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Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

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Berti A1, Warner R2, Johnson K2, Cornec D3, Schroeder D4, Kabat B4, Langford CA5, Hoffman GS5, Fervenza FC4, Kallenberg CGM6, Seo P7, Spiera R8, St Clair EW9, Brunetta P10, Stone JH11, Merkel PA12, Specks U4, Monach PA13; RAVE-ITN Research Group. Arthritis Rheumatol. 2018 Apr 25. doi: 10.1002/art.40471. [Epub ahead of print]


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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.


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.