Publications by authors named "Alvise Berti"

66 Publications

Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis.

JCI Insight 2021 Nov 22;6(22). Epub 2021 Nov 22.

Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.

BACKGROUNDLittle is known about the autoreactive B cells in antineutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3-reactive (PR3+) B cells.METHODSMulticolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets).RESULTSThe frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%-6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%-5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%-2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001).CONCLUSIONThis study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells.Trial registrationClinicalTrials.gov NCT00104299.FundingThe Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.
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http://dx.doi.org/10.1172/jci.insight.150999DOI Listing
November 2021

Immune and cellular damage biomarkers to predict COVID-19 mortality in hospitalized patients.

Curr Res Immunol 2021 16;2:155-162. Epub 2021 Sep 16.

Department of Pulmonary Medicine, Thoracic Disease Research Unit, Mayo Clinic, Rochester, USA.

Early prediction of COVID-19 in-hospital mortality relies usually on patients' preexisting comorbidities and is rarely reproducible in independent cohorts. We wanted to compare the role of routinely measured biomarkers of immunity, inflammation, and cellular damage with preexisting comorbidities in eight different machine-learning models to predict mortality, and evaluate their performance in an independent population. We recruited and followed-up consecutive adult patients with SARS-Cov-2 infection in two different Italian hospitals. We predicted 60-day mortality in one cohort (development dataset, n = 299 patients, of which 80% was allocated to the development dataset and 20% to the training set) and retested the models in the second cohort (external validation dataset, n = 402). Demographic, clinical, and laboratory features at admission, treatments and disease outcomes were significantly different between the two cohorts. Notably, significant differences were observed for %lymphocytes (p < 0.05), international-normalized-ratio (p < 0.01), platelets, alanine-aminotransferase, creatinine (all p < 0.001). The primary outcome (60-day mortality) was 29.10% (n = 87) in the development dataset, and 39.55% (n = 159) in the external validation dataset. The performance of the 8 tested models on the external validation dataset were similar to that of the holdout test dataset, indicating that the models capture the key predictors of mortality. The shap analysis in both datasets showed that age, immune features (%lymphocytes, platelets) and LDH substantially impacted on all models' predictions, while creatinine and CRP varied among the different models. The model with the better performance was model 8 (60-day mortality AUROC 0.83 ± 0.06 in holdout test set, 0.79 ± 0.02 in external validation dataset). The features that had the greatest impact on this model's prediction were age, LDH, platelets, and %lymphocytes, more than comorbidities or inflammation markers, and these findings were highly consistent in both datasets, likely reflecting the virus effect at the very beginning of the disease.
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http://dx.doi.org/10.1016/j.crimmu.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444380PMC
September 2021

Dr. Berti et al reply.

J Rheumatol 2021 Sep 15. Epub 2021 Sep 15.

University of Trento and Santa Chiara Hospital, Trento, Italy; Rheumatology Department, Brest Teaching Hospital, Brest, France; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, and Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA; Division of Rheumatology, and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. This work was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R01AG034676, and Clinical and Translational Science Awards Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. E.L Matteson, Division of Rheumatology, and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine and Science, 200 1st St. SW, Rochester, MN 55902, USA. Email:

We read with interest the comment of Dr. Kawada on our article that showed an inverse association between current smoking status and primary (p-) Sjögren syndrome (SS), and no association between obesity and pSS..
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http://dx.doi.org/10.3899/jrheum.210968DOI Listing
September 2021

Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis (EGPA): a European multicenter observational study.

Arthritis Rheumatol 2021 Aug 4. Epub 2021 Aug 4.

Nephrology and Dialysis Unit (ERKnet Member)-CMID, Center of Research of Immunopathology and Rare Diseases, San Giovanni Bosco Hospital and University of Turin, Turin, Italy.

Objective: Mepolizumab proved efficacious for eosinophilic granulomatosis with polyangiitis (EGPA, former Churg-Strauss) at the dosage of 300mg/4 weeks in the randomized controlled MIRRA trial. Few successful real-life experiences with the dosage approved for severe eosinophilic asthma (100mg/4 weeks) were recently reported. We retrospectively assessed the effectiveness and safety of mepolizumab 100 and 300mg/4 weeks in a large European EGPA cohort.

Methods: We included all EGPA patients treated with mepolizumab at the recruiting centres in 2015-2020. Treatment response was evaluated from month 3 through 24 (T3-T24) after mepolizumab starting. Complete response (CR) was defined as no disease activity (Birmingham Vasculitis Activity Score, BVAS=0) and a prednisone dose ≤4mg/day. Respiratory outcomes included asthma and ear-nose-throat (ENT) exacerbations.

Results: We included 203 patients, of whom 191 at stable dosage (158 mepolizumab 100mg/4 weeks, 33 300mg/4 weeks). At T3, 25 patients (12.3%) had a CR. CR rates increased to 30.4% and 35.7% at T12 and T24 and were comparable between mepolizumab 100 and 300mg/4 weeks. Mepolizumab led to a significant reduction in BVAS, prednisone dose, eosinophil counts from T3 through T24, with no significant differences between 100 and 300 mg/4weeks. Eighty-two patients (40.4%) experienced asthma exacerbations [57/158 (36%) on 100mg/4 weeks; 17/33 (52%) on 300mg/4 weeks]. Thirty-one (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events, most being non-serious (38/44).

Conclusion: Mepolizumab both at 100 and 300mg/4 weeks is effective for EGPA. The two dosages should be compared in the setting of a controlled trial.
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http://dx.doi.org/10.1002/art.41943DOI Listing
August 2021

Asthma and COVID-19: a dangerous liaison?

Asthma Res Pract 2021 Jul 15;7(1). Epub 2021 Jul 15.

Allergy and Pneumology Outpatient Clinic, Bergamo, Italy.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), provoked the most striking international public health crisis of our time. COVID-19 can cause a range of breathing problems, from mild to critical, with potential evolution to respiratory failure and acute respiratory distress syndrome. Elderly adults and those affected with chronic cardiovascular, metabolic, and respiratory conditions carry a higher risk of severe COVID-19. Given the global burden of asthma, there are well-founded concerns that the relationship between COVID-19 and asthma could represent a "dangerous liaison".Here we aim to review the latest evidence on the links between asthma and COVID-19 and provide reasoned answers to current concerns, such as the risk of developing SARS-CoV-2 infection and/or severe COVID-19 stratified by asthmatic patients, the contribution of type-2 vs. non-type-2 asthma and asthma-COPD overlap to the risk of COVID-19 development. We also address the potential role of both standard anti-inflammatory asthma therapies and new biological agents for severe asthma, such as mepolizumab, reslizumab, and benralizumab, on the susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes.
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http://dx.doi.org/10.1186/s40733-021-00075-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279806PMC
July 2021

The Survival of Patients With Alveolar Hemorrhage Secondary to Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

J Rheumatol 2021 03;48(3):314-317

U. Specks, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.

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http://dx.doi.org/10.3899/jrheum.201297DOI Listing
March 2021

Small airway dysfunction and poor asthma control: a dangerous liaison.

Clin Mol Allergy 2021 May 29;19(1). Epub 2021 May 29.

Ospedale Santa Chiara and Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.

Asthma is a common chronic condition, affecting approximately 339 million people worldwide. The main goal of the current asthma treatment guidelines is to achieve clinical control, encompassing both the patient symptoms and limitations and the future risk of adverse asthma outcomes. Despite randomized controlled trials showing that asthma control is an achievable target, a substantial proportion of asthmatics remain poorly controlled in real life. The involvement of peripheral small airways has recently gained greater recognition in asthma, and many studies suggest that the persistent inflammation at these sites leads to small airway dysfunction (SAD), strongly contributing to a worse asthma control. Overall, the impulse oscillometry (IOS), introduced in the recent years, seems to be able to sensitively assess small airways, while conventional spirometry does not. Therefore, IOS may be of great help in characterizing SAD and guiding therapy choice. The aim of this article is to review the literature on SAD and its influence on asthma control, emphasizing the most recent evidence.
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http://dx.doi.org/10.1186/s12948-021-00147-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164746PMC
May 2021

Anti-neutrophil cytoplasmic antibody specificity determines a different clinical subset in granulomatosis with polyangiitis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):107-113. Epub 2021 May 19.

Department of rheumatology, IRCCS Policlinico S. Matteo Fondazione, University of Pavia, Italy.

Objectives: It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity.

Methods: Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA).

Results: Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p<0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p<0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p<0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009].

Conclusions: ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.
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May 2021

Meta-analysis of immune-related adverse events in phase 3 clinical trials assessing immune checkpoint inhibitors for lung cancer.

Crit Rev Oncol Hematol 2021 Jun 12;162:103351. Epub 2021 May 12.

Medical Oncology, Santa Chiara Hospital, Trento, Italy. Electronic address:

Introduction: The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment.

Patients And Methods: We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade ≥3) irAEs, drug discontinuation due to irAEs or toxic death.

Results: Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs.

Conclusions: Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103351DOI Listing
June 2021

Obesity is a Major Risk Factor for Hospitalization in Community-Managed COVID-19 Pneumonia.

Mayo Clin Proc 2021 04 4;96(4):921-931. Epub 2021 Feb 4.

Ospedale Santa Chiara and Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Italy; Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN. Electronic address:

Objective: We aimed to investigate whether the stratification of outpatients with coronavirus disease 2019 (COVID-19) pneumonia by body mass index (BMI) can help predict hospitalization and other severe outcomes.

Patients And Methods: We prospectively collected consecutive cases of community-managed COVID-19 pneumonia from March 1 to April 20, 2020, in the province of Bergamo and evaluated the association of overweight (25 kg/m ≤ BMI <30 kg/m) and obesity (≥30 kg/m) with time to hospitalization (primary end point), low-flow domiciliary oxygen need, noninvasive mechanical ventilation, intubation, and death due to COVID-19 (secondary end points) in this cohort. We analyzed the primary end point using multivariable Cox models.

Results: Of 338 patients included, 133 (39.4%) were overweight and 77 (22.8%) were obese. Age at diagnosis was younger in obese patients compared with those overweight or with normal weight (P<.001), whereas diabetes, dyslipidemia, and heart diseases were differently distributed among BMI categories. Azithromycin, hydroxychloroquine, and prednisolone use were similar between BMI categories (P>.05). Overall, 105 (31.1%) patients were hospitalized, and time to hospitalization was significantly shorter for obese vs over- or normal-weight patients (P<.001). In the final multivariable analysis, obese patients were more likely to require hospitalization than nonobese patients (hazard ratio, 5.83; 95% CI, 3.91 to 8.71). Results were similar in multiple sensitivity analyses. Low-flow domiciliary oxygen need, hospitalization with noninvasive mechanical ventilation, intubation, and death were significantly associated with obesity (P<.001).

Conclusion: In patients with community-managed COVID-19 pneumonia, obesity is associated with a higher hospitalization risk and overall worse outcomes than for nonobese patients.
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http://dx.doi.org/10.1016/j.mayocp.2021.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859712PMC
April 2021

Small-airway dysfunction in paediatric asthma.

Curr Opin Allergy Clin Immunol 2021 04;21(2):128-134

Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy.

Purpose Of Review: Asthma is a chronic inflammatory airway disorder that can involve the entire bronchial tree. Increasing evidence shows that ventilation heterogeneity and small airway dysfunction are relevant factors in the pathogenesis of asthma and represent a hallmark in adults with persistent asthma. Little is known about the contribution of peripheral airway impairment in paediatric asthma, mainly due to the inaccessibility to evaluation by noninvasive techniques, which have only been widely available in recent years.

Recent Findings: Emerging evidence suggests that small airways are affected from the early stages of the disease in childhood-onset asthma. Conventional lung function measurement, using spirometry, is unable to sensitively evaluate small airway function and may become abnormal only once there is a significant burden of disease. Recent studies suggest that chronic inflammation and dysfunction in the small airways, as detected with new advanced techniques, are risk factors for asthma persistence, asthma severity, worse asthma control and loss of pulmonary function with age, both in adults and children. Knowing the extent of central and peripheral airway involvement is clinically relevant to achieve asthma control, reduce bronchial hyper-responsiveness and monitor response to asthma treatment.

Summary: This review outlines the recent evidence on the role of small airway dysfunction in paediatric asthma development and control, and addresses how the use of new diagnostic techniques available in outpatient clinical settings, namely impulse oscillometry and multiple breath washout, could help in the early detection of small airway impairment in children with preschool wheezing and school-age asthma and potentially guide asthma treatment.
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http://dx.doi.org/10.1097/ACI.0000000000000728DOI Listing
April 2021

Prevalence and features of IOS-defined small airway disease across asthma severities.

Respir Med 2021 01 19;176:106243. Epub 2020 Nov 19.

Santa Chiara Hospital and Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy and Thoracic Disease Research Unit, Mayo Clinic, Rochester, USA. Electronic address:

Background: Impulse oscillometry (IOS) is a noninvasive method based on the forced oscillation technique able to detect small airway dysfunction (SAD) in asthma. We aimed to analyze the prevalence and the functional features of IOS-defined SAD across the different Global Initiative for Asthma (GINA) steps.

Methods: A cross-sectional, single-center study in which 400 consecutive adult patients with physician-diagnosed, community-managed asthma underwent standard spirometry and IOS, and were stratified by stepwise GINA classification. SAD was defined by IOS as a fall in resistance from 5 to 20 Hz [R5-R20]>0.07kPa × s × L.

Results: The prevalence of IOS-defined SAD ranged between 58.3% (GINA step 2) and 78.6% (GINA step 5), without statistically significant difference within GINA steps (p > 0.05 in all comparisons). Isolated SAD (i.e. without proximal airways involvement) was similarly represented across GINA steps 2-4. Peripheral airways resistance (R5-R20) tended to a progressive increase with the worsening of GINA steps, and was significantly higher in steps 4-5 compared to the other steps (p < 0.05). The proportion of patients with FEFdefined SAD (<60%) was lower than the IOS-defined one in GINA steps 2-4 (p < 0.05). Only non-significant or weak inverse correlations between R5-R20 and FEF were observed within each GINA step, with the exception of GINA step 5, which showed a strong, inverse correlation (r = -0.80, p = 0.0005).

Conclusions: This study shows that first, IOS-defined SAD is overwhelmingly present across asthma severities; second, airways resistance increases with the worsening of GINA steps; and third, SAD may be overlooked by standard spirometry, especially in milder asthma.
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http://dx.doi.org/10.1016/j.rmed.2020.106243DOI Listing
January 2021

Beyond Giant Cell Arteritis and Takayasu's Arteritis: Secondary Large Vessel Vasculitis and Vasculitis Mimickers.

Curr Rheumatol Rep 2020 11 7;22(12):88. Epub 2020 Nov 7.

Rheumatology, Mayo Clinic, Rochester, MN, USA.

Purpose Of Review: To provide an overview of mimickers of large vessel vasculitis (LVV), by the main presenting manifestation, i.e., systemic, vascular, and cranial manifestations.

Recent Findings: The main differential diagnoses in patients with giant cell arteritis (GCA) and Takayasu arteritis (TAK) presenting with systemic manifestations (i.e., fever, anorexia, weight loss, night sweats, arthralgia/myalgia, and/or increased inflammatory indexes) are neoplastic, infectious, or other inflammatory conditions. In patients with vascular manifestations (such as peripheral ischemia, vascular stenoses, or aneurysms), atherosclerosis and non-inflammatory vascular diseases should be excluded. In those presenting with predominant cranial symptoms (i.e., temporal headache, jaw claudication, scalp tenderness, transient or permanent vision loss), other causes of headache, cerebrovascular accidents, optic neuropathy, and neuromuscular syndromes need to be considered. The diagnosis of LVV maybe challenging, especially when patients present with atypical or incomplete clinical forms. In these cases, a multidisciplinary approach is strongly recommended.
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http://dx.doi.org/10.1007/s11926-020-00965-wDOI Listing
November 2020

Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Disease.

J Am Soc Nephrol 2020 11 21;31(11):2688-2704. Epub 2020 Aug 21.

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota

Background: Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX).

Methods: A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared.

Results: Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (=161) or RTX (=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], =0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], =0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], =0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], =0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], =0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], =0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], =0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], =0.330).

Conclusions: The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
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http://dx.doi.org/10.1681/ASN.2019111197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608964PMC
November 2020

Predicting Disease Activity in Systemic Vasculitides: On the Hunt for Potential Candidates.

J Rheumatol 2020 07;47(7):947-950

Department of Rheumatology, Santa Chiara Hospital, Department of Cellular, Computational, and Integrative Biology, University of Trento, Trento, Italy.

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http://dx.doi.org/10.3899/jrheum.190885DOI Listing
July 2020

Health Literacy and Outcomes Among Patients With Heart Failure: A Systematic Review and Meta-Analysis.

JACC Heart Fail 2020 06;8(6):451-460

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Electronic address:

Objectives: The purpose of this study was to determine if health literacy is associated with mortality, hospitalizations, or emergency department (ED) visits among patients living with heart failure (HF).

Background: Growing evidence suggests an association between health literacy and health-related outcomes in patients with HF.

Methods: We searched Embase, MEDLINE, PsycINFO, and EBSCO CINAHL from inception through January 1, 2019, with the help of a medical librarian. Eligible studies evaluated health literacy among patients with HF and assessed mortality, hospitalizations, and ED visits for all causes with no exclusion by time, geography, or language. Two reviewers independently selected studies, extracted data, and assessed the methodological quality of the identified studies.

Results: We included 15 studies, 11 with an overall high methodological quality. Among the observational studies, an average of 24% of patients had inadequate or marginal health literacy. Inadequate health literacy was associated with higher unadjusted risk for mortality (risk ratio [RR]: 1.67; 95% confidence interval [CI]: 1.18 to 2.36), hospitalizations (RR: 1.19; 95% CI: 1.09 to 1.29), and ED visits (RR: 1.17; 95% CI: 1.03 to 1.32). When the adjusted measurements were combined, inadequate health literacy remained statistically associated with mortality (RR: 1.41; 95% CI: 1.06 to 1.88) and hospitalizations (RR: 1.12; 95% CI: 1.01 to 1.25). Among the 4 interventional studies, 2 effectively improved outcomes among patients with inadequate health literacy.

Conclusions: In this study, the estimated prevalence of inadequate health literacy was high, and inadequate health literacy was associated with increased risk of death and hospitalizations. These findings have important clinical and public health implications and warrant measurement of health literacy and deployment of interventions to improve outcomes.
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http://dx.doi.org/10.1016/j.jchf.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263350PMC
June 2020

Disease and treatment-related morbidity in young and elderly patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Semin Arthritis Rheum 2020 12 24;50(6):1441-1448. Epub 2020 Feb 24.

Department of Rheumatology, Santa Chiara Hospital, Trento, Italy.

Objective: Aging may be a risk factor for morbidity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We compared the rate and better characterized the type of disease- and treatment-related complications affecting young and elderly patients with AAV.

Methods: All new cases of granulomatosis with polyangiitis or microscopic polyangiitis diagnosed in three referral centers between 2000-2016 were included. Patients were stratified by age into young or elderly (< or ≥65 years old, respectively). Data were collected from diagnosis until end of follow-up, with scheduled annual visits or additional visits in case of relapse or complication requiring hospitalization.

Results: Of 141 patients included, 42 were elderly and 99 were young at the time of AAV diagnosis. Median follow-up was 58.0 [25-75% IQR, 31.0-60.0] months in young and 48.0 [23.25-60.0] months in elderly patients (p>0.05). Overall, the elderly group was associated to higher damage accrual assessed by Vasculitis Damage Index during follow-up (β=0.28, p<0.05). Sixty-three (44.7%) patients had acute kidney injury due to AAV-glomerulonephritis at diagnosis. In contrast to elderly, young patients showed significant improvement in renal function over time, particularly in the first 6 months while on induction treatment (ΔeGFR, median [25-75%IQR], 5.3 [0.4-14] versus 22.8 [5.9-52.1] ml/min/1.73m, p=0.008), without significant changes after ANCA type stratification. Despite similar immunosuppressive therapy approaches and relapse rates, elderly patients had a higher rate of severe infections compared to younger patients (HR 2.1, 95% CIs: 1.1-4.4, p=0.043).

Conclusions: Elderly patients with AAV had higher susceptibility to disease- and treatment-related morbidity than younger patients, particularly to renal and infective morbidity.
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http://dx.doi.org/10.1016/j.semarthrit.2020.02.008DOI Listing
December 2020

Myositis and myasthenia during nivolumab administration for advanced lung cancer: a case report and review of the literature.

Anticancer Drugs 2020 06;31(5):540-544

Medical Oncology.

The immunotherapy significantly improved survival of non-small cell lung cancer patients, but it may cause immune-related adverse events, which are severe in less than 10% of cases. We report the case of one patient who developed myositis and myasthenia during nivolumab treatment for metastatic lung squamous carcinoma. Moreover, we reviewed literature data in order to identify similar cases in cancer patients treated with immune-checkpoints inhibitors. A 65-year-old patient, who had previously received a first-line platinum-based therapy, developed diplopia and ptosis 4 weeks after the start of nivolumab. Although antibodies associated with myositis, myasthenia gravis and paraneoplastic syndromes were absent, immune-related myositis and myasthenia were diagnosed. Corticosteroids, immunoglobulin and pyridostigmine showed poor efficacy and the patient died 7 weeks after the appearance of the first symptoms. Fifteen similar cases were found in the literature. A close collaboration between different specialists is essential to rapidly identify and treat severe immune-related adverse events.
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http://dx.doi.org/10.1097/CAD.0000000000000903DOI Listing
June 2020

Eosinophilic Granulomatosis With Polyangiitis: Clinical Predictors of Long-term Asthma Severity.

Chest 2020 05 17;157(5):1086-1099. Epub 2020 Jan 17.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN. Electronic address:

Background: The long-term clinical course of asthma in patients with eosinophilic granulomatosis with polyangiitis (EGPA) remains unclear. We aimed to characterize long-term asthma in EGPA and to identify baseline predictors of long-term asthma severity.

Methods: This retrospective cohort study included patients who fulfilled standardized criteria for EGPA who were followed up in a single referral center between 1990 and 2017. Baseline and 3 (± 1) years of follow-up clinical, laboratory, and pulmonary function data were analyzed.

Results: Eighty-nine patients with EGPA and a documented asthma assessment at baseline and at 3 years from diagnosis were included. Severe/uncontrolled asthma was observed in 42.7% of patients at diagnosis and was associated with previous history of respiratory allergy (P < .01), elevated serum total IgE levels (P < .05), and increased use of high-dose inhaled corticosteroids (ICSs; P < .05) and oral corticosteroids (OCSs; P < .001) for respiratory symptoms the year before the EGPA diagnosis. During follow-up, an improvement or worsening in asthma severity was noted in 12.3% and 10.1% of patients, respectively. Severe/uncontrolled asthma was present in 40.5% of patients at 3 years and was associated with increased airway resistance on pulmonary function tests (PFTs; P < .05). Long-term PFTs did not improve during long-term follow-up regardless of ICS or OCS therapy. Multivariate binary logistic regression results indicated that severe rhinosinusitis (P = .038), pulmonary infiltrates (P = .011), overweight (BMI ≥ 25 kg/m; P = .041), and severe/uncontrolled asthma at vasculitis diagnosis (P < .001) independently predicted severe/uncontrolled asthma at the 3-year end point.

Conclusions: In patients with asthma with EGPA, long-term severe/uncontrolled asthma is associated with baseline pulmonary and ear, nose, and throat manifestations but not with clear-cut vasculitic features.
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http://dx.doi.org/10.1016/j.chest.2019.11.045DOI Listing
May 2020

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

J Autoimmun 2020 03 9;108:102397. Epub 2020 Jan 9.

Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.

Introduction: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV).

Objectives: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset.

Materials And Methods: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed.

Results: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality.

Conclusions: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.
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http://dx.doi.org/10.1016/j.jaut.2019.102397DOI Listing
March 2020

Asthma control in eosinophilic granulomatosis with polyangiitis treated with rituximab.

Clin Rheumatol 2020 May 2;39(5):1581-1590. Epub 2020 Jan 2.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Objectives: Rituximab (RTX) treatment is used for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but its benefits in eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. Our aim was to characterize asthma control and glucocorticoid (GC) sparing after RTX treatment.

Methods: A retrospective, computer-assisted search was performed to identify patients with EGPA and GC-dependent asthma diagnosed between 2000 and 2017 who received RTX for remission induction. Demographic and clinical features were analyzed.

Results: Of the 17 patients included, the majority were myeloperoxidase-ANCA positive (n = 13, 76.5%). Uncontrolled asthma symptoms and atopy were present in 13 patients (76.5%). RTX was used for initial remission induction in patients with new onset of severe disease (n = 5, 29.4%) and after failed remission induction with other immunosuppression (n = 12, 70.6%). It was used for remission maintenance in nine patients (52.9%). GCs were used for maintenance at a median dose of 25 mg/day (interquartile range, 16.25-37.5). At the end of follow-up, 13 patients (76.5%) had non-severe or controlled asthma, and remission was achieved in 12 (70.6%). Median serum eosinophil and C-reactive protein values decreased (1.06 vs 0.10 × 10/L [P = .012] and 27.0 vs 5.0 mg/dL [P = .001], respectively), whereas pulmonary function test results remained unchanged. Median GC dose was significantly reduced at 6, 12, 18, and 24 months (P < .0001). Patients receiving RTX for maintenance required less than 10 mg of GCs for asthma control.

Conclusion: RTX seems to be safe and have GC-sparing efficacy for asthma control in EGPA. Randomized controlled trials are needed for detailed study of RTX for treating EGPA.Key Points• In this retrospective study we have concluded that rituximab (RTX) might be considered for the control of severe corticosteroid-dependent asthma in eosinophilic granulomatosis polyangiitis (EGPA) patients especially when myeloperoxidase antibodies are positive.• Rituximab has not been studied particularly for asthma control in EGPA patients.• The most noticeable effect of RTX was the decrease in the use of corticosteroids for the control of asthma.
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http://dx.doi.org/10.1007/s10067-019-04891-wDOI Listing
May 2020

Chronic rhinosinusitis in eosinophilic granulomatosis with polyangiitis: clinical presentation and antineutrophil cytoplasmic antibodies.

Int Forum Allergy Rhinol 2020 02 2;10(2):217-222. Epub 2019 Dec 2.

Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, MN.

Background: In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution.

Results: Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution.

Conclusion: CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting.
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http://dx.doi.org/10.1002/alr.22503DOI Listing
February 2020

Remission maintenance in ANCA-associated vasculitis: does one size fit all?

Expert Rev Clin Immunol 2019 12 24;15(12):1273-1286. Epub 2019 Nov 24.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

: The majority of the patients with anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV) achieve remission with effective induction therapy. Therefore, prevention of relapses and avoiding long-term damage and treatment-related toxicity are major challenges.: This review provides an update on maintenance therapy in AAV, emphasizing the available treatment options for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Among the spectrum of all patients with AAV, those at higher risk of relapse have recently been identified. Clinical trials have yielded robust results about various options for maintenance of remission including common disease-modifying anti-rheumatic drugs (DMARDs, i.e. azathioprine, methotrexate, and mycophenolate mofetil) and rituximab (RTX). However, outcomes of these studies are not easy to compare.: Regardless of the treatment used, patients presenting with an anti-proteinase-3 ANCA, relapsing GPA have a substantially higher risk of relapse compared to patients with newly diagnosed MPA or positive anti-myeloperoxidase ANCA. While the efficacy of common DMARDs for remission maintenance is heterogeneous, the role of RTX seems particularly promising for the high-risk patients, although the most appropriate dose and timing of retreatment with RTX remain under controversial. Low-dose glucocorticoid use for remission maintenance versus complete discontinuation also remains under investigation.
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http://dx.doi.org/10.1080/1744666X.2020.1693260DOI Listing
December 2019

Eosinophilic granulomatosis with polyangiitis: the multifaceted spectrum of clinical manifestations at different stages of the disease.

Expert Rev Clin Immunol 2020 01 17;16(1):51-61. Epub 2020 Jan 17.

INSERM UMR1227, Lymphocytes B et Autoimmunité, Université de Bretagne Occidentale, CHU de Brest, Brest, France.

: Eosinophilic granulomatosis with polyangiitis (EGPA) usually occurs in patients with late-onset asthma and sustained peripheral blood eosinophilia and classically presents with a clinical multifaceted spectrum of manifestations, which may vary at the different stages of the natural history of the disease.: We reviewed EGPA clinical presentation, focusing on clinical manifestations at three different phases of the disease: 1/before the development of overt vasculitis, 2/at vasculitis diagnosis and 3/during the long-term follow-up. An update on current classification criteria and recent therapeutic advances has been provided as well.: Asthma, chronic rhinosinusitis and blood eosinophilia could anticipate the overt vasculitis for years. An atopic background may be present in a subset of patients (25-30%), while ANCA presence varies between 10 and 40%. Systemic vasculitis rapidly occurs and clinical features demonstrating vasculitis processes (neuropathy, purpura, scleritis, alveolar hemorrhage and glomerulonephritis) develop along with systemic symptoms (50%). After vasculitis resolution, asthma remains severe in up to 50% of patients and incidence of isolated-asthma and rhinosinus exacerbations remains constantly high. Different sets of classification criteria have been published so far, and DCVAS diagnostic criteria will be presented soon. Interleukin-5 blockers seem to be promising to control the disease and to spare corticosteroids.
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http://dx.doi.org/10.1080/1744666X.2019.1697678DOI Listing
January 2020

Clinical Characterization and Predictors of IOS-Defined Small-Airway Dysfunction in Asthma.

J Allergy Clin Immunol Pract 2020 03 11;8(3):997-1004.e2. Epub 2019 Nov 11.

Ospedale Santa Chiara and Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy; Thoracic Disease Research Unit, Mayo Clinic, Rochester, Minn. Electronic address:

Background: The involvement of small airways has recently gained greater recognition in asthma. Impulse oscillometry (IOS) is a simple and noninvasive method based on the forced oscillation technique, for the detection of small-airway dysfunction (SAD).

Objective: To identify the predictors of SAD in an unselected sample of 400 patients with physician-diagnosed asthma.

Methods: All patients underwent standard spirometry and IOS at the first visit, and were stratified by the presence of SAD defined by IOS (fall in resistance from 5 to 20 Hz [R5-R20] > 0.07 kPa × s × L). Univariable and multivariable analyses and classification tree method were used to analyze cross-sectional relationships between clinical variables and outcome (SAD).

Results: SAD was present in 62% of the cohort. Subjects with SAD showed a less well-controlled asthma, according to the Global Initiative for Asthma definition, and a higher mean inhaled corticosteroid dosage use compared with subjects without SAD (both P < .001). Increased fractional exhaled nitric oxide (odds ratio [OR], 2.05; 95% CI, 1.14-3.70), female sex (OR, 2.27; 95% CI, 1.29-4.06), smoking (OR, 3.06; 95% CI, 1.60-6.05), older age (OR, 3.08; 95% CI, 1.77-5.49), asthma-related night awakenings (OR, 3.34; 95% CI, 1.85-6.17), overweight (OR, 3.64; 95% CI, 1.99-6.85), and exercise-induced asthma symptoms (OR, 6.39; 95% CI 3.65-11.45) were independent predictors of SAD. Classification tree analysis confirmed that exercise-induced asthma, overweight, asthma-related night awakenings, smoking, and older age have potential for clinical use in distinguishing patients with SAD from those without it.

Conclusions: We identified predictors of SAD and showed that especially exercise-induced asthma, overweight, asthma-related night awakenings, smoking, and older age were strongly associated with SAD.
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http://dx.doi.org/10.1016/j.jaip.2019.10.040DOI Listing
March 2020

Orbital masses in ANCA-associated vasculitis: an unsolved challenge?

Rheumatology (Oxford) 2019 09;58(9):1520-1522

Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1093/rheumatology/kez136DOI Listing
September 2019

The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis.

J Autoimmun 2019 12 15;105:102302. Epub 2019 Jul 15.

University of Pennsylvania, Philadelphia, PA, USA.

Objective: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes.

Methods: sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases.

Results: At baseline, sIL6 levels were detectable in 81% of patients; 73% (n = 57) of subjects were proteinase 3 (PR3)-ANCA positive, sIL-6 levels were higher in subjects with PR3-ANCAs and positively correlated with their levels (r = 0.36,p < 0.01), but not with levels of myeloperoxidase (MPO)-ANCA (r = -0.17,p = 0.47). Higher baseline sIL-6 levels were associated with PR3-ANCA positivity, fever, pulmonary nodules/cavities, conductive deafness, and absence of urinary red blood cell casts (p < 0.05). Baseline sIL6 levels did not predict CR at month 6 (p = 0.71), and the median sIL-6 level declined from baseline with induction therapy, regardless of CR achievement. An increase in sIL-6 during CR was a predictor for subsequent severe relapse in RTX-treated patients (hazard ratio (HR):7.24,p = 0.01), but not in CYC/AZA-treated patients (HR:0.62,p = 0.50). In contrast, a sIL-6 increase did not predict B cell repopulation or ANCA titer increase in either treatment arm (p > 0.05).

Conclusion: At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.
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http://dx.doi.org/10.1016/j.jaut.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217333PMC
December 2019

The Incidence of Arterial and Venous Thrombosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

J Rheumatol 2019 09 1;46(9):1243. Epub 2019 Jul 1.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA, and INSERM UMR1227, Lymphocytes B et Autoimmunité, Université de Bretagne Occidentale, CHU de Brest, Brest, France.

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http://dx.doi.org/10.3899/jrheum.181351DOI Listing
September 2019

The severe long-term outcomes of 'non-severe' eosinophilic granulomatosis with polyangiitis.

Authors:
Alvise Berti

Rheumatology (Oxford) 2019 12;58(12):2081-2082

Department of Rheumatology, Santa Chiara Hospital, University of Trento, Trento, Italy.

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http://dx.doi.org/10.1093/rheumatology/kez250DOI Listing
December 2019
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