Publications by authors named "Cees G M Kallenberg"

216 Publications

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

Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2019 11 25;71(11):1888-1893. Epub 2019 Sep 25.

Massachusetts General Hospital, Harvard Medical School, Boston.

Objective: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors.

Methods: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV).

Results: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained.

Conclusion: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.
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http://dx.doi.org/10.1002/art.41017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899947PMC
November 2019

Disease Activity, Antineutrophil Cytoplasmic Antibody Type, and Lipid Levels in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2019 11 16;71(11):1879-1887. Epub 2019 Sep 16.

Massachusetts General Hospital, Boston.

Objective: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population.

Methods: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels.

Results: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure.

Conclusion: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.
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http://dx.doi.org/10.1002/art.41006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944270PMC
November 2019

The net effect of ANCA on neutrophil extracellular trap formation.

Kidney Int 2018 07;94(1):14-16

Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

The formation of neutrophil extracellular traps induced by antineutrophil cytoplasmic autoantibodies has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis. Kraaij et al. now provide evidence that excessive neutrophil extracellular trap formation in vitro induced by sera from patients with antineutrophil cytoplasmic autoantibody-associated vasculitis is associated with active disease but is not dependent on the presence of antineutrophil cytoplasmic autoantibodies.
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http://dx.doi.org/10.1016/j.kint.2018.03.010DOI Listing
July 2018

Brief Report: Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2018 07 7;70(7):1114-1121. Epub 2018 May 7.

Boston University and VA Boston Healthcare System, Boston, Massachusetts.

Objective: To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]).

Methods: A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest.

Results: Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-β, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis.

Conclusion: Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.
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http://dx.doi.org/10.1002/art.40471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093207PMC
July 2018

Review: What Is the Current Evidence for Disease Subsets in Giant Cell Arteritis?

Arthritis Rheumatol 2018 09 30;70(9):1366-1376. Epub 2018 Jul 30.

University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.
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http://dx.doi.org/10.1002/art.40520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175064PMC
September 2018

The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis.

Clin J Am Soc Nephrol 2018 02 25;13(2):251-257. Epub 2018 Jan 25.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear.

Design, Setting, Participants, & Measurements: A analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis.

Results: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; =0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; =0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; <0.01). The median time to renal relapse was 22 months.

Conclusions: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.
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http://dx.doi.org/10.2215/CJN.04160417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967421PMC
February 2018

Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

Rheumatology (Oxford) 2018 04;57(4):639-650

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

Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes.

Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission.

Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse.

Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.
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http://dx.doi.org/10.1093/rheumatology/kex484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888934PMC
April 2018

Towards precision medicine in ANCA-associated vasculitis.

Rheumatology (Oxford) 2018 08;57(8):1332-1339

Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personalized treatment strategies. In this review, we discuss current evidence for a better classification of AAV based on ANCA type. We describe how thus defined categories of AAV patients may differ in genetic background, clinical presentation, immune pathology, response to treatment and disease outcome. We also explore how these insights may provide a rationale for targeted treatments in different categories of AAV patients. Finally, we provide recommendations on how to further establish precision medicine in AAV.
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http://dx.doi.org/10.1093/rheumatology/kex367DOI Listing
August 2018

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

Sci Rep 2017 09 22;7(1):12211. Epub 2017 Sep 22.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB, Groningen, The Netherlands.

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse.
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http://dx.doi.org/10.1038/s41598-017-12450-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610336PMC
September 2017

Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.

Nat Rev Rheumatol 2017 Nov 14;13(11):683-692. Epub 2017 Sep 14.

Department of Internal Medicine, Rheumatology and Immunology, Vasculitis-Centre Tübingen-Kirchheim, Medius Klinik Kirchheim, University of Tübingen, Eugenstrasse 3, 73230 Kirchheim unter Teck, Germany.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.
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http://dx.doi.org/10.1038/nrrheum.2017.140DOI Listing
November 2017

Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

Am J Nephrol 2017 8;46(3):231-238. Epub 2017 Sep 8.

Division of Nephrology and Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.

Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy.

Methods: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined.

Results: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group.

Conclusions: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.
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http://dx.doi.org/10.1159/000480443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640633PMC
May 2018

Are cytokines and chemokines suitable biomarkers for Takayasu arteritis?

Autoimmun Rev 2017 Oct 2;16(10):1071-1078. Epub 2017 Aug 2.

Rheumatology Division, Universidade Federal de São Paulo - Escola Paulista de Medicina, Rua Botucatu, 740, 3rd Floor, São Paulo, SP zip code: 04032-900, Brazil. Electronic address:

There is a growing need for disease related biomarkers in Takayasu arteritis (TA).The assessment of pro-inflammatory cytokines and chemokines in TA may provide a better understanding of its pathophysiology, and circulating levels of these mediators may act as biomarkers of disease activity. Serum level of interleukin 6 (IL-6) is a potential biomarker for TA, which is mostly associated with TA status and disease activity. Associations between TA and serum/plasma levels of other cytokines are less clear. mRNA expression of IL-4 and tumor necrosis factor α (TNFα) are constitutively increased in peripheral blood mononuclear cells (PBMC) from TA patients and the expression of both cytokines increases even more after PBMC stimulation in vitro, while the expression of IL-10 mRNA decreases. In addition, circulating T cells from TA patients produce increased levels of both Th1- and Th17-related cytokines upon in vitro stimulation. In the aorta from TA patients, an increased expression of interferon γ (IFNγ), IL-6, IL-12 and IL-17 has been described. Regarding circulating chemokines in TA, serum/plasma levels of IL-8 (CXCL8), CCL2 and CCL5 were shown to be elevated in TA patients compared with healthy controls as well as in TA patients with active disease compared with those in remission. Serum IL-6 seems to be the best biomarker for disease state and disease activity in TA and increased Th1 and Th17 responses are predominant in the pathophysiology of TA.
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http://dx.doi.org/10.1016/j.autrev.2017.07.023DOI Listing
October 2017

Transancestral mapping and genetic load in systemic lupus erythematosus.

Nat Commun 2017 07 17;8:16021. Epub 2017 Jul 17.

Division of Rheumatology, Department of Medicine (DIMED), University of Padua, Padua 35122, Italy.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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http://dx.doi.org/10.1038/ncomms16021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520018PMC
July 2017

M2 macrophage is the predominant phenotype in airways inflammatory lesions in patients with granulomatosis with polyangiitis.

Arthritis Res Ther 2017 05 18;19(1):100. Epub 2017 May 18.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotypes in biopsies from the airways of patients with active granulomatosis with polyangiitis (GPA) and to analyze their associations with T and B cells in those biopsies, and with nasal carriage of Staphylococcus aureus, disease parameters and therapy.

Methods: Consecutive GPA patients (n = 35) with active airway disease, who underwent respiratory tract biopsy were included. Immunohistochemical evaluation was performed to assess the distribution of macrophages and T and B cells using the markers CD68, CD3 and CD20, respectively. CD86 was used as the M1 marker and CD163 as the M2 marker while Tbet and GATA-3 were used as Th1 and Th2 markers, respectively. At the time of the biopsy patients were assessed for nasal carriage of Staphylococcus aureus and treatment.

Results: Percentages of macrophages and T cells were significantly higher than those of B cells in lesional tissue from the respiratory tract in GPA. M2 macrophages and Th2 cells were more frequent than M1 macrophages (p = 0.0007) and Th1 cells (p < 0.0001), respectively. Percentages of T cells were higher in nose biopsies than in biopsies from other sites (p = 0.021); macrophages and CD163 macrophages were more predominant in biopsy sites other than the nose (p = 0.039 and p = 0.012, respectively). Carriage of Staphylococcus aureus was associated with higher T cell scores (p = 0.014). The frequency of macrophages, especially M2 macrophages, was higher in GPA patients treated with immunosuppressive agents (p = 0.010); daily prednisolone dose was positively correlated with all macrophage markers. However, in multivariate analysis no independent associations were found between disease parameters and therapy with macrophage markers or T cells.

Conclusion: In GPA, M2 is the predominant macrophage phenotype in the respiratory tract. Although some associations were observed between macrophages and T cells with therapy and nasal carriage of Staphylococcus aureus, they were not independently significant in multivariate analysis.
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http://dx.doi.org/10.1186/s13075-017-1310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437644PMC
May 2017

Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Care Res (Hoboken) 2017 07;69(7):1004-1010

Massachusetts General Hospital, Boston.

Objective: We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

Methods: We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured regularly during the trial period. We performed mixed-effects regressions to examine the associations of time-dependent cumulative average glucocorticoid use and disease activity with changes in BMI over time, while adjusting for potential confounders.

Results: The mean ± SD baseline BMI of the 197 patients enrolled was 28.8 ± 6.3 kg/m . Patients with newly diagnosed AAV tended to have a lower mean ± SD BMI than those with relapsing disease (28.0 ± 5.7 kg/m versus 29.6 ± 6.8 kg/m ) and higher disease activity (mean ± SD Birmingham Vasculitis Activity Score for Wegener's Granulomatosis 8.7 ± 3.3 versus 7.4 ± 2.7). The most significant change in BMI occurred during the first 6 months of the trial (mean ± SD increase of 1.1 ± 2.2 kg/m ; P < 0.0001). Disease activity improvement, glucocorticoid exposure, and randomization to rituximab were each independently associated with an increase in BMI (P < 0.001 for all analyses).

Conclusion: Our findings suggest that changes in BMI, as well as glucocorticoid exposure, are independently associated with improvements in disease activity in AAV. Rituximab may also have effects on BMI independent of its impact on disease activity.
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http://dx.doi.org/10.1002/acr.23099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611860PMC
July 2017

The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2017 01;69(1):169-175

Ohio State University, Columbus.

Objective: The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively.

Methods: Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests.

Results: No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001).

Conclusion: The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.
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http://dx.doi.org/10.1002/art.39822DOI Listing
January 2017

Association of Serum Calprotectin (S100A8/A9) Level With Disease Relapse in Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2017 01;69(1):185-193

University College London Centre for Nephrology, Royal Free Hospital, London, UK.

Objective: S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV.

Methods: Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained.

Results: Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group (P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 (P = 0.0043) and baseline and month 6 (P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse (P = 0.028).

Conclusion: An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment.
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http://dx.doi.org/10.1002/art.39814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839649PMC
January 2017

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's): Distinct Patient Subsets.

Arthritis Rheumatol 2016 12;68(12):2945-2952

Massachusetts General Hospital, Boston.

Objective: To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA).

Methods: We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA).

Results: Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement.

Conclusion: We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.
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http://dx.doi.org/10.1002/art.39812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541999PMC
December 2016

Opponent's comments.

Nephrol Dial Transplant 2016 07;31(7):1057-8

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/ndt/gfw068aDOI Listing
July 2016

Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial.

Nephrol Dial Transplant 2016 09 30;31(9):1453-9. Epub 2016 May 30.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.

Background: Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine maintenance therapy could reduce the incidence of relapse in this setting.

Methods: Patients newly diagnosed with PR3-AAV at 12 centres in The Netherlands during 2003-11 who received a standardized induction regimen consisting of oral cyclophosphamide and corticosteroids were enrolled (n = 131). Patients were randomized to standard or extended azathioprine maintenance therapy when C-ANCA was positive at the time of stable remission. Standard maintenance treatment consisted of azathioprine (1.5-2.0 mg/kg) until 1 year after diagnosis and subsequent tapering to 25 mg every 3 months. Extended azathioprine maintenance therapy (1.5-2.0 mg/kg) was continued until 4 years after diagnosis and tapered thereafter. The primary endpoint was relapse-free survival at 4 years after diagnosis.

Results: In patients with PR3-AAV who were C-ANCA positive at the time of stable remission, relapse-free survival at 4 years after diagnosis did not differ significantly between standard azathioprine (n = 24) and extended azathioprine (n = 21) maintenance therapy (P = 0.40). There was also no significant difference in relapse-free survival between patients receiving standard azathioprine (n = 106) versus extended azathioprine maintenance therapy (n = 21; P = 0.94). In addition, there was no difference in the relapse rate between patients with PR3-AAV who were C-ANCA positive (n = 45) at the time of remission versus patients who became C-ANCA negative at the time of remission (n = 82; P = 0.62).

Conclusions: This randomized trial suggests that extended azathioprine maintenance therapy has only a limited effect on the prevention of relapse in patients with PR3-AAV at 4 years after diagnosis. Moreover, positive C-ANCA status at stable remission was not associated with an increased rate of relapse.

Trial Registration: ClinicalTrials.gov NCT 00128895.
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http://dx.doi.org/10.1093/ndt/gfw211DOI Listing
September 2016

Using Mass Spectrometry to Quantify Rituximab and Perform Individualized Immunoglobulin Phenotyping in ANCA-Associated Vasculitis.

Anal Chem 2016 06 3;88(12):6317-25. Epub 2016 Jun 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, Minnesota 55905, United States.

Therapeutic monoclonal immunoglobulins (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. As pharmaceutical companies bring more fully humanized therapeutic mAb drugs to the healthcare market analytical platforms that perform therapeutic drug monitoring (TDM) without relying on mAb specific reagents will be needed. In this study we demonstrate that liquid-chromatography-mass spectrometry (LC-MS) can be used to perform TDM of mAbs in the same manner as smaller nonbiologic drugs. The assay uses commercially available reagents combined with heavy and light chain disulfide bond reduction followed by light chain analysis by microflow-LC-electrospray ionization-quadrupole-time-of-flight mass spectrometry (ESI-Q-TOF MS). Quantification is performed using the peak areas from multiply charged mAb light chain ions using an in-house developed software package developed for TDM of mAbs. The data presented here demonstrate the ability of an LC-MS assay to quantify a therapeutic mAb in a large cohort of patients in a clinical trial. The ability to quantify any mAb in serum via the reduced light chain without the need for reagents specific for each mAb demonstrates the unique capabilities of LC-MS. This fact, coupled with the ability to phenotype a patient's polyclonal repertoire in the same analysis further shows the potential of this approach to mAb analysis.
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http://dx.doi.org/10.1021/acs.analchem.6b00544DOI Listing
June 2016

Pro: Cyclophosphamide in lupus nephritis.

Nephrol Dial Transplant 2016 07 14;31(7):1047-52. Epub 2016 May 14.

Department of Rheumatology & Clinical Immunology, AA21, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up data available for low-dose pulse cyclophosphamide, the fact that compliance is guaranteed with this regimen and economic issues all favour the Euro-Lupus regimen in this author's opinion. For maintenance treatment, either azathioprine (AZA) or MMF may be used; AZA is preferred in case pregnancy is planned, while MMF is preferred when the disease relapses during use of AZA and, possibly, after successful induction of remission with MMF.
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http://dx.doi.org/10.1093/ndt/gfw069DOI Listing
July 2016

Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3.

Arthritis Rheumatol 2016 07;68(7):1700-10

Mayo Clinic and Mayo Foundation for Medical Education and Research, Rochester, Minnesota.

Objective: Relapse following remission is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly with ANCAs directed at proteinase 3 (PR3). This study was undertaken to evaluate the association of an increase in PR3-ANCA level with subsequent relapse.

Methods: Data from the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. Starting from the time of achieving complete remission, serial measurements by direct and capture enzyme-linked immunosorbent assays (ELISAs) were analyzed in 93 patients with PR3-ANCA, using Cox proportional hazards regression.

Results: An increase in PR3-ANCA level was identified in 58 of 93 subjects (62.4%) by direct ELISA and in 59 of 93 (63.4%) by capture ELISA. Relapses occurred in 55 of 93 subjects (59.1%), with 25 and 21 occurring within 1 year after an increase by direct ELISA and capture ELISA, respectively. An increase by direct ELISA was associated with subsequent severe relapses (hazard ratio [HR] 4.57; P < 0.001), particularly in patients presenting with renal involvement (HR 7.94; P < 0.001) and alveolar hemorrhage (HR 24.19; P < 0.001). Both assays identified increased risk for severe relapse in the rituximab group (HR 5.80; P = 0.002 for direct ELISA and HR 4.54; P = 0.007 for capture ELISA) but not the cyclophosphamide/azathioprine group (P = 0.103 and P = 0.197, respectively).

Conclusion: The association of an increase in PR3-ANCA level with the risk of subsequent relapse is partially affected by the PR3-ANCA detection methodology, disease phenotype, and remission induction treatment. An increase in PR3-ANCA level during complete remission conveys an increased risk of relapse, particularly severe relapse, among patients with renal involvement or alveolar hemorrhage and those treated with rituximab. Serial measurements of PR3-ANCA may be informative in this subset of patients, but the risk of relapse must be weighed carefully against the risks associated with therapy.
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http://dx.doi.org/10.1002/art.39637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137903PMC
July 2016

FSAP-mediated nucleosome release from late apoptotic cells is inhibited by autoantibodies present in SLE.

Eur J Immunol 2016 Mar 22;46(3):762-71. Epub 2015 Dec 22.

Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII-activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracellular environment. We investigated whether FSAP-mediated nucleosome release from late apoptotic cells is affected in SLE patients. Nucleosome release in sera of 27 SLE patients and 30 healthy controls was investigated by incubating late apoptotic Jurkat cells with serum and analyzing the remaining DNA content by flow cytometry. We found that nucleosome release in sera of SLE patients with high disease activity was significantly decreased when compared with that in SLE sera obtained during low disease activity or from healthy individuals. Upon removal of IgG/IgM antibodies from SLE sera, nucleosome release was restored. Similarly, monoclonal antinuclear antibodies inhibited nucleosome release in healthy donor serum or by plasma-purified FSAP. This inhibition was lost when Fab fragments were used, suggesting that antigen cross-linking is involved. In conclusion, FSAP-mediated nucleosome release from late apoptotic cells is greatly impaired in SLE patient sera, possibly hampering the clearance of these cells and thereby propagating inflammation.
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http://dx.doi.org/10.1002/eji.201546010DOI Listing
March 2016

Usefulness of antineutrophil cytoplasmic autoantibodies in diagnosing and managing systemic vasculitis.

Curr Opin Rheumatol 2016 Jan;28(1):8-14

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Purpose Of Review: Antineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions.

Recent Findings: Both the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisole-adulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab.

Summary: The techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion.
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http://dx.doi.org/10.1097/BOR.0000000000000233DOI Listing
January 2016

Complement system activation in ANCA vasculitis: A translational success story?

Mol Immunol 2015 Nov;68(1):53-6

Dept of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.

The ANCA-associated vasculitides (AAV) are characterized by pauci-immune necrotizing small to medium size vessel vasculitis frequently including necrotizing crescentric glomerulonephritis. Neutrophil activation by ANCA appears a primary pathogenic event. More recently, the complement system has been shown to be involved as well. Activation of the alternative pathway of complement, at least in part via activated neutrophils, results, amongst others, in the generation of C5a, a strong chemoattractant for neutrophils. C5a is also effective in neutrophil priming, a process leading to surface expression of the ANCA antigens so enabling neutrophils to be further activated by ANCA. Both in vitro and in vivo experimental data and histopathological studies from AAV patients underscore the role of complement, and particularly of C5a, in the pathophysiology of AAV. Preliminary data show that blocking of the C5a-receptor is a promising approach in the treatment of AAV.
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http://dx.doi.org/10.1016/j.molimm.2015.06.005DOI Listing
November 2015

Pathogenesis and treatment of ANCA-associated vasculitides.

Clin Exp Rheumatol 2015 Jul-Aug;33(4 Suppl 92):S11-4. Epub 2015 Oct 12.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands.

Recent studies have increased our insight into the pathogenesis of ANCA-associated vasculitis (AAV). Although many data from in vitro and in vivo experimental studies support the pathogenic role of the autoantibodies, cellular immunity seems involved as well. Besides, an amplification loop via the alternative pathway of complement is apparent. These new insights make a more targeted therapeutic approach possible. In particular, the B-cell depleting antibody rituximab has been shown non-inferior to cyclophosphamide for induction of remission, and even superior in patients with relapsing disease being positive for PR3-ANCA. Rituximab is also superior to cyclophosphamide for maintaining remission. Blocking the C5a-receptor seems promising as well as an alternative for high dose corticosteroids during induction of remission.
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December 2015

Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro.

Rheumatology (Oxford) 2016 Jan 28;55(1):162-72. Epub 2015 Aug 28.

Department of Pathology and Medical Biology,

Objectives: Granulomatosis with polyangiitis (GPA) is a relapsing small-vessel vasculitis characterized by circulating ANCA against PR3. The mechanisms that trigger PR3-ANCA production are unknown. The aim of this study was to determine whether endogenous factors [B cell activating factor (BAFF) and IL-21] and exogenous factors [oligodeoxynucleotides containing CpG motifs (CpG-ODN)] synergize in stimulating PR3-ANCA production in GPA patients.

Methods: Peripheral blood mononuclear cells from GPA patients and healthy controls (HCs) were cultured in the presence of BAFF and IL-21, with or without CpG-ODN, for 12 days. PR3-ANCA production in culture supernatants was quantified by Phadia EliA. Phenotypic characterization and the influence of CpG-ODN treatment on IL-21 receptor (IL-21R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and BAFF receptor (BAFF-R) expression on B cells was analysed by flow cytometry.

Results: Stimulation with BAFF and IL-21 significantly increased ANCA production in patient samples, which could be augmented further by addition of CpG-ODN. Stimulation with CpG-ODN increased the percentage of IL-21R(+) and TACI(+) B cells but did not affect BAFF-R expression. GPA patients had an increased percentage of circulating IL-21R(+) and a decreased percentage of TACI(+) circulating memory B cells when compared with HCs. Additionally, patients had decreased expression of BAFF-R on B cells, which was inversely correlated with BAFF concentrations in plasma.

Conclusion: Our data demonstrate that endogenous and exogenous factors can synergize to promote PR3-ANCA production. Mechanistically, CpG-ODN up-regulated IL-21R and TACI expression on B cells, possibly sensitizing these cells for IL-21- and BAFF-mediated signals. Agents inhibiting Toll-like receptor 9, BAFF and IL-21 signalling pathways may serve as potential therapeutics for intervention in GPA patients.
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http://dx.doi.org/10.1093/rheumatology/kev293DOI Listing
January 2016

Emerging role of high mobility group box 1 in ANCA-associated vasculitis.

Autoimmun Rev 2015 Nov 22;14(11):1057-65. Epub 2015 Jul 22.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands.

High mobility group box 1 (HMGB1) has been suggested to be involved in the pathogenesis of many autoimmune diseases. In addition to its nuclear functions, extracellular HMGB1 released from activated, injured or dying cells becomes a proinflammatory mediator via binding to various receptors on the surface of responding cells. HMGB1 interacts with various systems involved in inflammation, such as the complement system and the coagulation system. Thus, HMGB1 could amplify inflammation and enhance immune responses in pathophysiology of certain diseases. In the past years, HMGB1 has been studied in several vasculitides including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Kawasaki disease, Henoch-Schönlein purpura, Takayasu arteritis and giant cell arteritis. Several studies showed that circulating HMGB1 levels are higher in patients with active disease compared with healthy controls, and levels are associated with disease severity. Further studies on pathogenetic mechanisms revealed pathogenic roles of HMGB1 in some vasculitides. Here we review clinical and experimental studies dealing with the role of HMGB1 in vascular inflammation, and its relation to the manifestations and prognosis of specific vasculitides, in particular ANCA-associated vasculitis.
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http://dx.doi.org/10.1016/j.autrev.2015.07.010DOI Listing
November 2015