Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA‐like phenotype

Grandemange, Sylvie; Cabasson, Sébastien; Sarrabay, Guillaume; Pène, Jérôme; Rittore, Cécile; Sanchez, Elodie; Chastang, Marie-Caroline; Guyon, G.; Pillet, P.; Touitou, Isabelle

doi:10.1002/mgg3.229

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…The TRAPS patient carried the R92Q variant in the TNFRSF1A gene, which is a common variant in Caucasian populations but not undoubtedly considered to be a true mutation – it could represent a low‐penetrance variant, a functional polymorphism, or a susceptibility factor for inflammation, as it is associated with adult-onset and milder clinical features, as well as lower risk of amyloidosis. 22 , 23 …”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“… 52 Functional analysis of blood samples from R92Q carriers found an increased plasmatic level of monocyte chemoattractant protein-1 (MCP-1/CCL2) and TNF-induced IL-12p70 release. 11 Whether such molecular effects are sufficient to cause an autoinflammatory picture by themselves is still being discussed and the phenotypic variability of R92Q patients does not yet offer a clear pathophysiological explanation. A recent concept hypothesizes a synergic pro-inflammatory function of R92Q in a context of oligogenic transmission, intermediate in the continuum from monogenic to multifactorial polygenic inheritance: the affected individual would inherit multiple low-frequency allele variants that act synergistically in determining the clinical picture.…”

Section: Discussionmentioning

confidence: 99%

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

Gaggiano

Rigante

Hernández‐Rodríguez

et al. 2021

Therapeutic Advances in Musculoskeletal

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Background: This study aims at describing the therapeutic outcome of patients carrying the R92Q variant in the TNFRSF1A gene treated with anakinra (ANA) or canakinumab (CAN) and identifying any factors predictive of complete response to IL-1 inhibition. Methods: Clinical data of patients treated with ANA or CAN for recurrent inflammatory attacks due to the presence of the R92Q variant were retrospectively collected and analysed. Results: Data about 20 treatment courses with IL-1 inhibitors (16 with ANA and 4 with CAN) from 19 patients were collected. Mean age at disease onset was 20.2 ± 14.8 years. In 5 cases (26%) the R92Q variant was found in a family member affected by recurrent fever. The therapeutic response was complete in 13(68%) and partial in 2 patients (11%); treatment failure was observed in 4 cases (21%). Median AIDAI decreased from 10 (interquartile range [IQR] = 28) to 0 (IQR = 1) at the 12-month follow-up visit ( p < 0.001). Mean ESR and median CRP dropped respectively from 40.8 ± 24.8 to 9.1 ± 4.5 mm/h ( p < 0.001) and from 3.0 (IQR = 1.9) to 0.3 (IQR = 0.3) mg/dl ( p < 0.001) after 12 months of treatment. A steroid-sparing effect was observed from the third month of treatment ( p < 0.01). Thirteen patients (65%) were still on treatment at the last follow-up visit (median duration of treatment 17 (IQR = 38) months). The presence of R92Q mutation in a symptomatic relative ( p = 0.022), the relapsing remitting disease course ( p < 0.001) and the presence of migratory erythematous skin rashes during fever attacks ( p = 0.005) were associated with complete efficacy of IL-1 inhibitors. Conclusions: R92Q patients showed a favourable response to ANA and CAN, particularly when the mutation segregated in a family member and when a relapsing-remitting disease course or TNF-α receptor-associated periodic syndrome (TRAPS) typical skin rash were observed. In the subgroup of patients not taking advantage of IL-1 blockage different molecular mechanisms underlying the autoinflammatory picture are likely to exist.

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“…Best known examples include p.R121Q (R92Q) and p.P75L (P46L) in TNFRSF1A , p.E148Q and p.P369S in MEFV , and p.V198M (V200M), p.R488K (R490K) and p.Q703K (Q705K) in NLRP3 . Some of these variants have been identified at a higher frequency (also known as burden of variants ) in patients with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome [37–41].…”

Section: Monogenic Autoinflammatory Diseases and Mode Of Inheritancementioning

confidence: 99%

Current and future advances in genetic testing in systemic autoinflammatory diseases

Schnappauf

Aksentijevich

2019

Rheumatology

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Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.

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Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA‐like phenotype

Cited by 10 publications

References 15 publications

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

Current and future advances in genetic testing in systemic autoinflammatory diseases

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