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Oral Prednisolone in the Treatment of Acute Gout: A Pragmatic, Multicenter, Double-Blind, Randomized TrialOral Prednisolone in the Treatment of Acute Gout

Timothy Hudson Rainer, MD*; Chi Hung Cheng, MD*; Hein J.E.M. Janssens, MD, PhD; Chi Yin Man, MD; Lai Shan Tam, MD; Yu Fai Choi, MD; Wah Hon Yau, MD; Ka Hing Lee, MD; and Colin Alexander Graham, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 23 February 2016.

* Professor Rainer and Dr. Cheng contributed equally to this work.


From Chinese University of Hong Kong, Prince of Wales Hospital, North District Hospital, Pamela Youde Nethersole Eastern Hospital, Queen Elizabeth Hospital, and United Christian Hospital, Hong Kong, China; Radboud University Medical Centre, Nijmegen, the Netherlands; and Primary Health Care Centre Lobede, Lobith-Tolkamer, the Netherlands.

Financial Support: By the Health and Health Services Research Grant Committee of the Hong Kong Government.

Disclosures: Dr. Rainer reports grants from the Health and Health Services Research Grant Committee of the Hong Kong Government during the conduct of the study. Dr. Graham reports grants from the Health and Health Services Research Grant Committee of the Hong Kong Government during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2070.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy 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 Pfizer.

Reproducible Research Statement:Study protocol: See the Supplement. Statistical code and data set: Available from Dr. Rainer (e-mail, rainerth@cardiff.ac.uk).

Requests for Single Reprints: Timothy Hudson Rainer, MD, Emergency Medicine Academic Unit, Cardiff University, Room 127, Sir Geraint Evans Building, Cardiff, United Kingdom; e-mail, rainerth@cardiff.ac.uk.

Current Author Addresses: Dr. Rainer: Emergency Medicine Academic Unit, Cardiff University, Room 127, Sir Geraint Evans Building, Cardiff, United Kingdom.

Drs. Cheng and Graham: Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong, China.

Dr. Janssens: Department of Primary and Community Care, Radboud University Medical Centre, ELG 117, PO Box 9101, Nijmegen 6500, the Netherlands.

Dr. Man: Hospital Administration, North District Hospital, 11 Chuen On Road, Tai Po, New Territories, Hong Kong, China.

Dr. Tam: Department of Medicine & Therapeutics, Chinese University of Hong Kong, 9/F, Lui Che Woo Clinical Sciences Building, Shatin, New Territories, Hong Kong, China.

Dr. Choi: Accident and Emergency Department, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong, China.

Dr. Yau: Outpatient Department, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China.

Dr. Lee: Accident and Emergency Department, United Christian Hospital, 130 Hip Woo Street, Kwun Tong, Kowloon, Hong Kong, China.

Author Contributions: Conception and design: T.H. Rainer, C.H. Cheng, H.J.E.M. Janssens, C.Y. Man, C.A. Graham.

Analysis and interpretation of the data: T.H. Rainer, C.H. Cheng, H.J.E.M. Janssens, C.A. Graham.

Drafting of the article: T.H. Rainer, C.H. Cheng, H.J.E.M. Janssens, Y.F. Choi, C.A. Graham.

Critical revision of the article for important intellectual content: T.H. Rainer, H.J.E.M. Janssens, L.S. Tam, W.H. Yau, C.A. Graham.

Final approval of the article: T.H. Rainer, C.H. Cheng, H.J.E.M. Janssens, C.Y. Man, L.S. Tam, Y.F. Choi, W.H. Yau, K.H. Lee, C.A. Graham.

Provision of study materials or patients: Y.F. Choi, W.H. Yau, K.H. Lee.

Statistical expertise: T.H. Rainer.

Obtaining of funding: T.H. Rainer, C.A. Graham.

Administrative, technical, or logistic support: T.H. Rainer, Y.F. Choi, W.H. Yau.

Collection and assembly of data: C.H. Cheng, Y.F. Choi, W.H. Yau, K.H. Lee, C.A. Graham.


Ann Intern Med. 2016;164(7):464-471. doi:10.7326/M14-2070
© 2016 American College of Physicians
Text Size: A A A

Background: Two recent double-blind, randomized, controlled trials (RCTs) showed that oral steroids and nonsteroidal anti-inflammatory drugs have similar analgesic effectiveness for management of gout, but the trials had small sample sizes and other methodological limitations.

Objective: To compare the effectiveness and safety of oral prednisolone versus oral indomethacin in patients presenting to emergency departments (EDs) with acute gout.

Design: Multicenter, double-blind, randomized equivalence trial. Patients were randomly assigned (1:1 ratio) to receive either indomethacin or prednisolone. (ISRCTN registry number: ISRCTN45724113)

Setting: Four EDs in Hong Kong.

Participants: 416 patients aged 18 years or older.

Measurements: Analgesic effectiveness was defined as changes in pain (at rest or with activity) greater than 13 mm on a 100-mm visual analogue scale. Outcomes were measured during the first 2 hours in the ED and from days 1 to 14.

Results: 376 patients completed the study. Equivalent and clinically significant within-group reductions in mean pain score were observed with indomethacin and prednisolone in the ED (approximately 10 mm [rest] and 20 mm [activity]) and from days 1 to 14 (approximately 25 mm [rest] and 45 mm [activity]). No major adverse events occurred during the study. During the ED phase, patients in the indomethacin group had more minor adverse events than those in the prednisolone group (19% vs. 6%; P < 0.001). During days 1 to 14, 37% of patients in each group had minor adverse events.

Limitation: Diagnosis of gout was usually based on clinical criteria rather than examination of joint fluid.

Conclusion: Oral prednisolone and indomethacin had similar analgesic effectiveness among patients with acute gout. Prednisolone is a safe, effective first-line option for treatment of acute gout.

Primary Funding Source: Health and Health Services Research Grant Committee of the Hong Kong Government.

Figures

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Figure 2.

Mean pain scores and 95% CIs at each assessment (n = 376).

Data were analyzed per protocol. The means and 95% CIs of the coefficients (slopes) of change in pain over unit time for patients in each group were compared using the t test. ED = emergency department. A. Pain score at rest in the ED phase. We found no statistically or clinically significant differences between groups (P = 0.69). The mean decrease in pain score was 6.54 mm/h (95% CI, 5.02 to 8.06 mm/h) for indomethacin and 5.05 mm/h (CI, 3.56 to 6.55 mm/h) for prednisolone (mean difference, −1.49 mm/h [CI, 0.64 to −3.61 mm/h]). B. Pain score with activity in the ED phase. We found no statistically or clinically significant differences between groups (P = 0.56). The mean decrease in pain score was 11.69 mm/h (CI, 10.10 to 13.28 mm/h) for indomethacin and 11.38 mm/h (CI, 9.98 to 12.79 mm/h) for prednisolone (mean difference, −0.31 mm/h [CI, 1.80 to −2.42 mm/h]). C. Pain score at rest from days 1 to 14. We found no statistically or clinically significant differences between groups (P = 0.80). The mean decrease in pain score was 1.80 mm/d (CI, 1.46 to 2.13 mm/d) for indomethacin and 1.68 mm/d (CI, 1.39 to 1.97 mm/d) for prednisolone (mean difference, −0.12 mm/d [CI, 0.32 to −0.55 mm/d]). D. Pain score with activity from days 1 to 14. We found no statistically or clinically significant differences between groups (P = 0.20). The mean decrease in pain score was 2.96 mm/d (CI, 2.62 to 3.30 mm/d) for indomethacin and 3.19 mm/d (CI, 2.85 to 3.52 mm/d) for prednisolone (mean difference, 0.22 mm/d [CI, 0.70 to −0.25 mm/d]).

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Hypouricemic Effect of Oral Prednisolone in the Treatment of Acute Gout and Hyperuricemia: An Uneven Playing Field?
Posted on April 30, 2016
Chao Liu, and Kunshen Liu
Heart Center, The First Hospital of Hebei Medical University, Shijiazhuang, China.
Conflict of Interest: The work is supported by Hebei Province Government grant, title: Prednisone for Heart Failure Patients With Hyperuricemia (Hebei Provincial Major Medical Research Project: ZD2013083).
To the Editor:

We read with great interest the article of Rainer et al. on oral prednisolone in the treatment of acute gout (1). The pathogenesis of acute gout flares mostly involves innate immune responses. The value of prednisolone in acute gout in patients such as those in the study is due to the anti-inflammatory effect. Most recent clinical evidence also shows that corticosteroids can lower serum uric acid levels by increasing renal uric acid clearance (2-5). A rapid decrease of urate levels induced by uric acid lowering therapy will produce a huge amount of tiny monosodium urate crystals that can promote acute inflammation in joints. Therefore, the acute reduction in serum uric acid could paradoxically increase the risk of an acute attack. Hence, we hypothesize prednisolone may has lower efficacy in treatment of acute gout in patients with hyperuricemia. We noted that patients with hyperuricemia consisted of 36.5% the patients in prednisolone group in the study conducted by Rainer. The authors did not report the effect of prednisolone on uric acid lowering. Also, they did not perform a subgroup analysis to see whether prednisolone has a different efficacy in patients with acute gout and hyperuricemia. We suggest that a subgroup analysis should control the level of uric acid to better understand the efficacy of prednisolone in the treatment of gout.

References

1. Rainer TH, Cheng CH, Janssens HJ, Man CY, Tam LS, Choi YF, et al. Oral Prednisolone in the Treatment of Acute Gout: A Pragmatic, Multicenter, Double-Blind, Randomized Trial. Ann Intern Med. 2016;164(7):464-71.
2. Morato-Conceicao YT, Alves-Junior ER, Arruda TA, Lopes JC, Fontes CJ. Serum uric acid levels during leprosy reaction episodes. PeerJ. 2016;4:e1799.
3. Liu C, Zhen Y, Zhao Q, Zhai J-L, Liu K, Zhang J-X. Prednisone lowers serum uric acid levels in patients with decompensated heart failure by increasing renal uric acid clearance. Canadian Journal of Physiology and Pharmacology. 2015.
4. Meng H, Liu G, Zhai J, Zhen Y, Zhao Q, Zheng M, et al. Prednisone in Uric Acid Lowering in Symptomatic Heart Failure Patients with Hyperuricemia -- The PUSH-PATH3 Study. J Rheumatol. 2015;42(5):866-9.
5. Maly J, Nadvornikova H, Schuck O. The effect of prednisone and azathioprine (Imuran) on renal excretion of uric acid. Int J Clin Pharmacol Ther Toxicol. 1982;20(1):44-6.

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