Visceral adiposity is positively associated with UA levels, potentially due to the compounding effects of leptin, adiponectin and insulin on reducing renal excretion or from triglyceride-induced increased UA production.31
Weight gain itself is a risk factor for incident gout; a cohort study demonstrates that weight gain of 30 lbs. or more conferred twice the risk of developing gout in comparison with those who maintained weight.32
Fortunately, weight loss appears to mitigate risk. Data from the same cohort show weight loss of greater than 10 lbs. reduces gout risk; these findings taken together provide support for obesity and weight gain as causal factors for gout.32 As more people turn to surgical management for obesity, prospective studies have found a reduction in incident hyperuricemia and UA levels and an increase in recovery from hyperuricemia after bariatric surgery.33,34 Moreover, post-bariatric surgery patients were discovered to have a significant reduction in inflammatory response to monosodium urate crystals with a decrease in peripheral blood mononuclear cell production of IL-1β, IL-8 and IL-6, pointing to the proinflammatory nature of obesity.35
Conclusion
Gout is not a simple inflammatory arthritis, but has complex associations with many aspects of metabolism. The associations between hyperuricemia, gout, the MetS and its components are multi-faceted and may be causal. Further longitudinal evidence may shed light on these relationships. However, interventional studies could help discern whether hyperuricemia and gout in part precipitate metabolic abnormalities leading to development of the MetS and related morbidity. The high prevalence and clinical consequences associated with gout, hyperuricemia and its comorbidities beg for continued investigation into mechanism and treatment.
Lindsey A. MacFarlane, MD, works in the Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital in Boston.
Daniel H. Solomon, MD, MPH, works in the Division of Rheumatology, Immunology and Allergy and the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital in Boston.
Seoyoung C. Kim, MD, ScD, MSCE, works in the Division of Rheumatology, Immunology and Allergy and the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital in Boston.
Acknowledgments/Disclosures
- Dr. Kim is supported by the NIH grant K23 AR059677. She received a research grant from Pfizer.
- Dr. Solomon is supported by the NIH grant K24 AR055989. He receives salary grants from research support to Brigham and Women’s Hospital from Amgen, Lilly, Pfizer and CORRONA. He serves in unpaid roles on trials funded by Pfizer, Novartis, Lilly and Bristol-Myers Squibb. He receives royalties from UpToDate.
Current research in gout
Medication Adherence in Gout: A Systematic Review
Source: De Vera MA, Marcotte G, Rai S, et al. Arthritis Care Res (Hoboken). 2014 Oct.;66(10):1551–1559.
Objective
Recent data suggesting the growing problem of medication nonadherence in gout have called for the need to synthesize the burden, determinants, and impacts of the problem. Our objective was to conduct a systematic review of the literature examining medication adherence among patients with gout in real-world settings.
Methods
We conducted a search of Medline, Embase, International Pharmaceutical Abstracts, PsycINFO, and CINAHL databases and selected studies of gout patients and medication adherence in real-world settings. We extracted information on study design, sample size, length of followup, data source (e.g., prescription records versus electronic monitoring versus self-report), type of nonadherence problem evaluated, adherence measures and reported estimates, and determinants of adherence reported in multivariable analyses.
Results
We included 16 studies that we categorized according to methods used to measure adherence, including electronic prescription records (n = 10), clinical records (n = 1), electronic monitoring devices (n = 1), and self-report (n = 4). The burden of nonadherence was reported in all studies, and among studies based on electronic prescription records, adherence rates were all below 0.80 and the proportion of adherent patients ranged from 10–46%. Six studies reported on determinants, with older age and having comorbid hypertension consistently shown to be positively associated with better adherence. One study showed the impact of adherence on achieving a serum uric acid target.
Conclusion
With less than half of gout patients in real-world settings adherent to their treatment, this systematic review highlights the importance of health care professionals discussing adherence to medications during encounters with patients.
Contribution of Mast Cell–Derived Interleukin-1β to Uric Acid Crystal–Induced Acute Arthritis in Mice
Source: Reber LL, Marichal T, Sokolove J, et al. Arthritis Rheumatol. 2014 Oct.;66(10):2881–2891.
Objective
Gouty arthritis is caused by the precipitation of monosodium urate monohydrate (MSU) crystals in the joints. While it has been reported that mast cells (MCs) infiltrate gouty tophi, little is known about the actual roles of MCs during acute attacks of gout. This study was undertaken to assess the role of MCs in a mouse model of MSU crystal–induced acute arthritis.
Methods
We assessed the effects of intraarticular (IA) injection of MSU crystals in various strains of mice with constitutive or inducible MC deficiency or in mice lacking interleukin-1β (IL-1β) or other elements of innate immunity. We also assessed the response to IA injection of MSU crystals in genetically MC-deficient mice after IA engraftment of wild-type or IL-1β–/– bone marrow–derived cultured MCs.
Results
MCs were found to augment acute tissue swelling following IA injection of MSU crystals in mice. IL-1β production by MCs contributed importantly to MSU crystal–induced tissue swelling, particularly during its early stages. Selective depletion of synovial MCs was able to diminish MSU crystal–induced acute inflammation in the joints.
Conclusion
Our findings identify a previously unrecognized role of MCs and MC-derived IL-1β in the early stages of MSU crystal–induced acute arthritis in mice.
Brief Report: Granulocyte–Macrophage Colony-Stimulating Factor Drives Monosodium Urate Monohydrate Crystal–Induced Inflammatory Macrophage Differentiation and NLRP3 Inflammasome Up-Regulation in an In Vivo Mouse Model
Source: Shaw OM, Steiger S, Liu X, et al. Arthritis & Rheumatology. 2014 Sep;66(9):2423–2428.
Objective
To determine the role of granulocyte–macrophage colony-stimulating factor (GM-CSF) in the differentiation of inflammatory macrophages in an in vivo model of monosodium urate monohydrate (MSU) crystal–induced inflammation.
Methods
C57BL/6J mice were treated with either clodronate liposomes to deplete peritoneal macrophages or GM-CSF antibody and were then challenged by intraperitoneal injection of MSU crystals. Peritoneal lavage fluid was collected, and cellular infiltration was determined by flow cytometry. Purified resident and MSU crystal–recruited monocyte/macrophages were stimulated ex vivo with MSU crystals. The interleukin-1β (IL-1β) levels in lavage fluids and ex vivo assay supernatants were measured. GM-CSF–derived and macrophage colony-stimulating factor (M-CSF)–derived macrophages were generated in vitro from bone marrow cells. Protein expression of IL-1β, caspase 1, NLRP3, and ASC by in vitro– and in vivo–generated monocyte/macrophages was analyzed by Western blotting.
Results
Depletion of resident macrophages lowered MSU crystal–induced IL-1β and GM-CSF levels in vivo as well as IL-1β production by MSU crystal–recruited monocytes stimulated ex vivo. GM-CSF neutralization in vivo decreased MSU crystal–induced IL-1β levels and neutrophil infiltration. MSU crystal–recruited monocyte/macrophages from GM-CSF–neutralized mice expressed lower levels of the macrophage marker CD115 and produced less IL-1β following ex vivo stimulation. These monocytes exhibited decreased expression of NLRP3, pro/active IL-1β, and pro/active caspase 1. In vitro–derived GM-CSF–differentiated macrophages expressed higher levels of NLRP3, pro/active IL-1β, and pro/active caspase 1 compared to M-CSF–differentiated macrophages.
Conclusion
GM-CSF plays a key role in the differentiation of MSU crystal–recruited monocytes into proinflammatory macrophages. GM-CSF production may therefore contribute to the exacerbation of inflammation in gout.
