CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.

OBJECTIVE: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. METHODS: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. RESULTS: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. CONCLUSION: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

Assessing Risk of Disease Progression and Pharmacological Management of Autosomal Dominant Polycystic Kidney Disease: A Canadian Expert Consensus.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder worldwide. The disease is characterized by renal cysts and progressive renal failure due to progressive enlargement of cysts and renal fibrosis. An estimated 45% to 70% of patients with ADPKD progress to end-stage renal disease by age 65 years. Although both targeted and nontargeted therapies have been tested in patients with ADPKD, tolvaptan is currently the only pharmacological therapy approved in Canada for the treatment of ADPKD. The purpose of this consensus recommendation is to develop an evidence-informed recommendation for the optimal management of adult patients with ADPKD. This document focuses on the role of genetic testing, the role of renal imaging, predicting the risk of disease progression, and pharmacological treatment options for ADPKD. These areas of focus were derived from 2 national surveys that were disseminated to nephrologists and patients with ADPKD with the aim of identifying unmet needs in the management of ADPKD in Canada. Specific recommendations are provided for the treatment of ADPKD with tolvaptan.

La polykystose rénale autosomique dominante (PKRAD) est le trouble rénal héréditaire le plus fréquent dans le monde. La maladie est caractérisée par la présence de kystes rénaux et par une insuffisance rénale progressive provoquée par l'élargissement progressif des kystes et par une fibrose rénale. Environ 45 à 70% des patients atteints de PKRAD verront leur état évoluer vers l'insuffisance rénale terminale avant l'âge de 65 ans. Bien que les thérapies ciblées et non ciblées aient été testées chez des patients atteints de PKRAD, le tolvaptan est le seul médicament approuvé au Canada pour le traitement de la PKRAD. L'objectif de cette recommandation consensuelle est l'élaboration de recommandations fondées sur des données probantes pour une prise en charge optimale des patients adultes atteints de PKRAD. Ce document met l'accent sur le rôle du dépistage génétique et de l'imagerie rénale, sur les façons de prédire le risque de progression de la maladie et sur les options de traitement pharmacologique de la PKRAD. Ces domaines d'action dérivent de deux enquêtes nationales diffusées aux néphrologues et aux patients canadiens atteints de PKRAD, et qui avaient pour but d'identifier les besoins non satisfaits dans la prise en charge le la PKRAD au Canada. Des recommandations spécifiques sont fournies pour le traitement de la PKD avec le tolvaptan.

Complication rates after left- versus right-sided carotid endarterectomy.

BACKGROUND: Studies suggest that the side of carotid endarterectomy (CE) may influence the rate of postoperative complications. We sought to clarify this by (1) analysis of individual-level data from 3 large studies and (2) systematic review and meta-analysis of additional published descriptions of outcomes by side. METHODS AND RESULTS: The Western Canada Carotid Endarterectomy (WCCE) study (n=3164) was analyzed for outcomes by side along with data from the North American Symptomatic Carotid Endarterectomy Trial (NASCET; n=1415), and the ASA [Acetylsalicylic Acid] in Carotid Endarterectomy Trial (ACE; n=2469). Pooled analysis of individual-level data from these three studies allowed calculation of rate ratios for stroke or death by side. Medline and EMBASE were searched to identify additional studies reporting CE outcomes by side, and an overall risk ratio for outcomes by side was determined with fixed-effects meta-analysis. The WCCE in-hospital stroke or death rates for left and right-sided CE were 3.72% and 3.07%, respectively (P=0.27). A pooled analysis of the NASCET and ACE trials also revealed higher stroke or death rates for left-sided CE (5.39% versus 2.96%; P<0.001). The corresponding risk-adjusted rate ratios for stroke or death for left- versus right-sided surgery were 1.22 (95% CI, 0.83 to 1.77) for WCCE and 1.82 (1.32 to 2.50) for the pooled NASCET and ACE trials. Systematic review of the literature identified 2 additional studies. Meta-analysis of all 5 available studies yielded a corresponding pooled rate ratio for stroke or death of 1.36 (1.18 to 1.56). CONCLUSIONS: Left-sided CE is consistently associated with higher postoperative adverse event rates. Research into potential mechanisms is required to explain and address this finding.

PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions.

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease caused by expanded (GCN)12-17 stretches encoding the N-terminal polyalanine domain of the poly(A) binding protein nuclear 1 (PABPN1). OPMD is characterized by intranuclear inclusions (INIs) in skeletal muscle fibers, which contain PABPN1, molecular chaperones, ubiquitin, proteasome subunits, and poly(A)-mRNA. We describe an adenoviral model of PABPN1 expression that produces INIs in most cells. Microarray analysis revealed that PABPN1 overexpression reproducibly changed the expression of 202 genes. Sixty percent of upregulated genes encode nuclear proteins, including many RNA and DNA binding proteins. Immunofluorescence microscopy revealed that all tested nuclear proteins encoded by eight upregulated genes colocalize with PABPN1 within the INIs: CUGBP1, SFRS3, FKBP1A, HMG2, HNRPA1, PRC1, S100P, and HSP70. In addition, CUGBP1, SFRS3, and FKBP1A were also found in OPMD muscle INIs. This study demonstrates that a large number of nuclear proteins are sequestered in OPMD INIs, which may compromise cellular function.

Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains.

Mutations causing expansions of polyalanine domains are responsible for nine hereditary diseases. Other GC-rich sequences coding for some polyalanine domains were found to be polymorphic in human. These observations prompted us to identify all sequences in the human genome coding for polyalanine stretches longer than four alanines and establish their degree of polymorphism. We identified 494 annotated human proteins containing 604 polyalanine domains. Thirty-two percent (31/98) of tested sequences coding for more than seven alanines were polymorphic. The length of the polyalanine-coding sequence and its GCG or GCC repeat content are the major predictors of polymorphism. GCG codons are over-represented in human polyalanine coding sequences. Our data suggest that GCG and GCC codons play a key role in polyalanine-coding sequence appearance and polymorphism. The grouping by shared function of polyalanine-containing proteins in Homo sapiens, Drosophila melanogaster and Caenorhabditis elegans shows that the majority are involved in transcriptional regulation. Phylogenetic analyses of HOX, GATA and EVX protein families demonstrate that polyalanine domains arose independently in different members of these families, suggesting that convergent molecular evolution may have played a role. Finally polyalanine domains in vertebrates are conserved between mammals and are rarer and shorter in Gallus gallus and Danio rerio. Together our results show that the polymorphic nature of sequences coding for polyalanine domains makes them prime candidates for mutations in hereditary diseases and suggests that they have appeared in many different protein families through convergent evolution.