The expanding spectrum of rare monogenic autoinflammatory diseases.
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ABSTRACT:
SUBMITTER: Touitou I
PROVIDER: S-EPMC4016572 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
The expanding spectrum of rare monogenic autoinflammatory diseases.
Touitou Isabelle I Galeotti Caroline C Rossi-Semerano Linda L Hentgen Véronique V Piram Maryam M Koné-Paut Isabelle I
Orphanet journal of rare diseases 20131016
Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle di ...[more]
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Project description:ObjectiveThe present manuscript aims to describe an international, electronic-based, user-friendly and interoperable patient registry for monogenic autoinflammatory diseases (mAIDs), developed in the contest of the Autoinflammatory Diseases Alliance (AIDA) Network.MethodsThis is an electronic platform, based on the Research Electronic Data Capture (REDCap) tool, used for real-world data collection of demographics, clinical, laboratory, instrumental and socioeconomic data of mAIDs patients. The instrument has flexibility, may change over time based on new scientific acquisitions, and communicate potentially with other similar registries; security, data quality and data governance are corner stones of the platform.ResultsAIDA project will share knowledge and expertise on mAIDs. Since its start, 118 centers from 24 countries and 4 continents have joined the AIDA project. Fifty-nine centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 337 users (122 Principal Investigators, 210 Site Investigators, 2 Lead Investigators, and 3 data managers). The Registry collects baseline and follow-up data using 3,748 fields organized into 21 instruments, which include demographics, patient history, symptoms, trigger/risk factors, therapies, and healthcare information for mAIDs patients.ConclusionsThe AIDA mAIDs Registry, acts both as a research tool for future collaborative real-life studies on mAIDs and as a service to connect all the figures called to participate. On this basis, the registry is expected to play a pivotal role in generating new scientific evidence on this group of rare diseases, substantially improving the management of patients, and optimizing the impact on the healthcare system. NCT05200715 available at https://clinicaltrials.gov.
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Project description:The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.
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Project description:Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN's as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.
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Project description:Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.
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Project description:The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically determined recurrent sterile inflammation and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines, such as interleukin 1 and tumor necrosis factor, and intracellular cytokine signaling pathways have proved effective in many cases. Emerging next-generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. This review covers several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.
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