Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?

Welzel, Tatjana; Kuemmerle‐Deschner, Jasmin

doi:10.3390/jcm10010128

Cited by 62 publications

(55 citation statements)

References 122 publications

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“…syndromes [TRAPS] and systemic-onset juvenile idiopathic arthritis [Still's disease]) suggested a common etiological pathway (213)(214)(215)(216)(217)(218)(219)(220)(221)(222)(223)(224). Likely, relapsing pericarditis presents family aggregation in 10% of patients (225).…”

Section: The Autoinflammatory Processes In Recurrent Pericarditismentioning

confidence: 99%

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

et al. 2022

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The field of inflammatory disease of the heart or “cardio-immunology” is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

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Section: The Autoinflammatory Processes In Recurrent Pericarditismentioning

confidence: 99%

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

et al. 2022

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“…Regarding CAPS, it is well documented that some patients with a classical phenotype of this SAID may not have mutations in NLRP3 gene, which can be explained by mosaicism. 15 , 27 , 28 Interestingly, dominant inheritance is evident in about 75% of patients with Muckle-Wells-syndrome and FCAS, whereas CINCA is usually due to de novo mutations and somatic mosaicism occurring during fetal growth, which may explain late onset of the disease. 29–33 …”

Section: Discussionmentioning

confidence: 99%

“…The genetic characterization of these patients is provided by the analysis of one or more SAID-related genes. 5 , 14 , 15 This analysis is performed by a commercial laboratory with specific software either by Sanger sequencing for single genes, such as MEFV, TNFRSF1A , and MVK or by NGS for multigene panels associated with recurrent fever syndromes, which include the following genes: ADAR, AP1S3, ASAH1, CARD14, DDX58, ELANE, HAX1, IFIH1, IL10RA, IL10RB, IL1RN, IL36RN, LPIN2, MEFV, MVK, NLRC4, NLRP1, NLRP12, NLRP3, NOD2, OTULIN, PLCG2, PSMB8, PSTPIP1, RBCK1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, SLC29A3, TMEM173, TNFAIP3, TNFRSF11A, TNFRSF1A, TREX1 . This workflow allows us to detect already described as well as not yet reported genetic variants.…”

Section: Methodsmentioning

confidence: 99%

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases

Zinterl¹,

Costa-Reis²,

Esteves³

et al. 2022

JMDH

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Background Systemic autoinflammatory diseases (SAID) are characterized by inappropriate activation of the innate immune system and include not only monogenic periodic fever syndromes but also multifactorial conditions. As SAID are rare and represent a diagnostic challenge, a multidisciplinary approach is important to ensure successful diagnosis and adequate follow-up of these patients. Objective To describe the organization of our multidisciplinary SAID clinic and to characterize our clinical experience, highlighting the benefits of multidisciplinary team management. Methods Our SAID clinic takes place monthly and is managed by pediatric rheumatologists closely collaborating with pediatricians specialized in infectious diseases and immunodeficiencies and one medical geneticist. Patients’ data are systematically incorporated in the Rheumatic Diseases Portuguese Register (Reuma.pt). Biological samples are stored in a biobank. We describe our clinical experience based on SAID patients registered into Reuma.pt/SAID between July 2011 and June 2020. Results We have registered 176 patients, with a median age of disease onset of 3.1 ± 4.4 years and median age at disease diagnosis of 4.7 ± 4.0 years. Most patients were diagnosed with periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) (n=133), 20 with undefined SAID (uSAID) and 13 with monogenic SAID, including familial Mediterranean fever (FMF) (n=5), tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (n=1), cryopyrin-associated periodic disease (CAPS) (n=1), and hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) (n=2). A genetic test was performed in 31 patients (18%), and in 26% of these a mutation responsible for the phenotype was found. Thirty-four patients (19%) achieved remission. Conclusion FMF was the most common monogenic SAID and the percentage of patients with an identified causal mutation was low. A structured electronic clinical record coupled with a biobank and a multidisciplinary approach are crucial to ensure successful diagnosis and adequate follow-up of these patients.

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“…The aberrant activation of NLRP3 inflammasome is involved in the onset and progression of a wide range of human diseases [ 24 ], among which auto-inflammatory [ 25 ], inflammatory and autoimmune [ 26 , 27 , 28 , 29 ], neurodegenerative [ 30 , 31 ], cardiovascular [ 32 , 33 , 34 ] and metabolic diseases [ 35 , 36 , 37 ] are the most studied. It is not surprising that a concerted research effort toward the discovery of small molecules able to block NLRP3 activation is being performed both by industry and academia.…”

Section: Introductionmentioning

confidence: 99%

Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

et al. 2021

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In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds.

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Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?

Cited by 62 publications

References 122 publications

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases

Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

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