TY - JOUR
T1 - The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis
AU - RAVE-ITN Research Group
AU - Berti, Alvise
AU - Warner, Roscoe
AU - Johnson, Kent
AU - Cornec, Divi
AU - Schroeder, Darrell R.
AU - Kabat, Brian F.
AU - Langford, Carol A.
AU - Kallenberg, Cees G.M.
AU - Seo, Philip
AU - Spiera, Robert F.
AU - St Clair, E. William
AU - Fervenza, Fernando C.
AU - Stone, John H.
AU - Monach, Paul A.
AU - Specks, Ulrich
AU - Merkel, Peter A.
N1 - Funding Information:
The authors have no financial or non-financial potential conflicts of interest to declare related to this project. Dr. Paul A Monach was supported by an Arthritis Investigator Award from the Arthritis Foundation . Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital , France. Dr. John Stone and Dr. Robert Spiera participated in the Giacta trial blocking IL-6 receptor with tocilizumab in giant-cell arteritis and (sponsored by Roche ) and reported grant support and personal fees from Roche outside the submitted work. The authors have no other financial or non-financial potential conflicts of interest to declare related to this project. All the authors were involved in the writing and editing of the manuscript, and approved the final version.
Funding Information:
This work was sponsored by the Vasculitis Clinical Research Consortium which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319, RC1 AR058303 and P60 AR047785), the National Center for Research Resources (U54 RR019497), the National Institute of Neurological Disorders and Stroke (NS064808), and the Office of Rare Diseases Research. The RAVE Trial was performed with the support of the Immune Tolerance Network (NIH Contract N01 AI15416), an international clinical research consortium supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation (see online appendix for the list of all members of the RAVE-ITN Research Group). Genentech and Biogen Idec provided the study medications and partial funding. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) (RR024150-01), at Johns Hopkins University, by grants from the NCRR (RR025005) and career development awards (K24 AR049185 to JHS, and K23 AR052820 to PS), and at Boston University, by a Clinical and Translational Science Award (RR 025771), grants from the National Institutes of Health (M01 RR00533) and a career development award (K24 AR02224 to Dr. Peter A Merkel).The authors have no financial or non-financial potential conflicts of interest to declare related to this project. Dr. Paul A Monach was supported by an Arthritis Investigator Award from the Arthritis Foundation. Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital, France. Dr. John Stone and Dr. Robert Spiera participated in the Giacta trial blocking IL-6 receptor with tocilizumab in giant-cell arteritis and (sponsored by Roche) and reported grant support and personal fees from Roche outside the submitted work. The authors have no other financial or non-financial potential conflicts of interest to declare related to this project. All the authors were involved in the writing and editing of the manuscript, and approved the final version. We thank Francesca Dallago from the design service for her contribution in figures production.
Funding Information:
This work was sponsored by the Vasculitis Clinical Research Consortium which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( U54AR057319 , RC1 AR058303 and P60 AR047785 ), the National Center for Research Resources ( U54 RR019497 ), the National Institute of Neurological Disorders and Stroke ( NS064808 ), and the Office of Rare Diseases Research . The RAVE Trial was performed with the support of the Immune Tolerance Network (NIH Contract N01 AI15416 ), an international clinical research consortium supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation (see online appendix for the list of all members of the RAVE-ITN Research Group). Genentech and Biogen Idec provided the study medications and partial funding. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) ( RR024150-01 ), at Johns Hopkins University , by grants from the NCRR ( RR025005 ) and career development awards ( K24 AR049185 to JHS, and K23 AR052820 to PS), and at Boston University, by a Clinical and Translational Science Award ( RR 025771 ), grants from the National Institutes of Health ( M01 RR00533 ) and a career development award ( K24 AR02224 to Dr. Peter A Merkel).
Funding Information:
This work was sponsored by the Vasculitis Clinical Research Consortium which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319, RC1 AR058303 and P60 AR047785), the National Center for Research Resources (U54 RR019497), the National Institute of Neurological Disorders and Stroke (NS064808), and the Office of Rare Diseases Research. The RAVE Trial was performed with the support of the Immune Tolerance Network (NIH Contract N01 AI15416), an international clinical research consortium supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation (see online appendix for the list of all members of the RAVE-ITN Research Group). Genentech and Biogen Idec provided the study medications and partial funding. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) (RR024150-01), at Johns Hopkins University, by grants from the NCRR (RR025005) and career development awards (K24 AR049185 to JHS, and K23 AR052820 to PS), and at Boston University, by a Clinical and Translational Science Award (RR 025771), grants from the National Institutes of Health (M01 RR00533) and a career development award (K24 AR02224 to Dr. Peter A Merkel).The authors have no financial or non-financial potential conflicts of interest to declare related to this project. Dr. Paul A Monach was supported by an Arthritis Investigator Award from the Arthritis Foundation. Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital, France. Dr. John Stone and Dr. Robert Spiera participated in the Giacta trial blocking IL-6 receptor with tocilizumab in giant-cell arteritis and (sponsored by Roche) and reported grant support and personal fees from Roche outside the submitted work. The authors have no other financial or non-financial potential conflicts of interest to declare related to this project. All the authors were involved in the writing and editing of the manuscript, and approved the final version.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - ANCA-Associated vasculitis
KW - ANCA-type
KW - Cytokines
KW - IL-6
KW - Interleukin-6
KW - RAVE
UR - http://www.scopus.com/inward/record.url?scp=85068846981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068846981&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2019.07.001
DO - 10.1016/j.jaut.2019.07.001
M3 - Article
C2 - 31320177
AN - SCOPUS:85068846981
SN - 0896-8411
VL - 105
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
M1 - 102302
ER -