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Background: Immune complex vasculitides may be subdivided into adult IgA small vessel vasculitis (aIgA-SVV; i.e. adult Henoch-Schönlein purpura) and non-IgA-SVV (hypersensitivity vasculitis, etc.)., Objectives: To evaluate the clinical and laboratory parameters of inpatients fulfilling the diagnostic criteria for aIgA-SVV and non-IgA-SVV., Methods: Twenty-nine adults aged ≥ 20 years with aIgA-SVV [according to the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria] and 53 adults with non-IgA-SVV (according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides) were compared with respect to a variety of clinical and laboratory parameters by uni- and multivariable analyses., Results: Compared with patients with aIgA-SVV, the platelet-to-lymphocyte ratio was significantly higher in patients with non-IgA-SVV. Serum C3 levels and mean corpuscular haemoglobin concentration in patients with non-IgA-SVV were significantly lower compared with patients with aIgA-SVV. Proteinuria and haematuria were significantly more common in patients with aIgA SVV, and were significantly correlated with systemic immune-inflammation biomarkers only in patients with aIgA-SVV. In patients with aIgA-SVV, higher lactate dehydrogenase and C-reactive protein were strong independent predictors for the presence of proteinuria and proteinuria. In patients with non-IgA-SVV, female sex was a protective factor for proteinuria, while skin lesions on the upper extremities proved to be a significant independent predictor of haematuria., Conclusions: We detected several clinical and laboratory differences between patients with aIgA-SVV and non-IgA-SVV. Distinct predictors for renal involvement were not observed in either group, indicating that aIgA-SVV and non-IgA-SVV are similar conditions but do not appear to represent the same entity., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk., Methods: In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR., Results: We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms., Conclusions: Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT., Trial Registration: ClinicalTrials.gov ID NCT02374021., (© 2024. The Author(s).)

Introduction: IgA vasculitis diagnosis relies primarily on clinical features and is confirmed by pathological findings. To date, there is no reliable noninvasive diagnostic biomarker., Objective: We aimed to explore the baseline serum metabolome of adult patients with IgA vasculitis to identify potential diagnostic biomarkers., Methods: We performed a study comparing the serum metabolome of patients with IgA vasculitis to that of patients with inflammatory condition, namely spondyloarthritis. Serum analyses were performed by high-performance liquid chromatography-mass spectrometry., Results: Fifty-five patients with IgA vasculitis and 77 controls with spondyloarthritis (age- and sex-matched) were included in this study. The median age of IgA vasculitis patients was 53 years. Two-thirds of patients were female (n = 32). At the time of vasculitis diagnosis, 100% of patients had skin involvement and 69% presented with glomerulonephritis (n = 38). Joint and digestive involvement were observed in 56% (n = 31) and 42% (n = 23) of patients. Four discriminative metabolites between the two groups were identified: 1-methyladenosine, L-glutamic acid, serotonin, and thymidine. The multivariate model built from the serum metabolomes of patients with IgA vasculitis and spondyloarthritis revealed an accuracy > 90%. As this model was significant according to the permutation test (p < 0.01), independent validation showed an excellent predictive value of the test set: sensitivity 98%; specificity 98%, positive predictive value 97% and negative predictive value 98%., Conclusion: To our knowledge, this study is the first to use the metabolomic approach for diagnostic purposes in adult IgA vasculitis, highlighting a specific diagnostic metabolome signature., (© 2024. The Author(s).)

The diagnosis of systemic vasculitis (SV) is a major clinical challenge due to the very different forms of presentation and requires an interdisciplinary approach. Targeted laboratory diagnostics support making the diagnosis, differential diagnosis and classification and are also a key component in the detection of active organ manifestations and treatment complications. The basic laboratory tests include the erythrocyte sedimentation rate (ESR), C‑reactive protein (CRP), blood count, serum creatinine, urinalysis, specific autoantibodies, complement, immunoglobulins, cryoglobulins and hepatitis B and C serology. Antineutrophil cytoplasmic autoantibodies (ANCA), antiglomerular basement membrane antibodies (anti-GBM antibodies) and anti-C1q antibodies are valuable laboratory markers for the diagnosis of the various forms of small vessel vasculitis. There are no specific laboratory tests for the diagnosis of medium and large vessel vasculitis. Despite advances in our understanding of the pathogenesis of vasculitis, no biomarkers have yet been identified that can be reliably used to guide treatment or that are useful in distinguishing vasculitis from other inflammatory diseases such as infections or treatment complications., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background and Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome., Approach and Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively)., Conclusions: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the β 2 -integrin, CD18 (CD18 hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. In contrast, injured CD18 hypo mice showed significantly less venule engorgement and markedly reduced platelet and RBC extravasation; mast cell degranulation was also reduced compared to WT mice. Corneal abrasion in mast cell-deficient (Kit W-sh/W-sh ) mice showed less venule engorgement, delayed PMN extravasation, reduced platelet and RBC extravasation and delayed wound healing compared to WT mice. Finally, antibody-induced depletion of circulating PMNs prior to corneal abrasion reduced mast cell degranulation, venule engorgement, and extravasation of PMNs, platelets, and RBCs. In summary, in the injured cornea, platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation.

Background: Psoriasis is associated with increased cardiovascular risk that is not captured by traditional proinflammatory biomarkers., Objective: To investigate the relationship between Psoriasis Area and Severity Index, circulating proinflammatory biomarkers, and vascular health in psoriasis., Methods: In patients with psoriasis and in age and sex-matched controls, 273 proteins were analyzed with the Proseek Multiplex Cardiovascular disease reagents kit and Inflammatory reagents kit (Olink Bioscience), whereas vascular endothelial inflammation and health were measured via direct transcriptomic analysis of brachial vein endothelial cells., Results: In psoriasis, chemokine ligand 20 (CCL20), interleukin (IL) 6, and IL-17A were the top 3 circulating proinflammatory cytokines. Vascular endothelial inflammation correlated with CCL20 (r = 0.55; P < .001) and less so with IL-6 (r = 0.36; P = .04) and IL-17A (r = 0.29; P = .12). After adjustment for potential confounders, the association between CCL20 and vascular endothelial inflammation remained significant (β = 1.71; P = .02). In nested models, CCL20 added value (χ 2  = 79.22; P < .001) to a model already incorporating the Psoriasis Area and Severity Index, Framingham risk, high-sensitivity C-reactive protein, Il-17A, and IL-6 (χ 2  = 48.18; P < .001) in predicting vascular endothelial inflammation., Limitations: Our study was observational and did not allow for causal inference in the relationship between CCL20 and cardiovascular risk., Conclusion: We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The ambulatory arterial stiffness index (AASI) is an indirect measure of arterial stiffness obtained during ambulatory blood pressuring monitoring (ABPM). Its relationship to nocturnal blood pressure dipping status and major adverse cardiovascular events (MACE) are controversial and its association with vascular inflammation has not been examined. We aimed to investigate the relationship between the AASI, inflammation and nocturnal blood pressure dipping status and its association with MACE., Methods: Adults (aged 18-80 years) who underwent 24-h ABPM for the diagnosis of hypertension or its control were included. The inflammatory markers measured were the neutrophil-lymphocyte (NLR), platelet-lymphocyte (PLR) and monocyte-lymphocyte ratios (MLR). The primary MACE was a composite of cardiovascular death, acute limb ischaemia, stroke or transient ischaemic attack (TIA) or acute coronary syndrome., Results: A total of 508 patients (51.2% female) aged 58.8 ± 14.0 years were included; 237 (46.7%) were normal-dippers (≥ 10% nocturnal systolic dip), 214 (42.1%) were non-dippers (0-10% dip) and 57 (11.2%) were reverse-dippers (< 0% dip). The AASI was significantly higher among reverse (0.56 ± 0.16) and non-dippers (0.48 ± 0.17) compared with normal dippers (0.39 ± 0.16; p < 0.0001) and correlated with the NLR (r = 0.20; 95% CI 0.11 to 0.29: < 0.0001) and systolic blood pressure dipping % (r = - 0.34; - 0.42 to - 0.26: p < 0.0001). Overall 39 (7.7%) patients had ≥ 1 MACE which included a total of seven cardiovascular deaths and 14 non-fatal strokes/TIAs. The mean follow up was 113.7 ± 64.0 weeks. Increasing NLR, but not AASI or systolic dipping, was independently linked to MACE (overall model Chi-square 60.67; p < 0.0001) and MLR to cardiovascular death or non-fatal stroke/TIA (overall model Chi-square 37.08; p < 0.0001)., Conclusions: In conclusion AASI was associated with blood pressure dipping and chronic inflammation but not independently to MACE. The MLR and NLR were independent predictors of MACE.

Rituximab is a chimeric immunoglobulin G1-kappa (IgG1κ) antibody targeting the CD20 antigen on B-lymphocytes. Its applications are various, such as for the treatment of chronic lymphoid leukemia or non-Hodgkin's lymphoma in oncology, and it can also be used in the treatment of certain autoimmune diseases. Several studies support the interest in therapeutic drug monitoring to optimize dosing regimens of rituximab. Thus, two different laboratories have developed accurate and reproductive methods to quantify rituximab in human plasma: one using liquid chromatography quadripolar tandem mass spectrometer (LC-MS/MS) and the other, liquid chromatography orbitrap tandem mass spectrometer (LC-MS/HRMS). For both assays, quantification was based on albumin depletion or IgG-immunocapture, surrogate peptide analysis, and full-length stable isotope-labeled rituximab. With LC-MS/MS, the concentration range was from 5 to 500 µg/mL, the within- and between-run precisions were <8.5%, and the limit of quantitation was 5 µg/mL. With LC-MS/HRMS, the concentration range was from 10 to 200 µg/mL, the within- and between-run accuracy were <11.5%, and the limit of quantitation was 2 µg/mL. Rituximab plasma concentrations from 63 patients treated for vasculitis were compared. Bland-Altman analysis and Passing-Bablok regression showed the interchangeability between these two methods. Overall, these methods were robust and reliable and could be applied to routine clinical samples.

Purpose of Review: Large vessel vasculitides (LVVs) are inflammatory conditions of the wall of large-sized arteries, mainly represented by giant cell arteritis (GCA) and Takayasu arteritis (TA). The inflammatory process within the vessel wall can lead to serious consequences such as development of aneurysms, strokes and blindness; therefore, early diagnosis and follow-up of LVV are fundamental. However, the arterial wall is poorly accessible and blood biomarkers are intended to help physicians not only in disease diagnosis but also in monitoring and defining the prognosis of these conditions, thus assisting therapeutic decisions and favouring personalised management. The field is the object of intense research as the identification of reliable biomarkers is likely to shed light on the mechanisms of disease progression and arterial remodelling. In this review, we will discuss the role of blood biomarkers in LVVs in the light of the latest evidence., Recent Findings: In clinical practice, the most widely performed laboratory investigations are the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). However, these indices may be within normal limits during disease relapse and they are not reliable in patients receiving interleukin-6 (IL-6) receptor inhibitors. New biomarkers struggle to gain traction in clinical practice and no molecule with good accuracy has been identified to date. IL-6, a pro-inflammatory cytokine that drives CRP synthesis and increases the ESR, is one of the most promising biomarkers in the field. IL-6 analysis is increasingly performed, and serum levels are more sensitive than ESR for active GCA and might reflect persistent inflammation with high risk of relapse in patients on IL-6 receptor inhibitors. A future with biomarkers that reflect different disease features is an important aspiration. Accordingly, intense effort is being made to identify IL-6-independent inflammatory biomarkers, such as S100 proteins, pentraxin-3 and osteopontin. Moreover, metalloproteinases such as MMP2/9 and angiogenic modulators such as VEGF, YLK-40 and angiopoietins are being studied as markers of arterial remodelling. Lastly, biomarkers indicating organ damage may guide prognostic stratification as well as emergency therapeutic decisions: the most promising biomarkers so far identified are NT-proBNP, which reflects myocardial strain; pentraxin-3, which has been associated with recent optic nerve ischemia; and endothelin-1, which is associated with ischaemic complications. Currently, the use of these molecules in clinical practice is limited because of their restricted availability, lack of sufficient studies supporting their validity and associated costs. Further evidence is required to better interpret their biological and clinical value.

Aim: Atherosclerosis involves vascular endothelial damage and lipid metabolism disorder, which is closely related to the occurrence and development of diabetic kidney disease (DKD). However, studies on non-high albuminuria DKD (NHADKD) with an albumin to creatinine ratio (ACR) <30 mg/g are rare. This study is to investigate the relationship between atherogenic factors and the occurrence of NHADKD., Methods: Serum lipid indicators, lipoprotein-associated phospholipase A2 (Lip-PLA2) and homocysteine levels were measured in 1116 subjects to analyze their relationship with NHADKD., Results: Among all subjects, Lip-PLA2 had the closest but relatively weak correlation with ACR ( r  = 0.297, p  < 0.001) and only homocysteine was moderately correlated with eGFR ( r  = -0.465, p  < 0.001). However, in patients with NHADKD, these atherosclerotic factors were weakly correlated or uncorrelated with eGFR (max. | r | = 0.247). Stratified risk analysis showed that when ACR was <10 mg/g, homocysteine [OR = 6.97(4.07-11.95)], total cholesterol (total-Chol) [OR = 6.04(3.03-12.04)], and high-density lipoprotein cholesterol (HDL-Chol) [OR = 5.09(2.99-8.64)] were risk factors for NHADKD. There was no significant difference of OR between these three factors ( Z  = 0.430-1.044, all p  > 0.05). When ACR was ⩾10mg/g, homocysteine [OR = 17.26(9.67-30.82)] and total-Chol [OR = 5.63(2.95-10.76)] were risk factors for NHADKD, and OR homocysteine was significantly higher than OR total-Chol ( Z  = 3.023, p  < 0.05)., Conclusions: The occurrence of NHADKD may be related to the levels of homocysteine, total-Chol, HDL-Chol, and Lip-PLA2 in blood. Among them, homocysteine may be most closely related to NHADKD.

Background: Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves., Objective: This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN., Methods: Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up., Results: Twenty-five patients with VPN were included (SVN, n = 10; NSVN, n = 15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, p = 0.009). Erythrocyte sedimentation rate (ESR) values over 20 mm/h were significantly more common in SVN patients (100% vs. 60%, p = 0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; p = 0.03), with a higher proportion of definite VPN cases (92 vs 46%; p = 0.04)., Conclusions: Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.

Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Diabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1 -/- mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.

Background: Tumor necrosis factor- α (TNF- α ) is a proinflammatory factor involved in the pathogenesis of immunoglobulin A vasculitis (IgAV). The association between serum TNF- α and disease severity in adult patients with IgAV nephritis (IgAV-N) has been inadequately evaluated., Methods: Serum TNF- α was measured by chemiluminescence immunoassay in 53 renal biopsy-proved IgAV-N patients, 53 healthy controls, and 53 IgA nephropathy (IgAN) patients. The correlations of clinicopathologic parameters of IgAV-N patients with serum TNF- α were analyzed., Results: In this cross-sectional study, the median age of IgAV-N patients was 29 (25-37) years, and 67.9% were female. Serum TNF- α was significantly higher in the IgAV-N group than in the healthy group [7.4 (5.7-9.4) pg/mL vs. 5.9 (5.0, 7.1) pg/mL, P = 0.001], but comparable with sex, age, and estimated glomerular filtration rate (eGFR) grade-matched IgAN patients. Serum creatinine ( P = 0.006) and serum cystatin C ( P = 0.001) were positively correlated with serum TNF- α level, while albumin ( P = 0.014) and eGFR ( P = 0.021) were negatively correlated with serum TNF- α level. Multivariate linear regression analysis revealed that eGFR ( P = 0.007) was an independent clinical predictor of serum TNF- α . Patients with higher pathological classification grade also had higher serum TNF- α ., Conclusions: Serum TNF- α is associated with renal function and the pathological classification of adult patients with IgAV-N. TNF- α is a potential biomarker for the assessment of IgAV-N severity., Competing Interests: The authors declare no conflict of interest related to this study., (Copyright © 2020 Haiting Wu et al.)

Background: Antibodies against neutrophil cytoplasm (ANCA) are associated with vasculitis. There are different methods to determine their presence. The interference of antinuclear antibodies (ANA) in the differentiation between P-ANCA and C-ANCA patterns has been described., Objective: To determine the frequency of ANCA in a population with manifestations of autoimmune disease, and evaluate the interference of ANA in its interpretation., Materials and Methods: Retrospective, descriptive nonexperimental cross-sectional study, including 3,330 data. The presumptive diagnosis was autoimmune disease and a test for ANCA was requested. The ANCA and ANA determinations were made by indirect immunofluorescence, L-ANCA® and CytoBead® ANCA. Anti-proteinase 3 and anti-myeloperoxidase were detected by ELISA and CytoBead® ANCA., Results: ANCAs were positive in 10.21% and 12.64% of those positive for ANCA were positive for ANA. The inter-rater agreement statistic (Kappa) for anti-PR3 between CytoBead ANCA and ELISA was 100% (K=1.00; P<.05) and the agreement between anti- myeloperoxidase by ELISA and CytoBead® ANCA was high (K=0.94; P<.05). 30% of those with ANCAs had a diagnosis of a type of vasculitis; 20% of them had an autoimmune disease., Conclusions: The results suggest an overestimated request for ANCAs as a diagnostic aid in primary care which was not addressed. For an adequate evaluation of ANCAs, the indirect immunofluorescence technique should be implemented for the control and confirmation with the determination of specific antigens for anti- proteinase 3 and anti- myeloperoxidase in any of the confirmatory assays. The high concordance shown by ANCA CytoBeads makes us consider the use of this alternative for the determination of ANCAs and the confirmation. Given the interference of ANAs, the ANA test by IFI in the presence of positive P-ANCA results is recommended in order to minimize "false positives"., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders., (© 2020 AABB.)

Serological analysis has a central role in the diagnostic work-up of patients with suspected small vessel vasculitis, both for establishing a specific diagnosis and for the monitoring of response to therapy. Autoantibodies can be detected in all forms of primary small vessel vasculitis as well as in the most common forms of secondary vasculitis. For primary vasculitis the most important serological test is for ANCA. ANCA can be found in 75-95% of patients with pauci-immune small vessel vasculitis leading to this subgroup of vasculitides being named ANCA associated vasculitis. ANCA levels often follow this disease course, but the value of serial ANCA testing is controversial. Other important autoantibodies in primary small vessel vasculitis are anti-glomerular basement membrane antibodies, anti-C1q, anti-galactose deficient IgA and cryoglobulins. A wide variety of systemic inflammatory diseases and infections can be complicated by small vessel vasculitis and detected by serological testing. Important examples are SLE, rheumatoid arthritis, Hepatitis C and HIV., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We describe an atypical pediatric case of immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, in which formation of spontaneous hematoma of the paraspinal muscles developed. Spontaneous or unprovoked hematomas rarely occur in IgAV. These manifestations have not been described specifically in the pediatric literature as coinciding with IgAV. These findings are alarming for nonaccidental trauma, particularly in a patient without underlying blood dyscrasia. Our objective for this report is to highlight the possible association of muscular hematoma formation with IgAV and to help providers consider this association when trauma and hemophilia has been ruled out., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of systemic vasculitis in children. Although the first case of IgAV was described more than 200 years ago, its etiology still remains unclear. Nephrological symptoms are observed in 30-50% of children during the course of the disease, and in up to 91% of cases within 6 weeks of the onset of the first symptoms. Whereas other organ manifestations of IgAV are mostly benign and self-limiting, nephritis may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Appropriate treatment commenced early enough can stop the disease progression. However, even in severe cases there are no evidence-based guidelines, which makes the therapeutic decisions more difficult. In this article, which is the most up-to-date overview regarding IgAV, we discuss the disease's pathogenesis, the clinical forms of renal involvement in the course of the disease, the risk factors for adverse prognosis and treatment options in accordance with current recommendations.

Ten patients with scurvy were evaluated by rheumatology; we review their clinical, laboratory, and dietary presentations. Eight patients had developmental delay or autism. All had elevated inflammatory markers. These clinical and laboratory features with imaging findings can mimic rheumatic conditions such as arthritis, vasculitis, and chronic nonbacterial osteomyelitis (CNO)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Aim: This study aims to characterize the role of Irisin in obesity and early onset metabolic and vascular sequelae in Chinese children. Furthermore, we aim to examine whether Irisin mediate endothelial cells dysfunction and vascular inflammation which eventually leads to obesity., Methods and Results: We quantified plasma Irisin levels using enzyme-linked immunosorbent assay (ELISA) among 85 lean and 120 obese children, and assessed the association of Irisin levels with anthropometric, metabolic, cardiovascular and inflammatory parameters of obese children comparing with lean children. We further characterized the markers for endothelial cells and inflammation between obese and lean children to assess potential correlations. In addition, a potential direct effect of Irisin on the expression of endothelial adhesion molecules was assessed in human coronary artery endothelial cells. Irisin levels from obese children was significantly lower than lean children, and this reduced Irisin levels is correlated with certain physical parameters of studied children. Moreover, we identified significant inverse associations between inflammation markers of endothelial activation with Irisin levels in obese children. Multiple regression analyses confirm Irisin serves as a strong predictor of SDS-SBP, Ang-2, ICAM-1, E-selectin and hsCRP levels, independent of SDS-BMI. Lifestyle intervention results in a significant improvement of these cardiovascular and inflammatory parameters, and these were accompanied by a significant improvement of Irisin levels and weight loss. Finally, in the mediation effect model, our data showed that Irisin changes act as partial mediators of the relationship between SDS-BMI changes and changes in inflammatory and endothelial parameters for ICAM-1, E-selectin and hsCRP after controlling for covariates. Likewise, on the cellular level, Irisin inhibition hsCPR, ICAM-1 and E-selectin expression in endothelial cells, whereas Ang-2, VCAM-1 and eNOS expression were unaffected., Conclusions: Our study showed that Irisin levels change may indicate the early stages of cardiovascular disease in obese children., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: Immunoglobulin A vasculitis (IgAV) is the most common form of vasculitis in children. Nephritis in the course of this disease (IgAVN) is observed in 30-50% of patients and might lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Finding a non-invasive biomarker to distinguish initially between patients with and without nephritis and to facilitate a therapeutic decision to reduce the risk of long-term renal impairment is currently the target of much research. The aim of this study was to evaluate the adiponectin concentration in children with IgAV and estimate whether it might be used as a marker of IgAVN., Material and Methods: The study involved 29 IgAV children and 34 healthy controls. Eleven (38%) patients had renal involvement (IgAV-N) and 18 (62%) did not exhibit nephritis (IgAV-noN). The serum adiponectin level was estimated in children in an acute phase of IgAV and after 2-6 months during a follow-up visit. The relationship between the concentration of adiponectin and anthropometric measurements, epidemiological data and laboratory parameters were evaluated., Results: The concentration of adiponectin in serum was significantly higher in children with acute phase of IgAV as compared to the control group (p < 0.001), and in patients without renal involvement in comparison with IgAV-N children (p < 0.049). In analysis of correlation we found a negative relationship between adiponectin level and serum creatinine concentration (r = -0.437, p = 0.02). The logistic regression evaluation demonstrated that a low adiponectin level increased the risk of nephritis in the course of IgAV., Conclusions: Our study revealed that the serum adiponectin level increased markedly in patients with IgAV. We also documented that higher risk of nephritis in the course of the disease was associated with lower concentration of this hormone.

Background: Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility., Aim: To explore the role of rs6677604 in complement activation of IgAVN., Methods: In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data., Results: The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN., Conclusion: Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN., (© 2019 Asian Pacific Society of Nephrology.)

Background: Immunoglobulin A vasculitis (IgAV) is still poorly defined in the adult population. We aimed to determine the predictors of gastrointestinal (GI) or renal involvement in adult IgAV., Methods: The prospective study included histologically proven adult IgAV cases diagnosed between January 2013 and July 2019 at our secondary/tertiary rheumatology center. We evaluated the role of clinical and the laboratory parameters as markers predicting the GI or renal involvement in IgAV, using the multiple logistic regression analysis., Results: During the 79-month observation period, we identified 214 new adult IgAV cases (59.3% males, median (interquartile range) age 64.6 (57.2-76.7) years). The GI tract and renal involvement developed in 58 (27.1%) and 83 (38.8%) cases, respectively (concurrently in 26 (12.1%) cases). In the multivariate logistic regression analysis, generalized purpura (OR 6.74 (95%CI 3.18-14.31)), the pre-treatment neutrophil to lymphocyte ratio (NLR) > 3.5 (OR 2.78 (95%CI 1.34-5.75)), and elevated serum IgA levels (OR 0.40 (95%CI 0.20-0.79)) were extracted as factors associated with GI complications, whereas current smoking (OR 3.23 (95%CI 1.50-6.98)), generalized purpura (OR 1.98 (95%CI 1.08-3.61)), elevated serum IgA (OR 2.25 (95%CI 1.21-4.18)), NLR > 3.5 (OR 1.96 (95%CI 1.02-3.77)), and marginally age (1.02 (95%CI 1.01-1.04)) emerged as factors associated with renal complications., Conclusion: Generalized purpura and pre-treatment NLR predicted both GI and renal involvement, whereas active smoking was associated with renal involvement, and the serum IgA level had a divergent effect on renal and GI involvement in adult IgAV.

Although more than 45 years have passed since hypocomplementemic urticarial vasculitis (HUVS) was first described by McDuffie and colleagues at the Mayo clinic, data on epidemiology, disease outcomes, prognosis and clinical features are scarce. Recently, we published the first epidemiological study of HUVS including data on incidence, prevalence, disease outcomes, prognosis and clinical features using data from two separate Swedish regions during a period of 16 years. The estimation of incidence and prevalence rates indicates that HUVS is rare but not always benign. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition. It is reasonable to suspect HUVS in patients with unexplained systemic inflammation combined with >6 months of urticaria. Special attention should be paid to patients with recent-onset dyspnea and proteinuria.

Background: IgA vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin, or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactose-deficient IgA1 (GD-IgA1) in kidneys (as in IgA nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown., Objective: We investigated whether GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV and whether its serum levels differ between both forms., Methods: In a case-control study, deposition of GD-IgA1 was analyzed immunohistochemically by KM55 antibody in skin biopsy specimens from 12 patients with skin-limited IgAV and 4 with systemic IgAV. GD-IgA1 levels were compared by enzyme-linked immunosorbent assay in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy individuals., Results: All biopsy samples from systemic IgAV, and also from skin-limited IgAV, revealed perivascular GD-IgA1 deposition. The average GD-IgA1 concentration in serum was significantly higher in systemic IgAV than in skin-limited IgAV, despite overlap between the groups., Limitations: Although high GD-IgA1 levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV., Conclusion: Perivascular GD-IgA1 deposition is a prerequisite for systemic and skin-limited IgAV; however, high GD-IgA1 levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare bleeding disorder caused by antiprothrombin antibodies. LAHPS is associated with systemic lupus erythematosus (SLE) or infections. We describe two Japanese brothers with immunoglobulin-A vasculitis (IgAV) who met the diagnostic criteria of LAHPS. They presented with palpable purpura and abdominal pain, and had a prolonged activated partial thromboplastin time (APTT) and prothrombin deficiency with the presence of lupus anticoagulant. Pediatric LAHPS was reviewed in abstracts from the Japan Medical Abstracts Society that were written in Japanese and PubMed or Web of Science-listed articles in English between 1996 and 2019. Including our cases, pediatric LAHPS has been reported in 40 Japanese and 46 non-Japanese patients. We summarized the clinical and laboratory characteristics of all 86 cases, and found only one Japanese LAHPS case with IgAV, except for our cases. Of the 86 cases, most were associated with infections followed by SLE. The presence of SLE, older age, lower prothrombin levels, severe bleeding symptoms, and positivity of immunoglobulin G anticardiolipin antibodies and anticardiolipin/β 2 -glycoprotein I antibodies and/or β 2 -glycoprotein I-dependent anticardiolipin antibodies had higher odds of requiring treatment. Measuring the APTT and prothrombin time (PT) might be required in patients with IgAV when they do not have a typical clinical course or distinctive symptoms. LAHPS should be considered with prolongation of the APTT and/or PT. Additionally, it is important to maintain a balance between the risk of thrombosis and hemorrhage when normalization of the PT and FII levels occurs in LAHPS cases under treatment.

Background: Antineutrophil cytoplasmic antibodies (ANCAs) have been reported to occur in 7% to 10% of patients with idiopathic pulmonary fibrosis (IPF), but their clinical relevance remains unclear. The aim of this study was to estimate the prevalence of ANCAs in a North American population with IPF and evaluate their clinical significance., Methods: This was a retrospective study of two independent cohorts of patients diagnosed with IPF at the University of California San Francisco (discovery cohort) and the University of Chicago (replication cohort). Myeloperoxidase (MPO) and proteinase 3 (PR3) ANCAs were measured in all patients. Prevalence and associations of ANCAs with clinical characteristics and transplant-free survival were evaluated., Results: A total of 14 of 353 (4.0%; 95% CI, 2.2-6.5) and 20 of 392 (5.1%; 95% CI, 3.1-7.8) patients with IPF were positive for ANCAs at the time of diagnosis in the discovery and replication cohorts, respectively. Among those positive for MPO antibodies, two of six (33%) in the discovery cohort and three of 12 (25%) in the replication cohort developed vasculitis. None of the patients who were PR3-positive developed vasculitis. Patients who were ANCA-positive were more likely to be women than patients who were ANCA-negative, and were more likely to have some ground-glass opacities on CT scan. In the combined cohort of 745 patients, median transplant-free survival was not significantly different in patients who were ANCA-positive vs ANCA-negative (P = .57)., Conclusions: ANCA positivity is uncommon in North American patients with IPF and not associated with baseline disease severity or transplant-free survival; however, a significant proportion of patients who are MPO-positive with IPF develop clinical vasculitis., (Copyright © 2019 American College of Chest Physicians. All rights reserved.)

Pentraxin-3 (PTX-3) is derived from the secretion of macrophages, neutrophils, endothelial cells, epithelial cells, and vascular smooth muscle cells, which can regulate the immune activity of macrophages. The objectives of our study were to investigate the serum PTX-3 levels and analyze this correlation with vasculitis (Vas), with hypertension. A total of 155 cases consisting 51 patients with Vas [including 7 cases of takayasu arteritis (TA), 24 cases of polyarteritis nodosa (PAN), and 20 cases of antineutrophil cytoplasmic antibody-associated Vas (AAV)] were screened by angiography and/or biopsy; 46 patients with essential hypertensions (PH) and 58 healthy controls (HC) were enrolled in this study from January 2013 to December 2016. Serum PTX-3 levels were determined by enzyme-linked immunosorbent assay. Compared with the HC and PH, the serum PTX-3 levels in systemic Vas were significantly higher (both P  < 0.001, 4.42 ± 0.95 vs. 2.67 ± 0.92 and 4.42 ± 0.95 vs. 2.95 ± 0.60), and there was no significant difference between HC and essential hypertension ( P  = 0.886, 2.67 ± 0.92 vs. 2.95 ± 0.60). There was no significant difference of PTX-3 levels among TA, PAN, and AAV, as well as active and inactive groups, and renal and nonrenal groups even if they had a significant difference from EH and HC, respectively. There was no significant correlation between PTX-3 levels and blood pressure, erythrocyte sedimentation rate, or Birmingham Vasculitis Activity Score. Receiver operating characteristic analysis has shown that the best cutoff point was at 3.618 ng/μL; the sensitivity and specificity were calculated as 84.3% and 93.5% for the diagnosis of Vas from heath control, and the best cutoff point was at 3.425 ng/μL, The sensitivity and specificity were calculated as 88.2% and 82.6% for the diagnosis of Vas from essential hypertension. Serum PTX-3 levels were significantly higher in patients with Vas than essential hypertension or health control, and elevated PTX-3 levels can help identify Vas patients from healthy or essential hypertensive populations.

Kidney transplantation is associated with increased cardiovascular risk. Endothelial dysfunction and vascular inflammation contribute to negative outcome. In experimental models, mineralocorticoid receptor antagonists improved endothelial function and reduced inflammation. The present study tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone improves endothelial function and reduces vascular inflammation in renal transplant patients. Eighty prevalent renal transplant patients from an ongoing, double-blind randomized placebo-controlled trial were included. Paired plasma samples before and after 1 yr of treatment ( n = 39 in the spironolactone-treated group and 41 in the placebo-treated group) were used to determine markers of endothelial dysfunction (nitrite, nitrate, cGMP, arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, N G -monomethyl-l-arginine, von Willebrand factor, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen) and markers of inflammation (intercellular adhesion molecule, vascular adhesion molecule, high-sensitivity C-reactive protein, and serum amyloid protein A). The median time since the transplantation was 4.6 (0.12-22.3) yr in the spironolactone-treated group and 2.1 (0.17-13.9) yr in the placebo-treated group ( P > 0.05). Spironolactone increased plasma aldosterone ( P < 0.001) and K + ( P < 0.001). Blood pressure did not change significantly. No significant differences were detected between groups in any of the measured markers of endothelial dysfunction or inflammation except in the subgroup analysis of patients with diabetes, where spironolactone decreased nitrite compared with placebo. In this study, mineralocorticoid receptor antagonism did not improve biomarkers of endothelial dysfunction or vascular inflammation in prevalent renal transplant patients. Further studies are needed to evaluate the potential beneficial effect of early or late mineralocorticoid receptor antagonism on vascular outcomes in renal transplant patients.

18 F-Fluorodeoxyglucose positron-emission tomography ( 18 F-FDG-PET) with computed tomography (CT) is effective for diagnosing large vessel vasculitis, but its usefulness in accurately diagnosing suspected, unselected vasculitis remains unknown. We evaluated the feasibility of 18 F-FDG-PET/CT in real-life cohort of patients with suspicion of vasculitis. The effect of the dose and the timing of glucocorticoid (GC) medication on imaging findings were in special interest. 82 patients with suspected vasculitis were evaluated by whole-body 18 F-FDG-PET/CT. GC treatment as prednisolone equivalent doses at the scanning moment and before imaging was evaluated. 38/82 patients were diagnosed with vasculitis. Twenty-one out of 38 patients had increased 18 F-FDG accumulation in blood vessel walls indicating vasculitis in various sized vessels. Vasculitis patients with a positive vasculitis finding in 18 F-FDG-PET/CT had a significantly shorter duration of GC use (median = 4.0 vs 7.0 days, P =0.034), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, p =0.004) compared to 18 F-FDG-PET/CT-negative patients. Vasculitis patients with a positive 18 F-FDG-PET/CT result had significantly higher C-reactive protein (CRP) than patients with a negative 18 F-FDG-PET/CT finding (mean value = 154.5 vs 90.4 mg/L, p =0.018). We found that 18 F-FDG-PET/CT positivity was significantly associated with a lower dose and shorter duration of GC medication and higher CRP level in vasculitis patients. 18 F-FDG-PET/CT revealed clinically significant information in over half of the patients and was effective in confirming the final diagnosis., Competing Interests: The authors declare that they have no conflicts of interest.

Objective: Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce the advances in understanding, detection, and treatment of this disease in recent years, with a particular concern to clinical practice., Data Sources: All the data in this review were from the English or Chinese literature in the PubMed and China National Knowledge Infrastructure databases as of March 2019., Study Selection: This review selected important original articles, meaningful reviews, and some reports on cryoglobulinemia published in recent years and in history, as well as the guidelines for treatment of underlying diseases which lead to cryoglobulinemia., Results: Diagnosis of cryoglobulinemia relies on serum cryoglobulin test, in which to ensure that the blood sample temperature is not less than 37°C in the entire pre-analysis phase is the key to avoid false negative results. Cryoglobulinemic vasculitis (Cryo Vas), including cryoglobulinemic glomerulonephritis (Cryo GN), usually occurs in types II and III mixed cryoglobulinemia, and can also be seen in type I cryoglobulinemia caused by monoclonal IgG3 or IgG1. Skin purpura, positive serum rheumatoid factor, and decreased serum levels of C4 and C3 are important clues for prompting types II and III Cryo Vas. Renal biopsy is an important means for diagnosis of Cryo GN, while membranous proliferative GN is the most common pathological type of Cryo GN. In recent years, great advances have been made in the treatment of Cryo Vas and its underlying diseases, and this review has briefly introduced these advances., Conclusions: Laboratory examinations of serum cryoglobulins urgently need standardization. The recent advances in the diagnosis and treatment of Cryo Vas and GN need to be popularized among the clinicians in related disciplines.

Objectives: Exaggerated blood pressure response (EBPR) to exercise tests is an additional cardiovascular risk factor and predictor of future development of hypertension. However, there are conflicting data on the diagnostic threshold of EBPR and its clinical importance in kidney disease. The aim of this study was to investigate vascular inflammation and subclinical nephropathy in otherwise healthy volunteers with EBPR., Patients and Methods: The study included 170 middle-aged, healthy volunteers (mean age: 43.3±6.9; range: 35-65 years: 100 men and 70 women). Participants performed a treadmill exercise test until they reached their age-adjusted maximum heart rate and were divided into EBPR and normal/physiological blood pressure response groups. Before exercise tests, serum high sensitive C-reactive protein (hs-CRP) and urine albumin-to-creatinine ratio were measured to evaluate vascular inflammation and subclinical nephropathy, respectively. Anthropometrical measurements, fasting serum glucose, fasting lipid profile, and the full blood count of participants were also evaluated., Results: EBPR was detected in 31 (18.2%) participants. Hs-CRP levels (1.03 vs. 0.46 mg/l) (P<0.001) and albumin-to-creatinine ratio levels (6.90 vs. 5.22 mg/g) (P=0.002) were higher in the EBPR group. BMI, abdominal obesity, and hs-CRP levels were found to be related to increased development of EBPR., Conclusion: EBPR is an overlooked clinical finding during exercise tests and should be evaluated in apparently healthy, middle-aged populations for the early detection of possible subclinical nephropathy.

PTX3 is a prototypic soluble pattern recognition receptor, expressed at sites of inflammation and involved in regulation of the tissue homeostasis. PTX3 systemic levels increase in many (but not all) immune-mediated inflammatory conditions. Research on PTX3 as a biomarker has so far focused on single diseases. Here, we performed a multi-group comparative study with the aim of identifying clinical and pathophysiological phenotypes associated with PTX3 release. PTX3 concentration was measured by ELISA in the plasma of 366 subjects, including 96 patients with giant cell arteritis (GCA), 42 with Takayasu's arteritis (TA), 10 with polymyalgia rheumatica (PMR), 63 with ANCA-associated systemic small vessel vasculitides (AAV), 55 with systemic lupus erythematosus (SLE), 21 with rheumatoid arthritis (RA) and 79 healthy controls (HC). Patients with SLE, AAV, TA and GCA, but not patients with RA and PMR, had higher PTX3 levels than HC. PTX3 concentration correlated with disease activity, acute phase reactants and prednisone dose. It was higher in females, in patients with recent-onset disease and in those with previous or current active vasculitis at univariate analysis. Active small- or large- vessel vasculitis were the main independent variables influencing PTX3 levels at multivariate analysis. High levels of PTX3 in the blood can contribute to identify an increased risk of vascular involvement in patients with systemic immune-mediated diseases.

Background: IgA vasculitis (IgAV, formerly Henoch-Schönlein purpura) is a type of systemic vasculitis. This study aimed to explore the clinicopathological features, treatment and renal outcomes of adult IgAV-related nephritis (Henoch-Schönlein purpura nephritis) patients with different degrees of crescent formation., Methods: Adult patients with biopsy-proven IgAV-related nephritis in Nanjing Jinling Hospital were enrolled and divided into three groups as follows: control (no crescents, n = 257), group 1 (crescents < 25%, n = 381), and group 2 (crescents ≥25%, n = 60). The clinicopathological features, treatment and renal outcomes were compared among the three groups., Results: There were no significant differences in gender and age at biopsy among the three groups. Groups with more crescents had shorter renal durations and higher prevalence of macroscopic hematuria, proteinuria and nephrotic syndrome than the control group. The presence of renal insufficiency at biopsy was similar, whereas laboratory findings indicated that patients with ≥25% crescents had higher levels of serum creatinine and blood urea nitrogen than the control and group 1. Histologically, the incidence of glomeruli-Bowman's capsule adhesion and capillary necrosis were proportional to the degree of crescent formation. Patients with more crescents received more positive immunosuppressive therapies. During follow-up, the levels of proteinuria and hematuria were in remission after treatment, and patients without crescents had lower levels of proteinuria. At the last follow-up, the renal function had deteriorated in the control and group 1, whereas the levels of serum creatinine at biopsy and last follow-up were similar in group 2. There was a significant difference in renal survival from end-stage renal disease (ESRD) or 50% decline in renal function among the three groups (log-rank, P = 0.030). However, no association between crescent formation and renal outcomes was found after adjusting potential confounders., Conclusions: Adult IgAV-related nephritis patients with more crescents had more-severe renal manifestations and worse treatment responses, whereas the proportions of crescents were not associated with higher risks for ESRD or 50% decline in renal function. A more suitable pathological classification standard is needed to predict renal prognosis.

Introduction: Galactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN., Methods: We retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55., Results: Although levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02-1.89; p = 0.038)., Conclusions: Although IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN., Competing Interests: The authors have declared that no competing interests exist.

Aim This report describes a case of large vessel vasculitis highlighting diagnostic and therapeutic challenges. It describes the use of the B cell depleting agent Rituximab in this setting. This is the case of a 50 year old lady with bipolar disorder presenting with lower limb pain. Method PET CT and CT angiography were employed in the diagnosis of a large vessel vasculitic process. Serum IgG4 was elevated. Histological sampling was not clinically feasible. A presumptive diagnosis of IgG4 related disease was made. Results The patient responded well to steroids and later rituximab. A prompt taper of steroids was required due to labile mood and Rituximab proved to be effective in this case as a maintenance therapy. Conclusion This case demonstrates that a combination of clinical findings, laboratory results and radiological imaging may be necessary for diagnosis for IgG4 related disease, especially in the absence of a histological diagnosis. Rituximab was used in this case as a maintenance therapy allowing for a relatively rapidly reducing course of steroids., Competing Interests: The authors have no conflicts of interest to declare.

A retired businessman presented to the infectious diseases department with a history of ongoing fevers and myalgia and raised inflammatory markers. This continued despite adequate antibiotic treatment of an epididymo-orchitis. Extensive investigations, including bone marrow and liver biopsies and a positron emission tomography, did not reveal a cause but showed reactive change in the bone marrow. Later, he developed a vasculitic rash and vision loss due to non-arteritic anterior ischaemic optic neuropathy. High-dose steroids were immediately initiated. A temporal artery biopsy was performed, which confirmed a healing large vessel vasculitis, possibly giant cell arteritis. He has responded very well to therapy. We must better appreciate the limitations of positron emission tomography in investigating a fever of unknown origin. The case also encourages awareness of autoimmune disorders as the leading category of causative diseases for this in older age groups., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Cocaine use causes significant cardiovascular morbidity from its hemodynamic effects. It is less clear whether cocaine promotes atherosclerosis. Vascular inflammation is one of the earliest steps in the pathophysiology of atherosclerosis. We hypothesized that cocaine results in an increase in inflammatory markers. Study objective was to measure the acute effects of intravenous cocaine on biomarkers of vascular inflammation. Eleven chronic cocaine users were enrolled. After a drug-free period, they received intravenous cocaine at 0.36 mg/kg dose in an in-hospital controlled environment. Serum levels of soluble CD40 ligand, monocyte chemoattractant protein-1, interleukin 6, and soluble intercellular adhesion molecule-1 were measured at baseline, 6 h, 24 h, and 6 days after cocaine challenge and at baseline for controls. After cocaine challenge, sCD40 ligand levels decreased in subjects and were significantly lower at 24 h. MCP-1 levels decreased and were significantly lower at the 6-day time point. No significant changes in IL-6 or sICAM-1 level were found. In conclusion, intravenous cocaine did not result in an increase in levels of inflammatory markers. Levels of MCP-1 and sCD40L decreased significantly. This unexpected finding suggests that chronic effects of cocaine on inflammation may be different from acute effects or that higher dosing may have differential effects as compared to lower dose used here.

Objectives: The aim was to describe the clinical characteristics and epidemiology of hypocomplementaemic urticarial vasculitis (HUV; anti-C1q vasculitis) in two geographically defined areas of Sweden., Methods: In the health-care districts surrounding Skåne University Hospital (mean population 950 560) and Linköping University Hospital (mean population 428 503), all incident cases of HUV residing within the study areas at the onset of disease were identified during the years 2000-15. The diagnosis of HUV was confirmed by review of medical records. Only patients meeting the proposed diagnostic HUV criteria and/or the 2012 Chapel Hill consensus definitions in combination with an ever-positive anti-C1q antibody test were included., Results: Sixteen patients (14 females) were identified during the study period. The median (interquartile range) age at diagnosis was 51 (40.7-56.7) years. Median (interquartile range) time of follow-up from diagnosis to 31 December 2015, or death, was 94 (46.5-136.2) months. The most frequent manifestations at diagnosis were urticaria (100%), arthritis (88%), followed by biopsy-proven glomerulonephritis (19%), episcleritis/scleritis (19%) and recurrent abdominal pain (13%). The annual incidence rate per million inhabitants was estimated as 0.7 (95% CI: 0.4, 1.1). Sixty-three per cent suffered from pulmonary disease at the last follow-up. Two patients died during the follow-up period. One patient underwent lung transplantation, and two patients proceeded to end-stage renal disease. The point prevalence on 31 December 2015 was 9.5/million (95% CI: 4.5, 14.5)., Conclusion: Hypocomplementaemic urticarial vasculitis constitutes a rare, but not always benign condition. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition.

Patients with hepatitis C virus-associated cryoglobulinemic vasculitis (HCV-CV) have high rates of clinical remission after treatment with direct-acting antivirals (DAAs), but circulating cryoglobulins persist, and vascular disorders reappear in some patients shortly after DAA treatment ends. We performed a prospective study to assess the long-term clinical and immune system effects of HCV eradication with DAAs in 46 patients with HCV-CV and 42 asymptomatic patients with circulating cryoglobulins. A median of 24 months after DAA treatment (range, 17-41 months), 66% of patients with HCV-CV and 70% of asymptomatic patients with circulating cryoglobulins had an immunologic response, with comparable reductions in cryocrit from 2.6% to 0% (P < .05). However, 20% of patients still had positive test results for cryoglobulins after DAA therapy. Among patients with HCV-CV, 42 (91%) had a clinical response, in that their Birmingham Vasculitis Activity Score (version 3) decreased from 7 to 0 (P < .01). Nevertheless, within 2 years after a sustained viral response to DAA therapy, 5 patients with HCV-CV (11%, 4 with cirrhosis) had relapses of vasculitis that included severe organ damage and death., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to investigate the clinical significance of the Wnt/β-catenin signaling pathway in glucocorticoid-induced osteoporosis. A total of 91 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg daily) were prospectively enrolled. We measured serum levels of N-terminal peptide of type I procollagen (P1NP), bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), N-telopeptide cross-linked type I collagen (NTX), sclerostin, Dickkopf-1 (Dkk-1), and Wnt3a before starting glucocorticoid therapy and every week for 4 weeks after its initiation. The effects of dexamethasone on expression of mRNA and protein of sclerostin and Dkk-1 by cultured normal human osteoblasts (NHOst) were evaluated by RT-PCR and ELISA, respectively. Serum levels of sclerostin and Dkk-1 increased significantly by 1 week of glucocorticoid therapy and then decreased from the second week onward. Serum Wnt3a tended to decrease and serum P1NP showed a significant decrease. However, TRACP-5b was significantly elevated from the first week of treatment onwards. In vitro study, dexamethasone increased Dkk-1 mRNA expression in cultured NHOst, but sclerostin mRNA was not detected. Dexamethasone also increased Dkk-1 protein production by osteoblasts, whereas sclerostin protein was not detected. Bone formation might be impaired at least in the first week of the initiation of glucocorticoid therapy by increase of the serum Wnt signaling inhibitors; however, their reductions in the subsequent weeks were contradictory to the maintained suppression of the bone formation markers after glucocorticoid therapy for patients with systemic autoimmune diseases.