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Russwurm M, Johannsen S, Kortus-Götze B, Haas CS. Long-term renal outcome of Cryopyrin-associated periodic syndrome (CAPS) under anti-Interleukin-1 therapy. Sci Rep 2024; 14:16595. [PMID: 39025961 PMCID: PMC11258286 DOI: 10.1038/s41598-024-67380-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024] Open
Abstract
Cryopyrin-associated periodic syndromes (CAPS) are orphan hereditary auto-inflammatory diseases with various phenotypes, including chronic kidney disease (CKD). Current therapies inhibit interleukin-1 (IL-1) to achieve clinical and serological remission; however, the effect on kidney involvement remains unclear. The objective of this study was to investigate the long-term efficacy of anti-IL-1 treatment with special emphasis on renal outcome. We retrospectively analysed clinical, genetic and laboratory data of patients with CAPS under anti-IL-1 therapy from a single-centre university outpatient clinic. Patients with CAPS (n = 28) were followed for a median of 11 (IQR 8.5-13) years. Four patients at various ages (19%), bearing the most common CAPS mutation R260W, had significant CKD at presentation. All affected patients were related; however, other family members with the same genetic variant did not develop CKD. While anti-IL-1 therapy was effective in lowering symptom burden and inflammatory parameters in all CAPS patients, two of the four individuals with significant CKD had persistent proteinuria and worsening kidney function. None of the patients without renal affection at therapy initiation developed relevant CKD in the follow-up period. We showed that in patients with CAPS: (1) CKD is a common complication; (2) renal involvement shows familial predisposition beyond the mutational status and is independent of age; (3) anti-IL-1 therapy results in sustained improvement of inflammatory parameters and symptom load and (4) may prevent development of CAPS-associated CKD but not affect kidney involvement when already present. Overall, early therapy initiation might sufficiently prevent renal disease manifestation and attenuate progression.
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Affiliation(s)
- Martin Russwurm
- Department of Internal Medicine, Nephrology and Intensive Care Medicine, Phillips-University, Baldingerstraße 1, 35043, Marburg, Germany.
- Pharmacological Institute, Philipps-University, Marburg, Germany.
| | - Sophia Johannsen
- Department of Internal Medicine, Nephrology and Intensive Care Medicine, Phillips-University, Baldingerstraße 1, 35043, Marburg, Germany
| | - Birgit Kortus-Götze
- Department of Internal Medicine, Nephrology and Intensive Care Medicine, Phillips-University, Baldingerstraße 1, 35043, Marburg, Germany
| | - Christian S Haas
- Department of Internal Medicine, Nephrology and Intensive Care Medicine, Phillips-University, Baldingerstraße 1, 35043, Marburg, Germany
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2
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Cetin Gedik K, Arici ZS, Kul Cinar O, Garcia-Bournissen F, Romano M, Demirkaya E. Practical Approach to Diagnosis and Management of IL-1-Mediated Autoinflammatory Diseases (CAPS, TRAPS, MKD, and DIRA). Paediatr Drugs 2024; 26:113-126. [PMID: 38376736 DOI: 10.1007/s40272-023-00615-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/11/2023] [Indexed: 02/21/2024]
Abstract
Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.
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Affiliation(s)
- Kader Cetin Gedik
- Division of Pediatric Rheumatology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Zehra Serap Arici
- Division of Rheumatology, Malatya Training and Research Hospital, Malatya, Turkey
| | - Ovgu Kul Cinar
- Department of Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK
| | - Facundo Garcia-Bournissen
- Department of Pediatrics, Division of Pediatric Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5W9, Canada
| | - Micol Romano
- Department of Pediatrics, Division of Pediatric Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5W9, Canada
- Canadian Behcet and Autoinflammatory Disease Center (CAN-BE-AID), University of Western Ontario, London, ON, N6A 4V2, Canada
| | - Erkan Demirkaya
- Department of Pediatrics, Division of Pediatric Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5W9, Canada
- Canadian Behcet and Autoinflammatory Disease Center (CAN-BE-AID), University of Western Ontario, London, ON, N6A 4V2, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5W9, Canada
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Fonollosa A, Carreño E, Vitale A, Jindal AK, Ramanan AV, Pelegrín L, Santos-Zorrozua B, Gómez-Caverzaschi V, Cantarini L, Fabiani C, Hernández-Rodríguez J. Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1337329. [PMID: 38984133 PMCID: PMC11182141 DOI: 10.3389/fopht.2024.1337329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 01/30/2024] [Indexed: 07/11/2024]
Abstract
Autoinflammatory diseases include disorders with a genetic cause and also complex syndromes associated to polygenic or multifactorial factors. Eye involvement is present in many of them, with different extent and severity. The present review covers ophthalmological lesions in the most prevalent monogenic autoinflammatory diseases, including FMF (familial Mediterranean fever), TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin-associated periodic syndromes), Blau syndrome, DADA2 (deficiency of adenosine deaminase 2), DITRA (deficiency of the interleukin-36 receptor antagonist), other monogenic disorders, including several ubiquitinopathies, interferonopathies, and the recently described ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Among polygenic autoinflammatory diseases, ocular manifestations have been reviewed in Behçet's disease, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome, Still's disease and autoinflammatory bone diseases, which encompass CRMO (chronic recurrent multifocal osteomyelitis) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome.
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Affiliation(s)
- Alex Fonollosa
- Department of Ophthalmology, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country, Barakaldo, Spain
- Department of Retina, Instituto Oftalmológico Bilbao, Bilbao, Spain
| | - Ester Carreño
- Department of Ophthalmology, Rey Juan Carlos University Hospital, Madrid, Spain
- Department of Ophthalmology, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Antonio Vitale
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Center of the European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), Siena, Italy
| | - Ankur K Jindal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Athimalaipet V Ramanan
- Department of Paediatric Rheumatology, Bristol Royal Hospital for Children and Translational Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Laura Pelegrín
- Department of Ophthalmology, Institut Clínic d'Oftalmologia (ICOF), Hospital Clinic de Barcelona, University of Barcelona, Institut de Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Borja Santos-Zorrozua
- Department of Biostatistics, Biocruces Bizkaia Health Research Institute, Bilbao, Spain
| | - Verónica Gómez-Caverzaschi
- Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clínic de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Center of the European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), Spanish Center of the Centros, Servicios y Unidades de Referencia (CSUR) and Catalan Center of the Xarxa d'Unitats d'Expertesa Clínica (XUEC) for Autoinflammatory Diseases, Barcelona, Spain
| | - Luca Cantarini
- Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Center of the European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), Siena, Italy
| | - Claudia Fabiani
- Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Center of the European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), Siena, Italy
| | - José Hernández-Rodríguez
- Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clínic de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Center of the European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), Spanish Center of the Centros, Servicios y Unidades de Referencia (CSUR) and Catalan Center of the Xarxa d'Unitats d'Expertesa Clínica (XUEC) for Autoinflammatory Diseases, Barcelona, Spain
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Touitou I, Jéziorski E, Al-Saleh A, Carbasse A, Piram M. Quality of life in monogenic autoinflammatory diseases. A review. Joint Bone Spine 2023; 90:105475. [PMID: 36404572 DOI: 10.1016/j.jbspin.2022.105475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Systemic autoinflammatory diseases (SAIDs) are a group of disorders related to defective regulation of the innate immune system. Recurrence of inflammation can severely affect the patients' outcomes with a direct or indirect impact on their physical and mental health and/or global quality of life (QoL). We therefore sought to identify currently available QoL studies for these diseases as well as measurement tools at our disposal. BASIC PROCEDURES A systematic literature review was carried out with a focus on monogenic SAIDs. We inventoried the study designs developed in the selected publications, grouped them into similar topics, and listed the different outcome measures used for QoL. MAIN FINDINGS We recorded 53 bibliographic references evaluating the impact of monogenic SAIDs on the patients' QoL. These publications revealed 150 different study designs and 82 outcome measures used for their assessment. The best-explored topics were the overall patients' QoL, followed by the evaluation of their psychosocial and physical functioning. We found fair coverage of familial Mediterranean fever, poor investigation of the mixed hereditary recurrent fever (HRF) group, cryopyrin-associated periodic diseases and cherubism, and almost no study of the other monogenic SAIDs. CONCLUSIONS This work revealed areas requiring further investigation such as homogenization of concepts, study of uncommon or more recent diseases, and development of more specific and validated outcome measures for SAIDs.
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Affiliation(s)
- Isabelle Touitou
- CeRéMAIA, Department of Genetics, CHU de Montpellier, Inserm, University of Montpellier, A. de Villeneuve Hospital, 371, avenue Doyen-Giraud, Montpellier, France.
| | - Eric Jéziorski
- CeRéMAIA, Department of Genetics, CHU de Montpellier, Inserm, University of Montpellier, A. de Villeneuve Hospital, 371, avenue Doyen-Giraud, Montpellier, France; CeRéMAIA, Department of Pediatrics, CHU de Montpellier, Pediatric Department, Montpellier, France
| | - Afnan Al-Saleh
- CHU de Sainte Justine Research Centre, Department of Pediatrics, CHU de Sainte Justine, University of Montreal, Montreal, QC, Canada
| | - Aurélia Carbasse
- CeRéMAIA, Department of Pediatrics, CHU de Montpellier, Pediatric Department, Montpellier, France
| | - Maryam Piram
- CHU de Sainte Justine Research Centre, Department of Pediatrics, CHU de Sainte Justine, University of Montreal, Montreal, QC, Canada; CeRéMAIA, Department of Pediatric Rheumatology, AP-HP, CHU de Bicêtre, Le Kremlin-Bicêtre, France
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Liu J, Zhang R, Yi Z, Lin Y, Chang H, Zhang Q. Identification of a variant in NLRP3 gene in a patient with Muckle-Wells syndrome: a case report and review of literature. Pediatr Rheumatol Online J 2023; 21:15. [PMID: 36765385 PMCID: PMC9918341 DOI: 10.1186/s12969-023-00795-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 01/22/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Cryopyrin-associated periodic syndrome (CAPS), a rare genetic autoimmune disease, is composed of familial cold autoinflammatory syndrome (FCAs), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). MWS is caused by dominantly inherited or de novo gain-of-function mutations in the NOD-like receptor 3 (NLRP3) gene. At present, there is no report about the variation of R262W in China. CASE PRESENTATION We reported a 3-year-old Chinese boy who had recurrent fever without obvious inducement, bilateral conjunctival congestion, and urticarial-like rash. Laboratory examination showed elevation in leukocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and serum amyloid protein (SAA) levels. Whole exome sequencing identified a missense variation c.784-786delinsTGG (p.R262W) in the coding region of the NLRP3 gene. CONCLUSION A classical variant of the NLRP3 gene in a patient with MWS was first reported in China.
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Affiliation(s)
- Jia Liu
- grid.412521.10000 0004 1769 1119Deparment of Pediatric Nephrology, Rheumatology and Immunity, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ranran Zhang
- grid.412521.10000 0004 1769 1119Deparment of Pediatric Nephrology, Rheumatology and Immunity, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhi Yi
- grid.412521.10000 0004 1769 1119Deparment of Pediatric Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yi Lin
- grid.412521.10000 0004 1769 1119Deparment of Pediatric Nephrology, Rheumatology and Immunity, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hong Chang
- grid.412521.10000 0004 1769 1119Deparment of Pediatric Nephrology, Rheumatology and Immunity, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiuye Zhang
- Deparment of Pediatric Nephrology, Rheumatology and Immunity, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Murakawa S, Yoneda T, Hoshina T, Ishimura M, Kusuhara K. Case report: The altered rate of monocytic cell death in a patient of Muckle-Wells syndrome with atypical clinical course. Front Pediatr 2023; 11:1133097. [PMID: 36873639 PMCID: PMC9978417 DOI: 10.3389/fped.2023.1133097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 01/31/2023] [Indexed: 02/18/2023] Open
Abstract
Muckle-Wells syndrome (MWS) is an autosomal dominant autoinflammatory disease recognized as the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS) caused by NLRP3 gene mutation. It often takes a long time before the diagnosis is made because the clinical presentation of MWS is variable. We report a pediatric case who had had persistently elevated serum C-reactive protein (CRP) level since infancy and was diagnosed with MWS by the development of sensorineural hearing loss in school age. The patient had no periodic symptoms of MWS until the development of sensorineural hearing loss. It is important to differentiate MWS in patients with persistent serum CRP elevation, even if no periodic symptoms, including fever, arthralgia, myalgia and rash, are observed. Furthermore, in this patient, lipopolysaccharide (LPS)-induced monocytic cell death occurred, but to a lesser degree than has been reported in patients with chronic infantile neurological cutaneous, and articular syndrome (CINCA). Because CINCA and MWS are phenotypic variants on the same clinical spectrum, this suggests that a further large-scale study is desired to investigate the association between degree of monocytic cell death and disease severity in CAPS patients.
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Affiliation(s)
- Saori Murakawa
- Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Toru Yoneda
- Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Takayuki Hoshina
- Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Masataka Ishimura
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koichi Kusuhara
- Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
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7
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Romano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron K, Benseler S, Berard RA, Broderick L, Dedeoglu F, Diebold M, Durrant K, Ferguson P, Foell D, Hausmann JS, Jones OY, Kastner D, Lachmann HJ, Laxer RM, Rivera D, Ruperto N, Simon A, Twilt M, Frenkel J, Hoffman HM, de Jesus AA, Kuemmerle-Deschner JB, Ozen S, Gattorno M, Goldbach-Mansky R, Demirkaya E. The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency, and Deficiency of the Interleukin-1 Receptor Antagonist. Arthritis Rheumatol 2022; 74:1102-1121. [PMID: 35621220 DOI: 10.1002/art.42139] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/02/2022] [Accepted: 03/02/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
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Affiliation(s)
- Micol Romano
- University of Western Ontario, London, Ontario, Canada
| | - Z Serap Arici
- Sanliurfa Training and Research Hospital, Sanliurfa, Turkey
| | - David Piskin
- University of Western Ontario, London, Ontario, Canada
| | - Sara Alehashemi
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
| | | | - Karyl Barron
- National Institute of Allergy and Immunology, NIH, Bethesda, Maryland
| | | | | | - Lori Broderick
- University of California and Rady Children's Hospital, San Diego, California
| | | | | | - Karen Durrant
- Autoinflammatory Alliance and Kaiser Foundation Hospital, San Francisco, California
| | | | - Dirk Foell
- University of Muenster, Muenster, Germany
| | - Jonathan S Hausmann
- Boston Children's Hospital and Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Olcay Y Jones
- Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Daniel Kastner
- National Human Genome Research Institute, NIH, Bethesda, Maryland
| | | | - Ronald M Laxer
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Anna Simon
- Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Joost Frenkel
- Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands
| | - Hal M Hoffman
- University of California and Rady Children's Hospital, San Diego, California
| | - Adriana A de Jesus
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
| | | | - Seza Ozen
- Hacettepe University, Ankara, Turkey
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8
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Romano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron KS, Benseler S, Berard R, Broderick L, Dedeoglu F, Diebold M, Durrant KL, Ferguson P, Foell D, Hausmann J, Jones OY, Kastner DL, Lachmann HJ, Laxer RM, Rivera D, Ruperto N, Simon A, Twilt M, Frenkel J, Hoffman H, de Jesus AA, Kuemmerle-Deschner JB, Ozen S, Gattorno M, Goldbach-Mansky R, Demirkaya E. The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Ann Rheum Dis 2022; 81:907-921. [PMID: 35623638 DOI: 10.1136/annrheumdis-2021-221801] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/02/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
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Affiliation(s)
- Micol Romano
- Department of Pediatrics, Division of Pediatric Rheumatology, Behcet and Autoinflammatory Disease Center, Western University, London, Ontario, Canada
| | - Z Serap Arici
- Department of Pediatric Rheumatology, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanliurfa, Sanliurfa, Turkey
| | - David Piskin
- Lawson Health Research Institute and Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Sara Alehashemi
- Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), NIAID, NIH, Bethesda, Maryland, USA
| | - Daniel Aletaha
- Division of Rheumatology, Medical University of Vienna, Wien, Austria
| | - Karyl S Barron
- Division of Intramural Research, National Institute of Allergy and Immunology, NIH, Bethesda, Maryland, USA
| | - Susanne Benseler
- Division of Rheumatology, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Roberta Berard
- Division of Pediatric Rheumatology, Department of Paediatrics, Schulich School of Medicine&Dentistry, Western University, London, Ontario, Canada
| | - Lori Broderick
- Division of Pediatric Allergy, Immunology, and Rheumatology, University of California and Rady Children's Hospital, San Diego, California, USA
| | - Fatma Dedeoglu
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Michelle Diebold
- Division of Pediatric Rheumatology, Department of Paediatrics, LHSC Children's Hospital, London, Ontario, Canada
| | | | - Polly Ferguson
- Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
| | - Jonathan Hausmann
- Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Olcay Y Jones
- Department of Pediatrics, Walter Reed National Military Medical Center (WRNMMC), Bethesda, Maryland, USA
| | - Daniel L Kastner
- Division of Intramural Research, National Institute of Allergy and Immunology, NIH, Bethesda, Maryland, USA
| | | | - Ronald M Laxer
- Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada
| | - Dorelia Rivera
- Autoinflammatory Alliance, San Francisco, California, USA
| | - Nicolino Ruperto
- IRCCS Istituto Giannina Gaslini, UOSID Centro Trial, Genova, Italy
| | - Anna Simon
- Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Marinka Twilt
- Division of Rheumatology, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Joost Frenkel
- Department of Pediatrics, Wilhelmina Kinderziekenhuis Polikliniek Algemene Kindergeneeskunde, Utrecht, Utrecht, The Netherlands
| | - Hal Hoffman
- Division of Pediatric Allergy, Immunology, and Rheumatology, University of California at San Diego, San Diego, California, USA
| | - Adriana A de Jesus
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | | | - Seza Ozen
- Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
| | - Marco Gattorno
- UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini
| | - Raphaela Goldbach-Mansky
- Translational Autoinflammatory Diseases Section (TADS), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Erkan Demirkaya
- Division of Paediatric Rheumatology, Department of Paediatrics, Behcet and Autoinflammatory Disease Center and Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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9
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The Efficacy of Anti-Tumor Necrosis Factor Therapy in Cryopyrin-Associated Periodic Syndromes: A Report of Two Cases. Case Rep Genet 2022; 2022:2898553. [PMID: 35281325 PMCID: PMC8913141 DOI: 10.1155/2022/2898553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023] Open
Abstract
Background Cryopyrin-associated periodic syndromes (CAPSs) are a group of autoinflammatory disorders caused by a mutation in the NLRP3 gene. NLRP3 mutations increase inflammasome activation; therefore, IL-1 targeted therapies are frequently used in the aforementioned disorders. Case Presentation. We report two cases of CAPS in which the diagnosis was confirmed by genetic tests and an evaluation of the therapeutic response to anti-tumor necrosis factor (anti-TNF) agents. Conclusion IL-1 inhibitors are highly effective in treating CAPS patients. Most patients with severe symptoms such as neurologic involvement improve with IL-1 blockade. Anti-TNF agents might be effective in reducing mild manifestation; however, they are not effective in improving more severe complications.
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10
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Maccora I, Marrani E, Mastrolia MV, Abu-Rumeileh S, Maniscalco V, Fusco E, Barbati F, Pagnini I, Simonini G. Ocular involvement in monogenic autoinflammatory disease. Autoimmun Rev 2021; 20:102944. [PMID: 34509650 DOI: 10.1016/j.autrev.2021.102944] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Monogenic Autoinflammatory diseases (AIDs) are a broad spectrum of rare hereditary diseases whose ocular involvement has not been well characterized yet. This systematic review aims to provide an overview of the current knowledge about ocular findings in AIDs. METHODS A systematic literature review was conducted using 2 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of AIDs and ophthalmology-related search terms were used. All articles were screened by 2 independent reviewers for title, abstract and full text level. We included solely studies that investigated ocular findings in AIDs. RESULTS 198 papers of 4268 records were retained. Data about 1353 patients with a diagnosis of autoinflammatory disease and ocular involvement were collected (680 CAPS, 211 FMF, 138 TRAPS, 238 Blau, 32 MKD, 21 SIFD, 7 Aicardi Goutières, 3 CANDLE, 8 DADA2, 9 HA20, 6 APLAID). Conjunctivitis was significantly more frequent in CAPS (p < 0.00001), uveitis in Blau, MKD, HA20 and CANDLE (p < 0.00001), papillitis/papilledema in CAPS (p < 0.00001), optic neuritis in Aicardi and DADA2 (p < 0.008), retinal vasculitis in FMF (p < 0.00001), progressive reduction in choroidal thickness in FMF and DADA2 (p < 0.00001), periorbital oedema in TRAPS (p < 0.00001) and retinitis in SIFD (p < 0.00001). Among AIDs with uveitis, granulomatous inflammation was more common in Blau syndrome (p < 0.00001). CONCLUSION This systematic literature review characterized the ocular involvement of several AIDs, and the present data may encourage to consider a timely ophthalmological screening program for these rare diseases.
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Affiliation(s)
- Ilaria Maccora
- Rheumatology Unit, Meyer Children's University Hospital, NEUROFARBA Department, University of Florence, Florence, Italy.
| | - Edoardo Marrani
- Rheumatology Unit, Meyer Children's University Hospital, Florence, Italy
| | - Maria Vincenza Mastrolia
- Rheumatology Unit, Meyer Children's University Hospital, NEUROFARBA Department, University of Florence, Florence, Italy.
| | - Sarah Abu-Rumeileh
- Pediatric Rheumatology Unit, Meyer Children's University Hospital, School of Human Health Science, Florence, Italy
| | - Valerio Maniscalco
- Pediatric Rheumatology Unit, Meyer Children's University Hospital, School of Human Health Science, Florence, Italy
| | - Eleonora Fusco
- Pediatric Rheumatology Unit, Meyer Children's University Hospital, School of Human Health Science, Florence, Italy
| | - Federica Barbati
- Pediatric Rheumatology Unit, Meyer Children's University Hospital, School of Human Health Science, Florence, Italy
| | - Ilaria Pagnini
- Rheumatology Unit, Meyer Children's University Hospital, Florence, Italy.
| | - Gabriele Simonini
- Rheumatology Unit, Meyer Children's University Hospital, NEUROFARBA Department, University of Florence, Florence, Italy.
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11
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Meng T, Wu D, Luo Y, Wu N, Zhao M, Shen M, Yu W. Ocular manifestations in Chinese adult patients with NLRP3-associated autoinflammatory disease. Sci Rep 2021; 11:11904. [PMID: 34099780 PMCID: PMC8184759 DOI: 10.1038/s41598-021-91315-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/17/2021] [Indexed: 01/27/2023] Open
Abstract
NLRP3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant disorder involving multiple systems. We aim to assess the ocular manifestations of Chinese adult patients with NLRP3-AID. Twelve adult patients (> 18 years old) were diagnosed as NLRP3-AID at the Department of Rheumatology, Peking Union Medical College Hospital. All patients underwent ophthalmologic evaluation by an ophthalmologist. Clinical and genetic features of these patients were collected and compared with those from Caucasian population. A total of 7 NLRP3-AID patients (58%) 14 eyes had ocular manifestations. Five NLRP3 variants were identified, and 3 patients (43%) with severe ocular damages were all found to have the NLRP3 T348M variant. The incidences of papilledema and optic atrophy in the Chinese adult NLRP3-AID patients of moderate type were similar to those in the Caucasian NLRP3-AID patients of severe type. This is the first cohort of Chinese adult NLRP3-AID patients with ocular involvement. Ocular manifestations were diverse and even severe in NLRP3-AID, particularly in patients with the moderate phenotype, and may have relationship with genotypes. Awareness of these manifestations by rheumatologists and ophthalmologists could help to avoid the irreversible ocular damages.
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Affiliation(s)
- Tianli Meng
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.,Department of Rheumatology, Jilin Province People's Hospital, Changchun, China
| | - Di Wu
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Yi Luo
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Na Wu
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Mengzhu Zhao
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Min Shen
- Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Weihong Yu
- Department of Ophthalmology, Key Laboratory of Ocular Fundus Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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12
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Welzel T, Kuemmerle-Deschner JB. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? J Clin Med 2021; 10:E128. [PMID: 33401496 PMCID: PMC7794776 DOI: 10.3390/jcm10010128] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022] Open
Abstract
The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle-Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.
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Affiliation(s)
- Tatjana Welzel
- Pediatric Rheumatology and Autoinflammation Reference Center Tuebingen (arcT), University Children’s Hospital Tuebingen, D-72076 Tuebingen, Germany;
- Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel (UKBB), University of Basel, CH-4031 Basel, Switzerland
| | - Jasmin B. Kuemmerle-Deschner
- Pediatric Rheumatology and Autoinflammation Reference Center Tuebingen (arcT), University Children’s Hospital Tuebingen, D-72076 Tuebingen, Germany;
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13
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Additional Benefit of Canakinumab on Proteinuria in a Case With Muckle-Wells Syndrome in Remission Under Anakinra. Arch Rheumatol 2020; 35:149-150. [PMID: 32637933 DOI: 10.5606/archrheumatol.2020.7378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 05/25/2019] [Indexed: 01/07/2023] Open
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14
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Fingerhutová Š, Fráňová J, Hlaváčková E, Jančová E, Procházková L, Beránková K, Tesařová M, Honsová E, Doležalová P. Muckle-Wells Syndrome Across Four Generations in One Czech Family: Natural Course of the Disease. Front Immunol 2019; 10:802. [PMID: 31057541 PMCID: PMC6477140 DOI: 10.3389/fimmu.2019.00802] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 03/26/2019] [Indexed: 01/07/2023] Open
Abstract
Background: Muckle-Wells syndrome (MWS) represents a moderate phenotype of cryopyrinopathies. Sensorineural hearing loss and AA amyloidosis belong to the most severe manifestations of uncontrolled disease. Simultaneous discovery of MWS in four generations of one large kindred has enabled us to document natural evolution of untreated disease and their response to targeted therapy. Methods: A retrospective case study, clinical assessment at the time of diagnosis and 2-year prospective follow-up using standardized disease assessments were combined. Results: Collaborative effort of primary care physicians and pediatric and adult specialists led to identification of 11 individuals with MWS within one family. Presence of p.Ala441Val mutation was confirmed. The mildest phenotype of young children suffering with recurrent rash surprised by normal blood tests and absence of fevers. Young adults all presented with fevers, rash, conjunctivitis, and arthralgia/arthritis with raised inflammatory markers. Two patients aged over 50 years suffered with hearing loss and AA amyloidosis. IL-1 blockade induced disease remission in all individuals while hearing mildly improved or remained stable in affected patients as did renal function in one surviving individual with amyloidosis. Conclusions: We have shown that severity of MWS symptoms gradually increased with age toward distinct generation-specific phenotypes. A uniform trajectory of disease evolution has encouraged us to postpone institution of IL-1 blockade in affected oligosymptomatic children. This report illustrates importance of close interdisciplinary collaboration.
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Affiliation(s)
- Šárka Fingerhutová
- Paediatric Rheumatology and Autoinflammatory Diseases Unit, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czechia
| | - Jana Fráňová
- Department of Paediatric Rheumatology, University Hospital Brno, Brno, Czechia
| | - Eva Hlaváčková
- Department of Clinical Immunology and Allergology, St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Eva Jančová
- Department of Nephrology, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czechia
| | - Leona Procházková
- Department of Rheumatology, St. Anne's University Hospital Brno, Brno, Czechia
| | - Kamila Beránková
- Laboratory for Study of Mitochondrial Disorders, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czechia
| | - Markéta Tesařová
- Laboratory for Study of Mitochondrial Disorders, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czechia
| | - Eva Honsová
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Pavla Doležalová
- Paediatric Rheumatology and Autoinflammatory Diseases Unit, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czechia
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15
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Abstract
Purpose: To present the ocular findings of the members of a family that has the diagnosis of Muckle Wells syndrome, a form of cryopyrin associated periodic syndrome (CAPS).Materials and Methods: Nine patients with MWS were included in this study. Each study participant underwent a systemic evaluation, comprehensive ophthalmic examination, and auxillary testings.Results: In this study, conjunctivitis was the most prominent ocular finding. Other relatively common ocular findings included band keratopathy, clinical signs of past uveitis, and corneal topography abnormalities. Nystagmus, corneal leukoma, and optic nerve pallor with epiretinal membrane were also detected. Rare ocular manifestations were posterior stromal corneal opacification with edema, anterior iris snychecia, and mild cataract.Conclusion: MWS is a rare systemic autoinflammatory disorder that presents with a variety of ocular findings. Exacerbation of systemic and ocular findings with cold is a hallmark of the disease.
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Affiliation(s)
- Sukru Cekic
- Pediatric Allergy and Clinical Immunology, Uludag University School of Medicine, Bursa, Turkey
| | - Ozgur Yalcinbayir
- Department of Ophthalmology, Uludag University School of Medicine, Bursa, Turkey
| | - Sara Sebnem Kilic
- Pediatric Allergy and Clinical Immunology, Uludag University School of Medicine, Bursa, Turkey
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16
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Ter Haar NM, Annink KV, Al-Mayouf SM, Amaryan G, Anton J, Barron KS, Benseler SM, Brogan PA, Cantarini L, Cattalini M, Cochino AV, De Benedetti F, Dedeoglu F, De Jesus AA, Della Casa Alberighi O, Demirkaya E, Dolezalova P, Durrant KL, Fabio G, Gallizzi R, Goldbach-Mansky R, Hachulla E, Hentgen V, Herlin T, Hofer M, Hoffman HM, Insalaco A, Jansson AF, Kallinich T, Koné-Paut I, Kozlova A, Kuemmerle-Deschner JB, Lachmann HJ, Laxer RM, Martini A, Nielsen S, Nikishina I, Ombrello AK, Ozen S, Papadopoulou-Alataki E, Quartier P, Rigante D, Russo R, Simon A, Trachana M, Uziel Y, Ravelli A, Gattorno M, Frenkel J. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis 2017; 76:821-830. [PMID: 27811147 DOI: 10.1136/annrheumdis-2016-210092] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/27/2016] [Accepted: 10/08/2016] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency. METHODS We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds. RESULTS More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain. CONCLUSIONS An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.
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Affiliation(s)
- Nienke M Ter Haar
- Laboratory for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Department of Paediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Kim V Annink
- Department of Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Sulaiman M Al-Mayouf
- Department of Paediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Gayane Amaryan
- National Paediatric Centre for Familial Mediterranean Fever and Gastroenterology Service, Arabkir Medical Centre-Institute of Child & Adolescent Health, Yerevan, Armenia
| | - Jordi Anton
- Paediatric Rheumatology Unit, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Karyl S Barron
- Division of Intramural Research and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Susanne M Benseler
- Department of Paediatrics and Department of Rheumatology, Alberta Children's Hospital, Calgary, Canada
| | - Paul A Brogan
- Department of Infection, Inflammation and Rheumatology, University College London Institute of Child Health, London, UK
| | - Luca Cantarini
- Department of Medical Sciences, Surgery and Neurosciences, Rheumatology Unit, University of Siena, Siena, Italy
| | - Marco Cattalini
- Paediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy
| | - Alexis-Virgil Cochino
- Paediatrics Department, National Institute for Mother and Child Health Alessandrescu-Rusescu, Bucharest, Romania
| | | | - Fatma Dedeoglu
- Division of Immunology, Rheumatology Program, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Adriana A De Jesus
- Translational Autoinflammatory Disease Section, NIAID, National Institutes of Health, Bethesda, USA
| | | | - Erkan Demirkaya
- Department of Paediatric Rheumatology, Gulhane Military Medical Faculty, Ankara, Turkey
| | - Pavla Dolezalova
- Department of Paediatrics and Adolescent Medicine, Charles University, General University Hospital, Prague, Czech Republic
| | | | - Giovanna Fabio
- Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Romina Gallizzi
- Department of Paediatrics, Rheumatology, AOU G Martino, Messina, Italy
| | - Raphaela Goldbach-Mansky
- Translational Autoinflammatory Disease Section, NIAID, National Institutes of Health, Bethesda, USA
| | - Eric Hachulla
- Département de Médecine Interne et Immunologie Clinique, Université de Lille, Lille, France
| | - Veronique Hentgen
- Reference centre for autoinflammatory diseases (CEREMAI), Versailles Hospital, Le Chesnay, France
| | - Troels Herlin
- Department of Paediatrics, Aarhus University Hospital, Aarhus, Denmark
| | - Michaël Hofer
- Department of Paediatric Rheumatology, University of Lausanne, Lausanne, Switzerland
- Department of Paediatric Rheumatology, University Hospital of Geneva, Geneva, Switzerland
| | - Hal M Hoffman
- Department of Paediatrics, University of California, San Diego, USA
| | - Antonella Insalaco
- Dipartimento di Medicina Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Annette F Jansson
- Department of Rheumatology&Immunology, Dr. von Hauner Childrens Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Tilmann Kallinich
- Paediatric Pneumology and Immunology and Interdisciplinary Centre for Social Paediatrics, Charité University Medicine Berlin, Berlin, Germany
| | - Isabelle Koné-Paut
- Department of Paediatric Rheumatology and CEREMAI, Bicêtre Hospital, APHP, University of Paris Sud, Paris, France
| | - Anna Kozlova
- Department of Immunology, Federal Research and Clinical Centre for Paediatric Haematology, Oncology and Immunology, Moscow, Russia
| | - Jasmin B Kuemmerle-Deschner
- Division of Paediatric Rheumatology, Department of Paediatrics, University Hospital Tuebingen, Tuebingen, Germany
| | | | - Ronald M Laxer
- Department of Paediatrics and Medicine, University of Toronto and the Hospital for Sick Children, Toronto, Canada
| | | | - Susan Nielsen
- Paediatric Rheumatology unit 4272, Rigshospitalet, Copenhagen, Denmark
| | - Irina Nikishina
- Department of Paediatric Rheumatic diseases, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
| | - Amanda K Ombrello
- Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, USA
| | - Seza Ozen
- Department of Paediatric Rheumatology, Hacettepe University, Ankara, Turkey
| | | | - Pierre Quartier
- Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France
| | - Donato Rigante
- Institute of Paediatrics, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica Sacro Cuore, Rome, Italy
| | - Ricardo Russo
- Servicio de Inmunología y Reumatología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina
| | - Anna Simon
- Internal Medicine, Radboud Expertise Centre for Immunodeficiency and Autoinflammation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Maria Trachana
- Paediatric Immunology and Rheumatology Referral Centre, first Paediatric clinic, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Yosef Uziel
- Department of Paediatrics, Meir Medical Centre, Kfar Saba, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel
| | - Angelo Ravelli
- Institution Università degli Studi di Genova and G. Gaslini Institute, Genova, Italy
| | | | - Joost Frenkel
- Department of Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands
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17
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Wu D, Shen M. Muckle-Wells syndrome in Chinese patients: a single center case series. Clin Rheumatol 2016; 36:965-969. [PMID: 28028683 DOI: 10.1007/s10067-016-3523-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 12/18/2016] [Indexed: 10/20/2022]
Abstract
Muckle-Wells syndrome (MWS) is a rare autoinflammatory disease. This study aimed to report the clinical features and gene variations of the first case series of MWS patients in Chinese population. Four Han Chinese patients were diagnosed with MWS and followed up at our adult clinic for autoinflammatory diseases. All relevant phenotypes and genotypes were collected. All patients were adult male. The median age of disease onset was 4.5 years, and one patient had adult-onset disease. No positive family history was observed. All patients had a remittent disease course. The duration of fever attacks ranged from 0.5 to 7 days. Skin rashes were present in all patients. The other manifestations included polyarthralgia/arthritis (n = 3), oral ulcers (n = 2), conjunctivitis (n = 2), myalgia (n = 2), headache (n = 2), pharyngitis (n = 1), abdominal pain (n = 1), severe sensorineural hearing loss (n = 1), and chronic meningitis with communicating hydrocephalus (n = 1). None of the patients showed evidence of renal amyloidosis. Each patient carried a heterozygous mutation in an NLRP3 gene, including D29V, V70M, T348M, and Q703K, respectively. D29V and V70M variants were novel mutations in exon 1 of NLRP3. All patients had good response to corticosteroids. Our study suggests that MWS could be identified in Chinese population. Our finding of novel mutations in NLRP3 may expand the diversity of MWS.
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Affiliation(s)
- Di Wu
- Peking Union Medical College Hospital, Beijing, 100730, China
| | - Min Shen
- Peking Union Medical College Hospital, Beijing, 100730, China.
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18
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Sobolewska B, Angermair E, Deuter C, Doycheva D, Kuemmerle-Deschner J, Zierhut M. NLRP3 A439V Mutation in a Large Family with Cryopyrin-associated Periodic Syndrome: Description of Ophthalmologic Symptoms in Correlation with Other Organ Symptoms. J Rheumatol 2016; 43:1101-6. [DOI: 10.3899/jrheum.150681] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2016] [Indexed: 11/22/2022]
Abstract
Objective.Cryopyrin-associated periodic syndrome (CAPS) is a group of inherited autoinflammatory disorders caused by mutations in the NLRP3 gene resulting in the overproduction of interleukin 1β. NLRP3 mutations cause a broad clinical phenotype of CAPS. The aims of the study were to evaluate clinical, laboratory, and genetic features of a 5-generation family with CAPS focusing in detail on ocular symptoms.Methods.In a retrospective observational cohort study, consecutive family members were screened for the presence of the NLRP3 mutation. Patients underwent standardized clinical, laboratory, and ophthalmological assessments. The genotype-specific risk of ophthalmological findings and other organ symptoms was determined.Results.Twenty-nine patients were clinically affected. The A439V mutation encoded by exon 3 of the NLRP3 gene was found in 15 of 37 family members (41%). The most common clinical features were musculoskeletal symptoms, headaches, and ophthalmological symptoms. The mutation-positive patients were characterized by more frequent skin rashes, ocular symptoms, arthralgia, arthritis, and severe Muckle-Wells syndrome (MWS) Disease Activity Score. Rosacea was diagnosed in 8 patients.Conclusion.The NLRP3 mutation A439V is associated with a heterogeneous clinical spectrum of familial cold autoinflammatory syndrome/MWS-overlap syndrome. Skin rash and eye diseases, such as conjunctivitis and uveitis, were positively correlated with this mutation.
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Houx L, Hachulla E, Kone-Paut I, Quartier P, Touitou I, Guennoc X, Grateau G, Hamidou M, Neven B, Berthelot JM, Lequerré T, Pillet P, Lemelle I, Fischbach M, Duquesne A, Le Blay P, Le Jeunne C, Stirnemann J, Bonnet C, Gaillard D, Alix L, Touraine R, Garcier F, Bedane C, Jurquet AL, Duffau P, Smail A, Frances C, Grall-Lerosey M, Cathebras P, Tran TA, Morell-Dubois S, Pagnier A, Richez C, Cuisset L, Devauchelle-Pensec V. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol 2016; 67:3027-36. [PMID: 26245507 DOI: 10.1002/art.39292] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 07/16/2015] [Indexed: 11/05/2022]
Abstract
OBJECTIVE To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS). METHODS We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test. RESULTS The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes. CONCLUSION Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time.
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Affiliation(s)
| | - Eric Hachulla
- Nord-de-France University and Claude-Huriez University Hospital, Lille, France
| | | | - Pierre Quartier
- Necker-Enfants Malades University Hospital and Paris Descartes University, Paris, France
| | | | | | - Gilles Grateau
- Tenon University Hospital, AP-HP, and Paris VI Pierre et Marie Curie University, Paris, France
| | | | - Bénédicte Neven
- Necker-Enfants Malades University Hospital, AP-HP, and INSERM U768 Laboratory, Paris, France
| | | | | | - Pascal Pillet
- Pellegrin-Enfants University Hospital, Bordeaux, France
| | | | | | - Agnès Duquesne
- Women-Mothers-Children University Hospital, Lyon, France
| | | | | | - Jérome Stirnemann
- Jean Verdier University Hospital, AP-HP, Paris XIII University, Paris, France
| | | | | | | | | | | | | | | | - Pierre Duffau
- Saint André Hospital, and Bordeaux University Hospital, Bordeaux, France
| | - Amar Smail
- North University Hospital, Amiens, France
| | | | | | | | | | | | | | | | - Laurence Cuisset
- Cochin Institute and University Hospital, AP-HP, Paris Descartes University, Paris, France
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Scarpioni R, Ricardi M, Albertazzi V. Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage. World J Nephrol 2016; 5:66-75. [PMID: 26788465 PMCID: PMC4707170 DOI: 10.5527/wjn.v5.i1.66] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
The release of proinflammatory cytokines during inflammation represents an attempt to respond to injury, but it may produce detrimental effects. The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 (NLRP3). Once activated, inflammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 inflammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A (SAA), as acute-phase protein with also proinflammatory properties, has been shown to induce the secretion of cathepsin B and inflammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration.
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Kuemmerle-Deschner JB, Koitschev A, Tyrrell PN, Plontke SK, Deschner N, Hansmann S, Ummenhofer K, Lohse P, Koitschev C, Benseler SM. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J 2015; 13:43. [PMID: 26531310 PMCID: PMC4632838 DOI: 10.1186/s12969-015-0041-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 10/27/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Muckle-Wells-syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. METHODS A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. RESULTS A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5-4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. CONCLUSIONS Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.
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Affiliation(s)
- Jasmin B. Kuemmerle-Deschner
| | - Assen Koitschev
- Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Stuttgart, Stuttgart, Germany.
| | - Pascal N. Tyrrell
| | - Stefan K. Plontke
| | - Norbert Deschner
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Tuebingen, Tuebingen, Germany.
| | - Sandra Hansmann
- Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Hoppe-Seyler-Str. 1, D-72076, Tuebingen, Germany.
| | - Katharina Ummenhofer
- Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Hoppe-Seyler-Str. 1, D-72076, Tuebingen, Germany.
| | - Peter Lohse
- CeGaT, Center for Genomics and Transcriptomics, Tuebingen, Germany.
| | - Christiane Koitschev
- Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Stuttgart, Stuttgart, Germany.
| | - Susanne M. Benseler
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ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, Cantarini L, Galeotti C, Grateau G, Hentgen V, Hofer M, Kallinich T, Kone-Paut I, Lachmann HJ, Ozdogan H, Ozen S, Russo R, Simon A, Uziel Y, Wouters C, Feldman BM, Vastert SJ, Wulffraat NM, Benseler SM, Frenkel J, Gattorno M, Kuemmerle-Deschner JB. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis 2015; 74:1636-44. [PMID: 26109736 DOI: 10.1136/annrheumdis-2015-207546] [Citation(s) in RCA: 199] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 06/09/2015] [Indexed: 12/15/2022]
Abstract
: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.
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Affiliation(s)
- Nienke M ter Haar
- Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands Department of Paediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marlen Oswald
- Division of Paediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Jerold Jeyaratnam
- Department of Paediatrics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jordi Anton
- Paediatric Rheumatology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
| | - Karyl S Barron
- Division of Intramural Research, National Institute of Health, Bethesda, USA
| | - Paul A Brogan
- Department of Rheumatology, UCL Institute of Child Health, London, UK
| | - Luca Cantarini
- Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy
| | - Caroline Galeotti
- Department of Pediatric Rheumatology, Reference Centre for Autoinflammatory Disorders CEREMAI, Bicêtre Hospital, Paris, France
| | - Gilles Grateau
- Department of Internal Medicine, APHP, Hôpital Tenon, University Pierre-et-Marie-Curie, Paris, France
| | - Veronique Hentgen
- French Reference Centre for Auto-Inflammatory Diseases in Children, Centre Hospitalier de Versailles, Le Chesnay Cedex, France
| | - Michael Hofer
- Department of Paediatrics, University of Lausanne, Lausanne, Switzerland
| | - Tilmann Kallinich
- Department of Paediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany
| | - Isabelle Kone-Paut
- Department of Paediatric Rheumatology, Reference Centre for Autoinflammatory Disorders CEREMAI, Bicêtre Hospital, University of Paris SUD, Paris, France
| | - Helen J Lachmann
- National Amyloidosis Centre, University College London Medical School, London, UK
| | - Huri Ozdogan
- Division of Rheumatology, Cerrahpasa Ic Hastaliklari Klinigi, University Istanbul, Istanbul, Turkey
| | - Seza Ozen
- Department of Paediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ricardo Russo
- Service of Immunology and Rheumatology, Hospital de Pediatría Garrahan, Buenos Aires, Argentina
| | - Anna Simon
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Yosef Uziel
- Department of Paediatrics, Meir Medical Center, Tel-Aviv University, Tel-Aviv, Israel
| | - Carine Wouters
- Department of Microbiology and Immunology, University Hospital Leuven, Leuven, Belgium
| | - Brian M Feldman
- Division of Rheumatology, The Hospital for Sick Children, Toronto, Canada
| | - Sebastiaan J Vastert
- Department of Paediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Nico M Wulffraat
- Department of Paediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Susanne M Benseler
- Department of Paediatrics, Rheumatology, Alberta Children's Hospital, University of Calgary, Calgary, Canada
| | - Joost Frenkel
- Department of Paediatrics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marco Gattorno
- Division of Paediatrics II, G. Gaslini Institute, Genoa, Italy
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Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens. Arthritis Res Ther 2014; 15:R64. [PMID: 23718630 PMCID: PMC4060562 DOI: 10.1186/ar4237] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 02/17/2013] [Accepted: 05/29/2013] [Indexed: 12/22/2022] Open
Abstract
Objectives Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1β monoclonal antibody, can abolish excess IL-1β. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.
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Kuemmerle-Deschner JB, Dembi Samba S, Tyrrell PN, Koné-Paut I, Marie I, Deschner N, Benseler SM. Challenges in Diagnosing Muckle-Wells Syndrome: Identifying Two Distinct Phenotypes. Arthritis Care Res (Hoboken) 2014; 66:765-72. [DOI: 10.1002/acr.22206] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 10/08/2013] [Indexed: 01/01/2023]
Affiliation(s)
| | | | - Pascal N. Tyrrell
- The Hospital for Sick Children, University of Toronto; Toronto, Ontario Canada
| | | | - Isabelle Marie
- CEREMAI, CHU Bicêtre APHP, University of Paris SUD; Paris France
| | | | - Susanne M. Benseler
- The Hospital for Sick Children, University of Toronto; Toronto, Ontario Canada
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Omoyinmi E, Melo Gomes S, Standing A, Rowczenio DM, Eleftheriou D, Klein N, Aróstegui JI, Lachmann HJ, Hawkins PN, Brogan PA. Brief Report: whole-exome sequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheumatol 2014; 66:197-202. [PMID: 24431285 PMCID: PMC3995009 DOI: 10.1002/art.38217] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 09/26/2013] [Indexed: 02/01/2023]
Abstract
OBJECTIVE To identify the genetic cause of chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) using whole-exome sequencing in a child who had typical clinical features but who was NLRP3 mutation negative based on conventional Sanger sequencing. METHODS We performed whole-exome sequencing on DNA from peripheral blood, using Illumina TruSeq Exome capture and the HiSeq sequencing platform. Exome data were analyzed in the Galaxy Web-based suite. Whole-exome sequencing findings were confirmed by massively parallel sequencing. RESULTS Analysis of variants in known autoinflammatory genes led to the identification of the pathogenic p.F556L NLRP3 missense mutation in 17.7% of Illumina reads (25 of 141). No new candidate genes were identified. Massively parallel sequencing of DNA from peripheral blood (performed in duplicate) unequivocally confirmed the presence of this mutation in 14.5% of alleles. Reexamination of the original Sanger chromatograms revealed a small peak at nucleotide position c.1698 corresponding to the mutated allele. This had initially been regarded as background noise, but in retrospect is completely consistent with somatic mosaicism for the p.F556L NLRP3 mutation in this child with CINCA syndrome. CONCLUSION This is the first description of somatic NLRP3 mosaicism detected using whole-exome sequencing in a "mutation-negative" patient with CINCA syndrome. Our findings suggest that whole-exome sequencing could be an important diagnostic tool for detecting somatic mosaicism, as well as for the discovery of novel causative gene mutations, in patients with clinical features of cryopyrin-associated periodic syndromes who are NLRP3 mutation negative by conventional sequencing. This approach could also be applicable to patients with other autosomal-dominant autoinflammatory diseases characterized by gain-of-function mutations who are mutation negative by conventional Sanger sequencing.
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Scarpioni R, Rigante D, Cantarini L, Ricardi M, Albertazzi V, Melfa L, Lazzaro A. Renal involvement in secondary amyloidosis of Muckle-Wells syndrome: marked improvement of renal function and reduction of proteinuria after therapy with human anti-interleukin-1β monoclonal antibody canakinumab. Clin Rheumatol 2014; 34:1311-6. [PMID: 24510061 DOI: 10.1007/s10067-013-2481-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 12/20/2013] [Accepted: 12/26/2013] [Indexed: 12/11/2022]
Abstract
Muckle-Wells syndrome (MWS) is a rare hereditary autoinflammatory disorder characterized by recurrent urticaria-like skin rashes, arthralgias, conjunctivitis, hypoacusia, and risk of reactive AA amyloidosis due to the progressive accumulation of amyloid fibrils in different organs. Its genetic defect lies in mutations in the NLRP3 gene, encoding the cryopyrin protein, and resulting in interleukin (IL)-1β oversecretion. Renal involvement, in terms of proteinuria or renal insufficiency, can be observed in up to 25% of patients. Herein, we describe our experience with two Caucasian patients, father and son, aged 52 and 26 years, respectively, heterozygous for both V198M and R260W NLRP3 mutations who had AA amyloid deposits on renal biopsy. The fully human monoclonal antibody canakinumab, providing selective and prolonged IL-1β blockade, was administered in both patients every 60 days over a period of 18 months. This treatment allowed to obtain amazing results: a rapid disappearance of any clinical symptoms, the stable normalization of serum amyloid-A and, furthermore, a marked improvement of glomerular filtration rate and proteinuria with no adverse events. Our data, though limited to only two patients, emphasize that therapeutic intervention with canakinumab, suppressing both inflammation and IL-1β-mediated manifestations, can contribute to improve kidney function in MWS with overt renal amyloidosis.
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Affiliation(s)
- Roberto Scarpioni
- Nephrology and Dialysis Unit, Department of Medicine, "Guglielmo da Saliceto" Hospital AUSL Piacenza, via Taverna 49, Piacenza, 29121, Italy,
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Kuemmerle-Deschner JB, Haug I. Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians. Ther Adv Musculoskelet Dis 2013; 5:315-29. [PMID: 24294305 DOI: 10.1177/1759720x13502629] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1-2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.
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Affiliation(s)
- Jasmin B Kuemmerle-Deschner
- Division of Pediatric Rheumatology, Department of Pediatrics, University Children's Hospital Tuebingen, Hoppe-Seyler-Strasse 1, 72076 Tuebingen, Germany
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Sudden bilateral sensorineural hearing loss associated with urticarial vasculitis. The Journal of Laryngology & Otology 2013; 127:708-11. [PMID: 23683939 DOI: 10.1017/s0022215113001047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Bilateral sensorineural hearing loss associated with recurrent urticarial skin lesions may be signs of underlying Muckle-Wells syndrome. Previous reports have described the hearing loss to be progressive in nature. METHOD To our knowledge, this paper presents the first published case of sudden onset, bilateral sensorineural hearing loss associated with urticarial vasculitis due to underlying Muckle-Wells syndrome. RESULTS The patient underwent a cochlear implantation with a modest outcome. CONCLUSION Cochlear implantation may help to rehabilitate sudden hearing loss associated with this condition, but early diagnosis may allow treatment with interleukin-1β inhibitors such as anakinra.
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Oberg TJ, Vitale AT, Hoffman RO, Bohnsack JF, Warner JE. Cryopyrin-associated periodic syndromes and the eye. Ocul Immunol Inflamm 2013; 21:306-9. [PMID: 23662681 DOI: 10.3109/09273948.2013.765016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
AIM To describe the ophthalmologic findings in two patients with Muckle-Wells Syndrome, a phenotype of the Cryopyrin Associated Periodic Syndromes (CAPS) spectrum. There is currently sparse ophthalmic literature regarding the ocular manifestations of CAPS. We hope to increase awareness of this spectrum of diseases and the importance of proper treatment amongst eye care professionals. METHODS Interventional Case Series. RESULTS Patient 1 experienced resolution of aseptic meningitis, papilledema, and anterior uveitis following treatment with anikinra. Patient 2 experienced resolution of panuveitis following treatment with anikinra. CONCLUSIONS The severe ocular manifestations of the most severe CAPS phenotype, Chronic Infantile Neurological Cutaneous and Articular Syndrome/Neonatal Onset Multisystem Inflammatory Disease Syndrome (CINCA/NOMID) have been previously described. There is increasing evidence that patients may experience similar ocular disease with the milder phenotype of Muckle-Wells Sydnrome. There is also increasing evidence that appropriate therapy can have a profound effect on patient prognosis.
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Enríquez R, Sirvent AE, Padilla S, Noguera-Pons R, Andrada E, Ardoy F, Millán I, Amorós F. Nephrotic syndrome and AA amyloidosis revealing adult-onset cryopyrin-associated periodic syndrome. Ren Fail 2013; 35:738-41. [PMID: 23650909 DOI: 10.3109/0886022x.2013.790300] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Cryopyrin-associated periodic syndrome (CAPS) is due to gain-of-function mutations in the cryopyrin gene, which determines an overactive inflammatory response. AA amyloidosis is a complication of this syndrome. A 53-year-old man was referred to us because of lower limb edema. Past history: at the age of 20, he complained of arthralgia/arthritis and bilateral hypoacusis. At the age of 35, he presented posterior uveitis, several episodes of conjunctivitis, and progressive loss of visual acuity. Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis. A genetic study revealed the p.D303N mutation in the cryopyrin gene, and he was diagnosed as having AA amyloidosis due to CAPS. Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted. It is important to be aware of cryopyrin-associated periodic syndrome because it can cause irreversible complications, and there is effective therapy.
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Affiliation(s)
- R Enríquez
- Nephrology Section, Hospital General de Elche, Elche, Spain.
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Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, Wittkowski H, Bialkowski A, Tzaribachev N, Lohse P, Koitchev A, Deuter C, Foell D, Benseler SM. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. ACTA ACUST UNITED AC 2013; 63:840-9. [PMID: 21360513 DOI: 10.1002/art.30149] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.
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Abstract
The cryopyrin-associated periodic syndrome is a very rare disease. It is estimated that there are 1-2 cases out of 1 million inhabitants in the USA and 1/360,000 in France. However, many patients are diagnosed very late or not at all. Therefore the real prevalence is likely to be higher. CAPS encompasses the three entities familial cold autoinflammatory syndrome (FCAS), the Muckle-Wells syndrome and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3-gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of IL-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and CNS symptoms (NOMID/CINCA only). With the advent of the IL-1 inhibitors anakinra, rilonacept and canakinumab for the first time safe and effective therapeutic options are available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory.
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Affiliation(s)
- J B Kümmerle-Deschner
- Klinik für Kinder- und Jugendmedizin, Abteilung für pädiatrische Rheumatologie, Autoinflammation Reference Center Tübingen, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Deutschland.
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Jesus AA, Fujihira E, Watase M, Terreri MT, Hilario MO, Carneiro-Sampaio M, Len CA, Oliveira SK, Rodrigues MC, Pereira RM, Bica B, Silva NA, Cavalcanti A, Marini R, Sztajnbok F, Quintero MV, Ferriani VP, Moraes-Vasconcelos D, Silva CA, Oliveira JB. Hereditary autoinflammatory syndromes: a Brazilian multicenter study. J Clin Immunol 2012; 32:922-32. [PMID: 22566169 DOI: 10.1007/s10875-012-9688-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 03/21/2012] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. METHODS The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. RESULTS Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. CONCLUSION We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.
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Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 2012; 167:391-404. [PMID: 22288582 DOI: 10.1111/j.1365-2249.2011.04533.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
UNLABELLED OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Allergy, Host Responses, Cancer, Type 1 diabetes and viruses, Metabolic diseases. SUMMARY The disease-based discovery of the molecular basis for autoinflammatory diseases has led not only to a rapidly growing number of clinically and genetically identifiable disorders, but has unmantled key inflammatory pathways such as the potent role of the alarm cytokine interleukin (IL)-1 in human disease. Following its initial failures in the treatment of sepsis and the moderate success in the treatment of rheumatoid arthritis, IL-1 blocking therapies had a renaissance in the treatment of a number of autoinflammatory conditions, and IL-1 blocking therapies have been Food and Drug Administration (FDA)-approved for the treatment of the autoinflammatory conditions: cryopyrin-associated periodic syndromes (CAPS). CAPS and deficiency of the IL-1 receptor antagonist (DIRA), both genetic conditions with molecular defects in the IL-1 pathway, have provided a pathogenic rationale to IL-1 blocking therapies, and the impressive clinical results confirmed the pivotal role of IL-1 in human disease. Furthermore, IL-1 blocking strategies have shown clinical benefit in a number of other genetically defined autoinflammatory conditions, and diseases with clinical similarities to the monogenic disorders and not yet identified genetic causes. The discovery that IL-1 is not only triggered by infectious danger signals but also by danger signals released from metabolically 'stressed' or even dying cells has extended the concept of autoinflammation to disorders such as gout, and those that were previously not considered inflammatory, such as type 2 diabetes, coronary artery disease, obesity and some degenerative diseases, and provided the conceptual framework to target IL-1 in these diseases. Despite the tremendous success of IL-1 blocking therapy, the use of these agents in a wider spectrum of autoinflammatory conditions has uncovered disease subsets that are not responsive to IL-1 blockade, including the recently discovered proteasome-associated autoinflammatory syndromes such as chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures (CANDLE), Japanese autoinflammatory syndrome with lipodystrophy (JASL), Nakajo-Nishimura syndrome (NNS) and joint contractures, muscle atrophy, panniculitis induced lipodystrophy (JMP), and urge the continued quest to characterize additional dysregulated innate immune pathways that cause autoinflammatory conditions.
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Affiliation(s)
- R Goldbach-Mansky
- Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Kuemmerle-Deschner JB, Lohse P, Koetter I, Dannecker GE, Reess F, Ummenhofer K, Koch S, Tzaribachev N, Bialkowski A, Benseler SM. NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment. Arthritis Res Ther 2011; 13:R196. [PMID: 22146561 PMCID: PMC3334646 DOI: 10.1186/ar3526] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2011] [Revised: 07/29/2011] [Accepted: 12/06/2011] [Indexed: 12/11/2022] Open
Abstract
Introduction Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. Methods A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. Results All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. Conclusion The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.
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Affiliation(s)
- Jasmin B Kuemmerle-Deschner
- Division of Pediatric Rheumatology, Dept, of Pediatrics, University Hospital Tübingen, Hoppe-Seyler-Straße 1, 72076 Tuebingen, Germany.
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Weegerink N, Schraders M, Leijendeckers J, Slieker K, Huygen P, Hoefsloot L, Oostrik J, Pennings R, Simon A, Snik A, Kremer H, Kunst H. Audiometric characteristics of a Dutch family with Muckle-Wells syndrome. Hear Res 2011; 282:243-51. [DOI: 10.1016/j.heares.2011.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 07/14/2011] [Accepted: 07/18/2011] [Indexed: 01/30/2023]
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Hedrich CM, Bruck N, Paul D, Hahn G, Gahr M, Rösen-Wolff A. "Mutation negative" familial cold autoinflammatory syndrome (FCAS) in an 8-year-old boy: clinical course and functional studies. Rheumatol Int 2011; 32:2629-36. [PMID: 21833523 DOI: 10.1007/s00296-011-2019-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 07/10/2011] [Indexed: 11/28/2022]
Abstract
Cryopyrinopathies are a subgroup of autoinflammatory syndromes. Most cases have mutations in the CIAS1/NLRL3 gene, encoding the cryopyrin/NLRP3 protein. Cryopyrin, together with other proteins, is involved in the assembly of the cryopyrin/NLRP3 inflammasome. Mutations in CIAS1/NLRP3 result in increased IL-1β cleavage from biologically inactive pro-IL-1β. This results in systemic inflammation and three associated disorders of different severity, forming a clinical continuum with overlapping features. The mildest from, familial cold autoinflammatory syndrome (FCAS), is characterized by remitting fevers, urticaria-like rash, polyarthralgia/arthritis, and usually caused by cold exposure. More severe forms are Muckle-Wells syndrome (MWS) and CINCA/NOMID. We report an 8-year-old boy with FCAS, who presented with overlapping features with MWS. He showed good response to seasonal anakinra treatment. Mutation analysis in CIAS1/NLRP3, PYCARD, and CASP1 was performed. Serum cytokine profiles, and cytokine expression from resting monocytes, and in response to mild hypothermia, and LPS stimulation were determined. Mutations in CIAS1/NLRP3, PYCARD, and CASP1 were not found. In response to mild hypothermia, an enhanced IL-1β expression by patient monocytes resulted in increased IL-6 and TNF-α secretion, as compared to control cells. The addition of the IL-1β receptor antagonist (anakinra) reversed these effects. In response to LPS stimulation, patient monocytes produced high level of IL-1β, IL-6 and TNF-α. This was markedly less pronounced in control monocytes. FCAS results in cold-induced cytokine dysregulation and systemic inflammation. Symptoms can be treated, using IL-1β antagonists. Further research is warranted, particularly in order to investigate pathophysiological mechanisms in "mutation negative" individuals.
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Affiliation(s)
- C M Hedrich
- Christian Hedrich, Children's Hospital Dresden, Pediatric Rheumatology and Immunology, University Medical Center Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
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