scholarly journals Total Haemolytic Complement Activity at Diagnosis as an Indicator of the Baseline Activity of Antineutrophil Cytoplasmic Antibody-associated Vasculitis

2021 ◽  
Vol 28 (2) ◽  
pp. 85-93
Author(s):  
Jung Yoon Pyo ◽  
Lucy Eunju Lee ◽  
Sung Soo Ahn ◽  
Jason Jungsik Song ◽  
Yong-Beom Park ◽  
...  
Keyword(s):  
Antineutrophil Cytoplasmic Antibody ◽  
Complement Activity ◽  
Baseline Activity

SKY59, A Novel Recycling Antibody for Complement-mediated Diseases

2020 ◽  
Vol 27 (25) ◽  
pp. 4157-4164 ◽  
Author(s):  
Taku Fukuzawa ◽  
Junichi Nezu
Keyword(s):  
Inhibitory Effect ◽  
Biologic Agent ◽  
Microbial Infection ◽  
Duration Of Action ◽  
Complement Activity ◽  
Body Of Knowledge ◽  
Therapeutic Benefits ◽  
Long Duration ◽  
Recycling Technology ◽  
Current Therapies

Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders. Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently. Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation. Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

scholarly journals ANCA Status or Clinical Phenotype — What Counts More?

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Martin Windpessl ◽  
Erica L. Bettac ◽  
Philipp Gauckler ◽  
Jae Il Shin ◽  
Duvuru Geetha ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Granulomatosis With Polyangiitis ◽  
Clinical Phenotype ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Cardiovascular Death ◽  
Genetic Associations ◽  
Ongoing Debate ◽  
The Past ◽  
Anca Associated Vasculitis

Abstract Purpose of Review There is ongoing debate concerning the classification of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. That is, whether classification should be based on the serotype (proteinase 3 (PR3)- or myeloperoxidase (MPO)-ANCA) or on the clinical phenotype (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)). To add clarity, this review focused on integration of the most recent literature. Recent Findings Large clinical trials have provided evidence that a serology-based risk assessment for relapses is more predictive than distinction based on the phenotype. Research conducted in the past decade indicated that a serology-based approach more closely resembles the genetic associations, the clinical presentation (i.e., lung involvement), biomarker biology, treatment response, and is also predicting comorbidities (such as cardiovascular death). Summary Our review highlights that a serology-based approach could replace a phenotype-based approach to classify ANCA-associated vasculitides. In future, clinical trials and observational studies will presumably focus on this distinction and, as such, translate into a “personalized medicine.”

scholarly journals A 44-kb deleted-type copy number variation is associated with decreasing complement component activity and calf mortality in Japanese Black cattle

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shinji Sasaki ◽  
Youko Miki ◽  
Takayuki Ibi ◽  
Hiroyuki Wakaguri ◽  
Yuichi Yoshida ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Copy Number Variation ◽  
Copy Number ◽  
Risk Allele ◽  
Wild Type ◽  
Japanese Black Cattle ◽  
Complement Activity ◽  
Categorical Trait ◽  
Number Variation ◽  
Calf Mortality

Abstract Background Calf mortality generally occurs in calves prior to weaning, which is a serious problem in cattle breeding. Several causative variants of monogenic Mendelian disorders in calf mortality have been identified, whereas genetic factors affecting the susceptibility of calves to death are not well known. To identify variants associated with calf mortality in Japanese Black cattle, we evaluated calf mortality as a categorical trait with a threshold model and performed a genome-wide copy number variation (CNV) association study on calf mortality. Results We identified a 44-kb deleted-type CNV ranging from 103,317,687 to 103,361,802 bp on chromosome 5, which was associated with the mortality of 1–180-day-old calves. The CNV harbored C1RL, a pseudogene, and an IncRNA localized in the C1R and C1S gene cluster, which is a component of the classical complement activation pathway for immune complexes for infectious pathogens. The average complement activity in CNVR_221 homozygotes at postnatal day 7 was significantly lower than that of wild-type animals and heterozygotes. The frequency of the risk allele in dead calves suffering from diarrhea and pneumonia and in healthy cows was 0.35 and 0.28, respectively (odds ratio = 2.2, P = 0.016), suggesting that CNVR_221 was associated with the mortality of Japanese Black calves suffering from an infectious disease. Conclusions This study identified a deleted-type CNV associated with the mortality of 1–180-day-old calves. The complement activity in CNVR_221 homozygotes was significantly lower than that in heterozygotes and wild type animals. The frequency of the risk allele was higher in dead calves suffering from an infectious disease than in healthy cows. These results suggest that the existence of CNVR_221 in calves could be attributed to a reduction in complement activity, which in turn leads to susceptibility to infections. Thus, the risk allele could serve as a useful marker to reduce the mortality of infected Japanese Black calves.

scholarly journals AB1176 UTILITY OF REDOSER TOOL IN DOSE OPTIMIZATION OF BIOLOGICAL THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS IN CLINICAL PRACTICE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1879.2-1879
Author(s):  
A. M. Cabezas-Lucena ◽  
M. Morales-Águila ◽  
S. Manrique Arija ◽  
C. Fuego-Varela ◽  
L. Cano Garcia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Practice ◽  
Dose Reduction ◽  
Biological Therapy ◽  
Activity Index ◽  
Standard Dose ◽  
Disease Evolution ◽  
Independent Variables ◽  
Outpatient Unit ◽  
Baseline Activity

Background:Objectives:To describe the characteristics of patients with rheumatoid arthritis (RA) in dose reduction of biological therapy (BT) in clinical practice and identify possible factors associated with the time in dose reduction and verify the utility of REDOSER tool.Methods:Design:A retrospective, observational longitudinal study under conditions of clinical practice.Patients:RA in BT dose reduction between 2007- 2019 were selected. Inclusion criteria: RA according to ACR 2010 criteria which have been initiated BT dose reduction. Patients with BT are followed prospectively every 3-4 months in a specialized outpatient unit of BT dose reduction with a pre-established protocol for data collection and registered in a database.Variables: Primary:Time in reduction: was defined as the time in which patients maintained the BT optimization andRelapse at 12 and 24 months: percentage of patients who, after starting BT optimization, return to the previous or standard dose.Secondary variables:REDOSER:Appropriate, Doubtful and Inappropriate (If dose reduction was adequate according to the REDOSER tool applied retrospectively were evaluated). Other variables: Demographic, clinical-analytical: time of disease evolution, RF, anti CCP antibodies, Number of Tender Joints, Number of swollen joints, erosions, activity index (DAS28, SDAI, CDAI) and physical function (HAQ). Previous treatments.Statistical Analysis:descriptive, bivariate using x2 and T-Student among patients with and without relapse at 24 months and multivariate linear regression to identify independent variables associated with the time in BT dose reduction (DV: time in reduction).Results:59 patients with RA were included. Table 1 shows the main characteristics of the subjects. The average (SD) of optimization in months was 17.9 (17.7). Ten patients (16.9%) relapsed at 12 months and 16 (27.1%) at 24 months. The mean (SD) of DAS28 and SDAI of patients who relapsed at 24 months was higher compared to baseline DAS28 (2.3 [0.9] vs. 1.5 [0.8]; p = 0.015) and SDAI (7.8 [6.3] versus 3.3 [1.6]; p 0.05). These patients who relapsed at 24 months compared to patients who did not have more erosions at the start of BT (p = 0.004), longer duration of disease (p = 0.072) and greater baseline activity of DAS28 (p = 0.017), of SDAI (p = 0.030) and CDAI (p = 0.036). After simulating the REDOSER tool to all patients at the beginning of the OBT, 28 patients (56%) were “Appropriate”, 20 (40%) “Doubtful” and 2 (4%) “Inappropriate” of which they continue in OBT at the conclusion of study 22, 10 and 0, respectively (p = 0.020). In the multivariant analysis, the independent variables that are associated with time in dose reduction of BT were baseline DAS28 (β = -0.660, 95% CI[2.7-14.0]; p=0.014) and age (β=-0.800, 95% CI [0.8-0.0]; p=0.038).Conclusion:The majority of the patients with RA who initiate BT dose reduction maintain the optimization after 24 months. REDOSER can be useful in clinical practice to assess the BT optimization in patients with RA. A longer time in BT dose reduction was associated with lower values of DAS28 at the beginning and younger age of the patients.Figure 1:Disclosure of Interests:None declared

scholarly journals Proteinuria Indicates Decreased Normal Glomeruli in ANCA-Associated Glomerulonephritis Independent of Systemic Disease Activity

2021 ◽  
Vol 10 (7) ◽  
pp. 1538
Author(s):  
Désirée Tampe ◽  
Peter Korsten ◽  
Philipp Ströbel ◽  
Samy Hakroush ◽  
Björn Tampe
Keyword(s):  
Disease Activity ◽  
Systemic Disease ◽  
Renal Involvement ◽  
Kidney Injury ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Clinicopathological Characteristics ◽  
Renal Outcome ◽  
Study Results ◽  
Renal Biopsies ◽  
Stage Renal Disease

Background: Renal involvement is a common and severe complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), potentially resulting in a pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. There is recent evidence that the degree of proteinuria at diagnosis is associated with long-term renal outcome in ANCA GN. Therefore, we here aimed to systematically describe the association between proteinuria and clinicopathological characteristics in 53 renal biopsies with ANCA GN and corresponding urinary samples at admission. Methods: A total number of 53 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included from 2015 to 2021 in a single-center study. Results: Proteinuria correlated with myeloperoxidase (MPO) subtype, diagnosis of microscopic polyangiitis (MPA) and severe deterioration of kidney function. Proteinuria was most prominent in sclerotic class ANCA GN and ANCA renal risk score (ARRS) high risk attributed to nonselective proteinuria, including both glomerular and tubular proteinuria. Finally, there was no association between proteinuria and systemic disease activity, suggesting that proteinuria reflected specific renal involvement in AAV rather that systemic disease activity. Conclusions: In conclusion, proteinuria correlated with distinct clinicopathological characteristics in ANCA GN, mostly attributed to a reduced fraction of normal glomeruli. Furthermore, proteinuria in ANCA GN reflected specific renal involvement in AAV rather than systemic disease activity. Therefore, urinary findings could further improve our understanding of mechanisms promoting kidney injury and progression of ANCA GN.

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