Abstract: It has been recently demonstrated that interleukin 1β (IL-1β) plays a central role in monosodium urate crystal–induced inflammation and that the NALP3 inflammasome plays a major role in IL-1β production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which monosodium urate crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids) and biologic agents (e.g., the IL-1β antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1β pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic adverse effects associated with them. The therapeutic margins of nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1β antagonists act on very specific targets of inflammation, which may decrease the potential for systemic adverse effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1β antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic adverse effects. Results of ongoing trials of IL-1β antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.
From the *NYU School of Medicine, New York, NY; and †Clear Lake Rheumatology, Nassau Bay, TX.
Certain sections of the manuscript, including the “Introduction” and the sections titled “Inflammation, An Overview,” “Monosodium Urate Crystals and Inflammation,” and “Termination of Acute Gouty Arthritis,” were written by Dr Cronstein. Sections focusing on the clinical management of gouty arthritis were prepared by Dr Sunkureddi, with editorial assistance provided by Cherie Koch, PhD, of Oxford PharmaGenesis Inc. Each author’s contribution was merged together by Dr Koch who provided editorial assistance to improve the flow and eliminate any redundancies. Dr Koch also provided assistance with figure preparation and styling of the manuscript for submission. Funding for this assistance was provided by Novartis Pharmaceuticals Corporation. The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript.
Dr Cronstein is a consultant to Bristol-Myers Squibb; Novartis; CanFite Biopharmaceuticals; Cypress Laboratories; Regeneron (Westat; DSMB); Endocyte; Protalex; Allos, Inc; Savient; Gismo Therapeutics; Antares Pharmaceutical; and Medivector (all <$10,000). Grants were received from King Pharmaceuticals; NIH; Vilcek Foundation; OSI Pharmaceuticals; URL Pharmaceuticals, Inc; and Gilead Pharmaceuticals. He is/was a board member of Vilcek Foundation. He held stock in CanFite Biopharmaceuticals (received for membership in Scientific Advisory Boards). Four patents held on the use of adenosine A2A receptor agonists to promote wound healing and to inhibit fibrosis; adenosine A1 receptor antagonists to treat osteoporosis and other diseases of the bone; adenosine A1 and A2B receptor antagonists to treat fatty liver; and adenosine A2A receptor agonists to prevent prosthesis loosening. Dr Sunkureddi is member of the speaker’s bureau for/consultant to Novartis, Bristol Myers Squibb, UCB, Pfizer (all >$10,000).
The opinions expressed in the manuscript are those of the authors, and Novartis Pharmaceuticals Corporation had no influence on the contents.
Correspondence: Bruce N. Cronstein, MD, NYU School of Medicine, 550 First Ave, NBV16N1, New York, NY 10016. E-mail: Bruce.Cronstein@nyumc.org.