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

J Autoimmun. 2019 Dec;105:102302. doi: 10.1016/j.jaut.2019.07.001. Epub 2019 Jul 15.


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 (rs = 0.36,p < 0.01), but not with levels of myeloperoxidase (MPO)-ANCA (rs = -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.

Keywords: ANCA-Associated vasculitis; ANCA-type; Cytokines; IL-6; Interleukin-6; RAVE.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / blood*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / drug therapy
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology*
  • Antibodies, Antineutrophil Cytoplasmic / immunology*
  • Azathioprine / therapeutic use
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Cyclophosphamide / therapeutic use
  • Cytoplasm / immunology*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Interleukin-6 / blood*
  • Interleukin-6 / immunology
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Myeloblastin / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Peroxidase / immunology
  • Remission Induction / methods
  • Rituximab / therapeutic use


  • Antibodies, Antineutrophil Cytoplasmic
  • IL6 protein, human
  • Immunosuppressive Agents
  • Interleukin-6
  • Rituximab
  • Cyclophosphamide
  • Peroxidase
  • Myeloblastin
  • Azathioprine