Daniel H. Solomon, MD; Robert J. Glynn, PhD; Jean G. MacFadyen, BA; Peter Libby, MD; Tom Thuren, MD; Brendan M. Everett, MD; Paul M Ridker, MD
Financial Support: Novartis funded the CANTOS trial and the statistical analyses conducted for this manuscript. Dr. Solomon receives salary support from the National Institutes of Health (K24 AR09889).
Disclosures: Dr. Solomon reports that Novartis funded the CANTOS trial. He has no financial relationship with Novartis. Dr. Glynn reports grants from Novartis during the conduct of the study and grants from AstraZeneca, Kowa, and Pfizer outside the submitted work. Ms. MacFadyen reports grants from Novartis during the conduct of the study. Dr. Libby reports research support from Novartis during the conduct of the study and grants from Novartis outside the submitted work. Dr. Thuren reports employment, salary, and stock from Novartis during the conduct of the study. Dr. Everett reports personal fees from Novartis during the conduct of the study and grants from Novartis, grants and personal fees from Roche Diagnostics and Abbott Laboratories, and personal fees from the U.S. Food and Drug Administration and UpToDate outside the submitted work. Dr. Ridker reports grants and personal fees from Novartis during the conduct of the study and personal fees from Inflazome outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1167.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See Supplement. Statistical code and data set: Not available.
Corresponding Author: Daniel H. Solomon, MD, Division of Rheumatology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Solomon: Division of Rheumatology, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115.
Dr. Glynn: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA 02120.
Ms. MacFadyen and Drs. Everett and Ridker: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215.
Dr. Libby: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-741-G, Boston, MA 02115.
Dr. Thuren: Novartis, One Health Plaza, East Hanover, NJ 07936.
Author Contributions: Conception and design: D.H. Solomon, R.J. Glynn, P. Libby, P.M Ridker.
Analysis and interpretation of the data: D.H. Solomon, R.J. Glynn, J.G. MacFadyen, T. Thuren, B.M. Everett, P.M Ridker.
Drafting of the article: D.H. Solomon, P.M Ridker.
Critical revision of the article for important intellectual content: R.J. Glynn, P. Libby, B.M. Everett, P.M Ridker.
Final approval of the article: D.H. Solomon, R.J. Glynn, J.G. MacFadyen, P. Libby, T. Thuren, B.M. Everett, P.M Ridker.
Statistical expertise: D.H. Solomon, R.J. Glynn, P.M Ridker.
Obtaining of funding: R.J. Glynn, P.M Ridker.
Administrative, technical, or logistic support: D.H. Solomon, J.G. MacFadyen, T. Thuren, B.M. Everett, P.M Ridker.
Collection and assembly of data: R.J. Glynn, T. Thuren, B.M. Everett, P.M Ridker.
Although studies have shown that interleukin-1β (IL-1β) inhibitors can shorten gout attacks, whether they can prevent gout attacks is unclear.
To examine the relationship among canakinumab, a monoclonal antibody targeting IL-1β; serum uric acid levels; and the incidence of gout attacks.
Secondary exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846)
Many clinical sites in 39 countries.
10 059 patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of at least 19.1 nmol/L.
Random allocation to canakinumab (50 mg, 150 mg, or 300 mg) versus placebo, administered subcutaneously every 3 months.
Rates of gout attacks were compared across patients with different baseline concentrations of serum uric acid (≤404.5 µmol/L, 404.6 to 535.3 µmol/L, and ≥535.4 µmol/L) and in different intervention groups in Cox proportional hazards regression models.
The median baseline concentration of serum uric acid was 362.9 µmol/L (interquartile range, 309.3 to 428.3 µmol/L), and median follow-up was 3.7 years. Among participants receiving placebo, incidence rates of gout attacks for serum uric acid concentrations of 404.5 µmol/L or lower, 404.6 to 535.3 µmol/L, and 535.4 µmol/L or higher were 0.28, 1.36, and 5.94, respectively, per 100 person-years. Canakinumab did not affect serum uric acid levels over time yet significantly reduced rates of gout attacks at all baseline concentrations of serum uric acid: Hazard ratios were 0.40 (95% CI, 0.22 to 0.73) for concentrations of 404.5 µmol/L or lower, 0.48 (CI, 0.31 to 0.74) for those between 404.6 and 535.3 µmol/L, and 0.45 (CI, 0.28 to 0.72) for those of 535.4 µmol/L or higher.
No adjudication of gout attacks.
Quarterly canakinumab administration was associated with significantly reduced risk for gout attacks without any change in serum uric acid levels. These data have relevance for the development of agents for gout that target the IL-1β pathway of innate immunity.
Solomon DH, Glynn RJ, MacFadyen JG, Libby P, Thuren T, Everett BM, et al. Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial. Ann Intern Med. ;169:535–542. doi: 10.7326/M18-1167
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Published: Ann Intern Med. 2018;169(8):535-542.
Published at www.annals.org on 18 September 2018
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