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Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

ABSTRACT: Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment. Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

SUBMITTER: Morishita M

PROVIDER: S-EPMC5519464 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Morishita Michiko M Watanabe Haruki H Yan Minglu M Zeggar Sonia S Hiramatsu Sumie S Ohashi Keiji K Miyawaki Yoshia Y Katsuyama Eri E Katsuyama Takayuki T Takano Narazaki Mariko M Toyota Tatebe Noriko N Sunahori Watanabe Katsue K Kawabata Tomoko T Sada Ken-Ei KE Wada Jun J

Internal medicine (Tokyo, Japan) 20170701 13

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' media ...[more]

PMID: 28674351

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Project description:OBJECTIVE:To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]). METHODS:A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. RESULTS:Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor ? [sIL-2R?], and nerve growth factor ? [NGF?]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2R?, and NGF?) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-?, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. CONCLUSION:Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.

Project description:ObjectiveThis study aimed to identify plasma biomarkers that are significantly altered in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and are closely associated with AAV disease activity, as well as to explore their role in the pathogenesis of AAV.MethodsCytokines were measured using Human Immune Response Panel 80-Plex in plasma from 59 patients with AAV and 20 healthy controls (HCs). The differentially expressed cytokines between the two groups and the possible signaling pathway involved in the pathogenesis of AAV were analyzed by bioinformatics. Relationship analysis was performed between these cytokines and clinical parameters to identify the biomarkers that can effectively indicate disease activity.ResultsWe identified 65 differentially expressed cytokines between the two groups. Among them, 43 cytokines significantly affected the risk of AAV. Bioinformatic analysis showed that the 43 cytokines were primarily enriched in signaling pathways such as cytokine-cytokine receptor interaction, viral protein interaction with cytokine and cytokine receptor, chemokine signaling pathway, and IL-17 signaling pathway. The levels of 25 cytokines were significantly positively correlated with Birmingham Vasculitis Activity Score (BVAS), and the levels of 2 cytokines were significantly negatively correlated with BVAS. Receiver operating characteristic analysis showed that 9 cytokines can distinguish between disease relapse and remission (PTX3: area under curve (AUC)=0.932, IL34: AUC=0.856, IL2RA: AUC=0.833, CCL23: AUC=0.826, VEGFA: AUC=0.811, TNFSF13: AUC=0.795, Granzyme A: AUC=0.788, CSF3: AUC=0.773 and IL1A: AUC=0.765). The elevated levels of these 9 cytokines suggested a risk of disease relapse. The AUC of CCL11 in disease relapse and remission was 0.811 (p=0.0116). Unlike the other 9 cytokines, a negatively association existed between CCL11 level and the risk of disease relapse.ConclusionA group of cytokines that may be involved in AAV pathogenesis was identified. Increased PTX3, IL34, IL2RA, CCL23, and VEGFA levels correlate with active disease in AAV and may be used as biomarkers to identify the disease relapse of AAV.

Project description:ImportanceAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic small vessel vasculitis characterized by circulating ANCAs targeting proteinase 3 (PR3) or myeloperoxidase (MPO) and associated with excess morbidity and mortality. Myeloperoxidase-ANCA-positive AAV and PR3-ANCA-positive AAV are increasingly recognized to have differences in genetic risk, pathogenesis, and response to treatment. Risk factors for AAV, including cigarette smoking, are poorly understood.ObjectiveTo examine the association between cigarette smoking and AAV.Design, setting, and participantsThis case-control study included a consecutive inception cohort of 484 patients with AAV diagnosed from 2002 to 2017 compared with a cohort of sex-, race-, and age-matched controls. Eleven cases were excluded owing to discordant smoking information in the electronic health record. Controls were randomly selected from participants recruited to the Partners HealthCare Biobank between its inception in 2010 and 2018 and who completed a smoking questionnaire and were not diagnosed with AAV (n = 30 536).ExposuresSmoking status (current, former, never) and pack-years of cigarette smoking were determined from review of the electronic medical record and smoking questionnaires.Main outcomes and measuresPatients with AAV were individually matched with 3 randomly-selected controls based on sex, race, and age (within 2 years difference). Conditional logistic regression was performed to examine the association between cigarette smoking and AAV using odds ratios (OR) and 95% confidence intervals (CIs).ResultsOverall, 473 cases were matched with 1419 controls (mean [SD] age, 59 [16] years; 281 women [59%], 396 white [84%]). Patients with AAV were more likely to be former (OR, 1.6; 95% CI, 1.3-2.0) or current smokers (OR, 2.7; 95% CI, 1.8-4.1); there was a dose-response relationship according to pack-years of exposure (P < .001). These associations were especially strong among participants with MPO-ANCA-positive disease (former smokers: OR, 1.7; 95% CI, 1.3-2.3; current smokers: OR, 3.5; 95% CI, 2.1-6.1) but not in participants with PR3-ANCA-positive AAV (former smokers: OR, 1.3; 95% CI, 0.9-2.0; current smokers: OR, 1.7; 95% CI, 0.8-3.5). After stratifying by selected demographics and disease manifestations, these associations remained strong.Conclusions and relevanceCigarette smoking was associated with AAV, especially MPO-ANCA-positive AAV. Further studies are needed to investigate a potential pathogenic mechanism.

Project description:Background: Patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) may require intensive care unit (ICU) admission due to different reasons, and the in-ICU mortality is high among AAV patients. The aim of this study was to explore the clinical features and risk factors of mortality of patients with AAV in the ICU. Methods: A retrospective study was conducted based on 83 AAV patients admitted to the ICU in a tertiary medical institution in China. Data on clinical characteristics, laboratory tests, treatment in ICU and outcomes were collected. The data were analyzed using univariate and multivariate logistic regression analysis to explore the variables that were independently related to mortality. Kaplan-Meier method was used to assess the long-term survival. Results: Among the 83 patients, 41 (49.4%) were female. The mean age of patients was 66 ± 13 years. Forty-four patients deceased, with the in-ICU mortality of 53%. The most common cause for ICU admission was active vasculitis (40/83, 48.2%). The main cause of death was infection (27/44, 61.4%) followed by active vasculitis (15/44, 34.1%). A multivariate analysis revealed that the Acute Physiology and Chronic Health Evaluation II (APACHE II) at ICU admission (OR = 1.333, 95% CI: 1.031-1.722) and respiratory failure (OR = 620.452, 95% CI: 11.495-33490.306) were independent risk factors of in-ICU death. However, hemoglobin (OR = 0.919, 95% CI: 0.849-0.995) was an independent protective factor. The nomogram established in this study was practical in predicting the risk of in-ICU mortality for AAV patients. Moreover, for 39 patients survived to the ICU stay, the cumulative survival rates at 0.5, 1, and 5 years were 58.3%, 54.2%, and 33.9%, respectively, and the median survival time was 14 months. Conclusion: In our study, active vasculitis was the most frequent reason for ICU admission, and the main cause of death was infection. APACHE II and respiratory failure were independent risk factors while hemoglobin was an independent protective factor of in-ICU mortality for AAV patients admitted to the ICU. The risk prediction model developed in this study may be a useful tool for clinicians in early recognition of high-risk patients and applying appropriate management.

Dataset Information

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Publications

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

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