Alvise Berti1, Roscoe Warner2, Kent Johnson2, Divi Cornec3, Darrell Schroeder4, Brian Kabat4, Carol A Langford5, Gary S Hoffman5, Fernanado C Fervenza4, Cees G M Kallenberg6, Philip Seo7, Robert Spiera8, E William St Clair9, Paul Brunetta10, John H Stone11, Peter A Merkel12, Ulrich Specks4, Paul A Monach13. 1. Mayo Clinic College of Medicine and Science, Rochester, Minnesota, San Raffaele University, Milan, Italy, and Santa Chiara Hospital, Trento, Italy. 2. University of Michigan Medical School, Ann Arbor. 3. Mayo Clinic College of Medicine and Science, Rochester, Minnesota, and Université de Bretagne Occidentale, CHU de Brest, Brest, France. 4. Mayo Clinic College of Medicine and Science, Rochester, Minnesota. 5. Cleveland Clinic, Cleveland, Ohio. 6. University Medical Center Groningen, Groningen, The Netherlands. 7. Johns Hopkins University, Baltimore, Maryland. 8. Hospital for Special Surgery, New York, New York. 9. Duke University Medical Center, Durham, North Carolina. 10. Genentech, South San Francisco, California. 11. Massachusetts General Hospital, Boston. 12. University of Pennsylvania, Philadelphia. 13. Boston University and VA Boston Healthcare System, Boston, Massachusetts.
Abstract
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.
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.
Authors: J H Stone; G S Hoffman; P A Merkel; Y I Min; M L Uhlfelder; D B Hellmann; U Specks; N B Allen; J C Davis; R F Spiera; L H Calabrese; F M Wigley; N Maiden; R M Valente; J L Niles; K H Fye; J W McCune; E W St Clair; R A Luqmani Journal: Arthritis Rheum Date: 2001-04
Authors: Paul A Monach; Gunnar Tomasson; Ulrich Specks; John H Stone; David Cuthbertson; Jeffrey Krischer; Linna Ding; Fernando C Fervenza; Barri J Fessler; Gary S Hoffman; David Ikle; Cees G M Kallenberg; Carol A Langford; Mark Mueller; Philip Seo; E William St Clair; Robert Spiera; Nadia Tchao; Steven R Ytterberg; Yi-Zhong Gu; Ronald D Snyder; Peter A Merkel Journal: Arthritis Rheum Date: 2011-12
Authors: John H Stone; Peter A Merkel; Robert Spiera; Philip Seo; Carol A Langford; Gary S Hoffman; Cees G M Kallenberg; E William St Clair; Anthony Turkiewicz; Nadia K Tchao; Lisa Webber; Linna Ding; Lourdes P Sejismundo; Kathleen Mieras; David Weitzenkamp; David Ikle; Vicki Seyfert-Margolis; Mark Mueller; Paul Brunetta; Nancy B Allen; Fernando C Fervenza; Duvuru Geetha; Karina A Keogh; Eugene Y Kissin; Paul A Monach; Tobias Peikert; Coen Stegeman; Steven R Ytterberg; Ulrich Specks Journal: N Engl J Med Date: 2010-07-15 Impact factor: 91.245
Authors: Paul A Monach; Roscoe L Warner; Gunnar Tomasson; Ulrich Specks; John H Stone; Linna Ding; Fernando C Fervenza; Barri J Fessler; Gary S Hoffman; David Iklé; Cees G M Kallenberg; Jeffrey Krischer; Carol A Langford; Mark Mueller; Philip Seo; E William St Clair; Robert Spiera; Nadia Tchao; Steven R Ytterberg; Kent J Johnson; Peter A Merkel Journal: Ann Rheum Dis Date: 2012-09-12 Impact factor: 19.103
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Authors: Nikola Lepse; Judith Land; Abraham Rutgers; Cees G M Kallenberg; Coen A Stegeman; Wayel H Abdulahad; Peter Heeringa Journal: Rheumatology (Oxford) Date: 2015-08-28 Impact factor: 7.580
Authors: J C Jennette; R J Falk; P A Bacon; N Basu; M C Cid; F Ferrario; L F Flores-Suarez; W L Gross; L Guillevin; E C Hagen; G S Hoffman; D R Jayne; C G M Kallenberg; P Lamprecht; C A Langford; R A Luqmani; A D Mahr; E L Matteson; P A Merkel; S Ozen; C D Pusey; N Rasmussen; A J Rees; D G I Scott; U Specks; J H Stone; K Takahashi; R A Watts Journal: Arthritis Rheum Date: 2013-01
Authors: Zachary S Wallace; Xiaoqing Fu; Katherine Liao; Cees G M Kallenberg; Carol A Langford; Peter A Merkel; Paul Monach; Philip Seo; Ulrich Specks; Robert Spiera; E William St Clair; Yuqing Zhang; Hyon Choi; John H Stone Journal: Arthritis Rheumatol Date: 2019-09-16 Impact factor: 10.995
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Authors: Eveline Y Wu; Elizabeth A McInnis; Sonia Boyer-Suavet; Carmen E Mendoza; Lydia T Aybar; Kristin B Kennedy; Caroline J Poulton; Candace D Henderson; Yichun Hu; Susan L Hogan; Peiqi Hu; Hong Xiao; Patrick H Nachman; J Charles Jennette; Ronald J Falk; Donna O Bunch Journal: Arthritis Rheumatol Date: 2019-10-08 Impact factor: 10.995