Team: Urate-Lowering Therapy (ULT) During Flare, aka the “Unapologetically Uricase-Deficient Mammals!”

Region: Get in the Game

Base article: Taylor, T. H., Mecchella, J. N., Larson, R. J., Kerin, K. D., & MacKenzie, T. A. (2012). Initiation of Allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. The American journal of medicine, 125(11), 1126-1134. PMID 23098865.

Authors: Medical College of Wisconsin Rheumatology Fellowship Program. Desh Nepal, MD, First-year rheumatology fellow; Rohan Mehta, DO, First-year rheumatology fellow; Yiran Jiang, MD, Second-year rheumatology fellow; Alison Fernandes, MD, Second-year rheumatology fellow; Michael Putman, MD, MSCI, Assistant Professor, Associate Rheumatology Fellowship Program Director

Team Overview

The urate-lowering agent, allopurinol, was discovered in 1956 and approved for mass consumption 10 years later. Allopurinol has remained the treatment of choice for gout management ever since. Yet, before the publication of this double-blind, placebo-controlled randomized control trial [1], it was believed initiation of allopurinol during an acute flare would prolong or exacerbate the attack due to uric acid mobilization [2]. Such practice was based on the observation that after allopurinol initiation, patients had frequent gout flares even as uric acid levels improved [3]. Based on this, rheumatological societies published guidelines recommending benching allopurinol until the flare has subsided [4] [5]. Known as the “delayed initiation and step-up approach,” the pervading thesis was introduced to start allopurinol at a low dose with a gradual increase. Consequently, the patient would only first see allopurinol come into play in low-stakes outpatient follow-up in the office 10-14 days later. Here are a few limitations of this traditional approach that continues to be recommended in the current 2020 ACR guideline [6]:

Delayed initiation equals missed opportunities. Only 64% of post-discharge appointments are generally kept [7]. Delayed initiation leads to prolonged disease burden. Within the traditional approach, the time to achieve the target uric acid goal of <6 is increased. At an average  allopurinol dose of 100 mg to 300 mg, 66 % of patients were not at the uric acid goal of < 6 [8]. You miss 100% of the shots you don’t take! Even among patients initiated on treatment, only <40% achieve the uric acid goal [9].

Gout affects 9.2 million US adults and has an annual healthcare cost of 24 million dollars. When taken together, delayed initiation of low-dose urate-lowering therapy of the most common cause of inflammatory arthritis contributes to increased healthcare utilization [12], decreased quality of life [13] and persistent premature mortality in gout patients [14].

Results of this publication:

In patients with crystal-proven acute gout arthritis (onset < 7 days), upon early initiation of allopurinol at 300 mg/day along with indomethacin and colchicine (treatment group), pain (measured by visual analog scale) in the first 10 days, and patient-reported gout flare in first 30 days did not differ when compared to initial treatment with only indomethacin and colchicine with delayed allopurinol initiation at day 10 (placebo group). Early initiation of allopurinol helped achieve uric acid at goal by day three and remained at goal throughout the 30 days. Starting allopurinol on day ten meant the uric acid goal was reached only around day 30 [1].

Despite the limitations of being a small, single-center study, this adequately powered study highlights an essential step in synergistically utilizing urate-lowering agents and anti-inflammatory medications to optimize the game plan.

Impact on Rheumatology

Starting Allopurinol early in patients with acute gout arthritis represents a paradigm shift in decades of clinical practice. It helped transform the management of acute gout arthritis, and gout in general, from a theoretical to an evidence-based approach.

It is worth noting that > 90% of gout is managed by Primary care providers [15]. In a survey of PCP, only about 50% of PCP felt their gout management practices are optimal. So, the clarity on the timing and dose of allopurinol initiation, along with the use of indomethacin and colchicine, impacted not only rheumatology but also primary care practices. Again, finding a publication with such broad impact beyond the specialty alone is not common.

For the healthcare system, it has the potential to translate into decreased healthcare resource utilization. Most importantly, achieving optimal gout management will mean enhanced quality of life and improved premature mortality for patients.

Chances in the Tournament

This article is a dark horse on the surface – gout is often not considered by many fellows as a high-flying topic. It’s not as flamboyant as vasculitis, and it’s not as colorful and varied as systemic lupus erythematosus. However, astute viewers will agree this article represents the fundamental essence of the field of rheumatology – continuously reassessing and improving our management of even the oldest and most common diseases to truly impact our patients’ lives. In addition, rheumatology is a part of the healthcare ecosystem where primary care practices are the foundations, and this publication directly impacts primary care practices.

While there have been many developments in managing various rheumatic diseases that have led to significant outcome improvements, given the scale of gout prevalence, we would be hard-pressed to find another paradigm-defining change in rheumatology that has the potential for such a material impact on both disease burden (quality of life, mortality) and healthcare cost/utilization.

We hope our humble report conveys the importance of this advancement and give it the recognition it undoubtedly deserves!

Next scouting report: RAVE Trial

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Get in the Game region: Are there patients in whom you would avoid initiating of ULT during acute gout flare? 

References

1. Taylor, T.H., et al., Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med, 2012. 125(11): p. 1126-1134 e7.
2. Neogi, T., Clinical practice. Gout. N Engl J Med, 2011. 364(5): p. 443-52.
3. Zhang, W., et al., EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2006. 65(10): p. 1312-24.
4. Jordan, K.M., et al., British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford), 2007. 46(8): p. 1372-4.
5. Yue, T.F. and A.B. Gutman, Effect of Allopurinol (4-Hydroxypyrazolo-(3,4-D)Pyrimidine) on Serum and Urinary Uric Acid in Primary and Secondary Gout. Am J Med, 1964. 37: p. 885-98.
6. FitzGerald, J.D., et al., 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken), 2020. 72(6): p. 744-760.
7. Kiefe, C.I., et al., Compliance with post-hospitalization follow-up visits: rationing by inconvenience? Ethn Dis, 1999. 9(3): p. 387-95.
8. Li-Yu, J., et al., Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol, 2001. 28(3): p. 577-80.
9. Pandya, B.J., et al., Relationship between physician specialty and allopurinol prescribing patterns: a study of patients with gout in managed care settings. Curr Med Res Opin, 2011. 27(4): p. 737-44.
10. Singh, G., B. Lingala, and A. Mithal, Gout and hyperuricaemia in the USA: prevalence and trends. Rheumatology (Oxford), 2019. 58(12): p. 2177-2180.
11. Kim, K.Y., et al., A literature review of the epidemiology and treatment of acute gout. Clin Ther, 2003. 25(6): p. 1593-617.
12. Khanna, P.P., et al., Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: Results from a cross-sectional survey. Health Qual Life Outcomes, 2012. 10: p. 117.
13. Khanna, P.P., et al., Long-term therapy for chronic gout results in clinically important improvements in the health-related quality of life: short form-36 is responsive to change in chronic gout. Rheumatology (Oxford), 2011. 50(4): p. 740-5.
14. Perez-Ruiz, F., et al., Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis, 2014. 73(1): p. 177-82.
15. Rott, K.T. and C.A. Agudelo, Gout. JAMA, 2003. 289(21): p. 2857-60.