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

Abstract

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.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Association of IL-6 levels and disease features at baseline according to BVAS/WG items and ANCA status.

(A) Patients (n=78) are grouped in three mutually exclusive subsets of patients; only granulomatous manifestation (n=11), only capillaritis (no=22), or both (n=45) (B) Patients were then grouped in two mutually exclusive subsets according to diagnosis (MPA, n=19; GPA, n=58); (C) disease at presentation (relapsing, n=42; newly diagnosed, n=36); and (D) ANCA status (MPO-ANCA=21, PR3-ANCA=57). Bars show the median and interquartile range. Footnotes. Granulomatous disease only: Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) items reflecting underlying necrotizing granulomatous inflammation included mouth ulcers, retro-orbital mass/proptosis, bloody nasal discharge, sinus involvement, salivary gland enlargement, subglottic inflammation, conductive deafness, other major or minor ear, nose, and throat involvement, pulmonary nodule/cavity, endobronchial involvement, meningitis, and cord lesion. Capillaritis only: defined as the presence of one or more of the following BVAS/WG items: purpura, scleritis, retinal hemorrhage or exudate, sensorineural deafness, hematuria, red blood cell casts on urinalysis or glomerulonephritis, increase in creatinine level, alveolar hemorrhage, mesenteric ischemia, sensory peripheral neuropathy, or motor mononeuritis multiplex. Granulomatous disease and capillaritis: patients positive for at least one granulomatous disease BVAS/WG item and at least one capillaritis BVAS/WG item.

Figure 2.. Longitudinal IL-6 levels at selected time-points before and during induction of remission treatment.

(A) Absolute value of serum IL-6 level in patients who achieved complete remission at 6 months (light grey, n=60) and in those who did not (dark grey, n=18) at baseline, 2 weeks, month 1, month 2, month 4, and month 6 after the initiation of treatment. Bars show the median and interquartile range (p>0.05 at each time-points). (B) Absolute value of serum IL-6 level in all the cohort of patients (n=78) at baseline and month 6th, showing a significant decrease as an effect of induction of remission therapy (p<0.01). Bars show the median and interquartile range.

Figure 3.. Interleukin-6 levels prior to flare in patients with AAV who severely relapsed according to treatment group (CYC/AZA n=14, RTX n=15).

Each line represents an individual patient.