dosage was subsequently reduced to 1.25 mg/day within 3 months, and MTX was discontinued. Her fevers, rashes, joint pain, headaches, lymphadenopathy, eye disease, hepatomegaly, and splenomegaly (4 cm and 3 cm, respectively, before anakinra treatment) have remained inactive throughout the 1.5 years of anakinra therapy. The patient's central nervous system (CNS) disease has stabilized, as demonstrated by her most recent MRI, which shows periventricular leukomalacia lesions that have decreased in size in the past 2 years. She has just completed her first year of college.
Skin, CNS, and joint symptoms in both patients were markedly improved following IL-1 blockade with anakinra. Significantly, laboratory test results showed improvement in the erythrocyte sedimentation rate in both patients, suggesting an impact of anakinra on systemic inflammation (Figure 1). The C-reactive protein (CRP) level, which was measured in patient 1, appeared to be unstable; levels of CRP in plasma decreased with initial treatment but was increased at 12 weeks of anakinra therapy. Although the CRP level after 12 weeks of anakinra therapy was below the baseline level, all values were above normal (<1.0 mg/dl) at all time points. These results suggest the involvement of factors other than IL-1, such as IL-6, in the continuously elevated expression of CRP in these patients (8). Patient 2 experienced a dramatic reduction in the number of circulating WBCs, whereas the WBC levels in patient 1 were variable. WBC counts in both patients were higher than normal throughout the study period. Anemia also persisted in both patients throughout treatment with anakinra, indicating a minimal role for IL-1 dysregulation in the abnormalities in hemoglobin levels in these 2 patients. No apparent adverse events were associated with the use of anakinra in these 2 patients.
Typical clinical features of NOMID include skin, CNS, and joint manifestations (9, 10). Skin rashes occur in all patients and persist throughout their lives. Chronic meningitis, cerebral atrophy, and sensory organ dysfunction, which result in vision and hearing loss, are common neurologic features. Joint symptoms may range in severity from arthralgia with no radiologic findings to severe arthropathy, which frequently presents as symmetric patellar overgrowth and epiphyseal and metaphyseal modifications. Biopsy specimens of all affected tissues are marked by infiltration of polymorphonuclear cells, without evidence of infection. The 2 patients described here displayed skin, CNS, and joint symptoms, and evidence of inflammation was supported by laboratory findings.
Several features of IL-1β biologic activity implicate this cytokine in the pathogenesis of NOMID and its related disorders. IL-1β is a potent pyrogen, a promoter of migration and infiltration of immune cells into the perivascular spaces, and a hematopoietic growth factor (11). IL-1β has also been shown to directly up-regulate expression of acute-phase reactants (8, 12). A unique feature of the IL-1 family of cytokines is that these proteins are transcribed and translated as precursor molecules, which are subsequently cleaved to active forms (11). Proteolytic cleavage can occur intracellularly or extracellularly and is accomplished by several different proteases. Therefore, many points in the IL-1 processing pathways may affect the levels of local and systemic IL-1 production. Consistent with the hypothesis that IL-1β mediates the symptoms associated with NOMID, mutations in the CIAS1 gene are frequently observed in patients with NOMID, FCAS, or Muckle-Wells syndrome (2, 7).
The protein encoded by CIAS1 has been shown to participate in the formation of inflammasomes, protein complexes that contain cysteine–aspartate proteases (caspases) involved in the proteolytic cleavage of IL-1 precursors to produce active forms of IL-1 (2). Mutations in CIAS1 are found in approximately half of patients with NOMID (7) and appear to be one of the underlying genetic defects in this group of diseases, which ultimately result in overproduction of IL-1β. This imbalance in IL-1β production can be alleviated with administration of a recombinant IL-1 receptor antagonist, apparently regardless of the mechanism of IL-1β overproduction. In contrast with the recent report of the use of anakinra in the treatment of NOMID patients with CIAS1 mutations (6), one of the patients described here had a normal CIAS1 genetic sequence. The successful treatment of this patient with anakinra suggests that correction of the downstream effect (IL-1 overproduction) ameliorates disease symptoms, regardless of the upstream mechanism (such as CIAS1 defects).
The successful use of anakinra in NOMID and Muckle-Wells syndrome suggests that anakinra therapy may be clinically beneficial to patients with FCAS and other IL-1–mediated disorders. At the time of publication, a clinical trial designed to more completely and formally examine the effects of anakinra on clinical and laboratory outcomes in patients with NOMID is enrolling study subjects. This study is being performed at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (principal investigator Raphaela Goldbach-Mansky, Bethesda, MD) and will provide valuable information regarding the pathophysiology of this disease.
We thank Julia R. Gage for editorial assistance.
- 7De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002; 46: 3340–8., , , , , , et al.