REVIEW URRENT C OPINION
The impact of gout guidelines Eric Wise and Puja P. Khanna
Purpose of review This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. Recent findings Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. Summary Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care. Keywords gout, guidelines, impact
INTRODUCTION Gout is currently the most common inflammatory arthritis in the United States and affects over 8 million Americans [1]. Acute episodes of gout typically manifest as attacks of intense joint pain resulting from an inflammatory response which is precipitated by uric acid crystal deposition in the synovial tissue surrounding synovial joints. Gout causes significant morbidity and is an economic burden with annual costs exceeding 6 billion dollars annually in direct costs and lost worker productivity [2]. Hyperuricemia is the single most identifiable parameter for the development of gout, and this risk of a gout attack increases with the degree of hyperuricemia. The management of gout focuses on the treatment of acute attacks as well as the underlying hyperuricemia to prevent future episodes. Treating hyperuricemia in gout with urate-lowering therapies (ULTs) is widely regarded as the principal strategy for preventing new attacks [3]. Multiple guidelines for the treatment and prevention of gout flares have been put forth, including those from the Dutch College of General Practitioners in 2002 [4], the British Society of
Rheumatology (BSR) in 2007 [5], the European League Against Rheumatism (EULAR) in 2006 [6], the Multinational Evidence, Expertise, Exchange Initiative (3e) in 2013 [7], the Japanese Society of Gout and Nucleic Acid Metabolism in 2011 [8], the American College of Rheumatology (ACR) in 2012 [9], and the updated EULAR set in 2014. Each of these guidelines contains recommendations for pharmacologic therapy as well as lifestyle modifications for treating both acute gout attacks along with recommendations for prophylaxis against further gout attacks. The respective guidelines are comparable in that all make similar recommendations for treating acute flares and for starting ULT after a second attack (Table 1). The ACR, 3e, and EULAR Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA Correspondence to Puja P. Khanna, MD, MPH, Assistant Professor, Division of Rheumatology, Department of Internal Medicine, 300 North Ingalls Street, Suite 7C27, Ann Arbor, MI 48109-5422, USA. Tel: +1 734 763 9151; fax: +1 734 763 1253; e-mail: [email protected] Curr Opin Rheumatol 2015, 27:225–230 DOI:10.1097/BOR.0000000000000168
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Clinical therapeutics
KEY POINTS Over the last decade, multiple guidelines have been developed to assist providers in the appropriate management of gout. The purpose of these guidelines is to change practice patterns of providers so that they initiate ULT early in the management of chronic gout. Adherence to these recommendations by both providers and patients remains poor because of variety of barriers. There are several initiatives in place to impact adherence and thus improve quality of care given to gout patients.
primary care providers on proper management [11]. Several studies, including a recent physician survey of primary care providers, have pointed to ongoing suboptimal treatment of gout in the primary care setting. A recent medical record review performed in the United Kingdom, for example, found that despite recommendations for the use of ULTs, only a minority of patients with a diagnosis of gout was actually taking uric acid-lowering agents [12]. Another survey of primary care providers’ gout management practices showed that only about half of the providers surveyed reported back management that was in accordance with current guidelines [13]. Even rheumatologists, who presumably are well aware of the guidelines, did only slightly better in a chart review of 350 patient records of gout patients seeking care in either a primary care provider’s office or a rheumatologist’s office [14 ]. Uptitration of ULT after initiation of any agent in order to achieve target serum urate levels in particular remains a significant barrier. A study [15 ] of a subset of 400 patients from the Febuxostat versus Allopurinol Streamline Trial (FAST) trial in the United Kingdom showed that with proper uptitration of a uric acid-lowering agent, 97% of patients could reach a target uric acid level of less than 6 mg/ dL. Yet, in this study, only 36% of patients were actually at a target level. Interestingly, the average number on uptitration was only slightly greater than one with most patients being controlled on 100–200 mg of allopurinol, although other studies have suggested that a significant number of patients need doses of allopurinol greater than 300 mg to achieve target uric acid levels. This finding suggests that majority of patients should be able to reach a target uric acid level without significant difficulty, though that is not happening at the present time. Monitoring of uric acid levels is also a significant barrier to achieving control. Only 22% of gout patients in a recent UK survey of primary care providers had a uric acid level recorded in the chart in the last year [12]. It is not clear whether provider concerns over the use of allopurinol, including liver toxicity, drug interactions, use in renal failure, and especially incidents of allopurinol-induced hypersensitivity syndrome, contribute to the unwillingness of primary care providers to uptitrate allopurinol. &
guidelines all recommend a target of 6 mg/dL, whereas the BSR guidelines recommend a target of 5 mg/dL. With the exception of the 3e guidelines, all recommend starting allopurinol 100 mg daily (50 mg in the presence of kidney disease) and uptitrating the dose to achieve the target serum uric acid. The guidelines each differ in subtle ways though. The BSR guidelines, for example, date from 2007 and recommend COX-2 inhibitors as a firstline therapy for acute gout or prophylaxis, whereas the newer guidelines do not and instead recommend equal efficacy for colchicine, steroids, and NSAIDs. The ACR and BSR are both aimed at assisting primary care providers and hospital physicians. The BSR guidelines include extensive diet recommendations, and the ACR guidelines are put forth in a flowchart format to assist decision making and contain a variety of scenarios such as treatment recommendations for patients who are unable to take oral medications. The Japanese Society guidelines are the only guidelines that contain a recommendation for treating asymptomatic hyperuricemia. The ACR guidelines, which are the newest, are also unique in that febuxostat is specifically recommended as a viable first-line therapy and also recommend the use of pegloticase, an intravenous recombinant uricase, for the treatment of refractory tophaceous gout.
Utilization of gout guidelines in the primary care setting: physician adherence Gout is primarily seen by primary care providers, and was responsible for over 2 million annual primary care visits in the years 2001 to 2005 [10]. Despite the availability of multiple guidelines, one of the biggest challenges of implementing strategies to prevent gout flares has been educating the 226
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&&
Patient adherence Patient adherence to their prescribed regimen is equally problematic. A study [16] of patient medication adherence to gout medications that involved over 1.3 million patients demonstrated that adherence rates for gout are among the lowest of common Volume 27 Number 3 May 2015
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2013
2006
2011
3E
EULAR
JSGNM
Yes
Yes
Yes
Yes
Yes
Yes
NSAIDS first, then colchicine, then corticosteroids
Colchicine or NSAIDs
NSAIDS, colchicine also an option
Colchicine NSAIDs
NSAIDs, coxibs, or colchicine
NSAIDs, corticosteroids, or colchicine
First line for acute attack
Not addressed
6 mg/dl (360 mmol/l)
6 mg/dl (360 mmol/l)
6 mg/dl (360 mmol/l)
5 mg/dl (300 mmol/l)
6 mg/dl (360 mmol/l)
Target uric acid level
N
Yes >8 with lifestyle, >9 with medications
N
N
N
N
Treatment of asymptomatic hyperuricemia
Not addressed
Not addressed
Not addressed
Renal impairment
Not addressed
First-line option
Febuxostat
Option as first-line therapy
Option as a first-line therapy
Second line
Second line
Second line
Second line or in combination
Use of uricosuric agents
Recommended for high uric acid excretors
50 mg starting dose
100 mg starting dose, decrease in renal impairment
Decrease dose in renal impairment
100 mg, may uptitrate to up to 900 mg
Start at 100 mg, may uptitrate beyond 300 mg
Allopurinol dose recommendations
Colchicine maintenance not advised
Colchicine recommended
Colchicine ‘reasonable’, less evidence for NSAIDs
Colchicine should be considered or else NSAIDs, steroids if contraindications are present
Colchicine/NSAIDs/ coxibs for 6 months
Colchicine/NSAIDs recommended for all patients
Prophylaxis when starting allopurinol
Losartan and fenofibrate when appropriate
Opiates as an adjunctive
Pegloticase for refractory cases
Other
3E, the Multinational Evidence, Exchange and Expertise Initiative; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; DCGP, Dutch College of General Practitioners; EULAR, the European League Against Rheumatism; JSGNM, Japanese Society of Gout and Nucleic Acid Metabolism.
2002
2007
BSR
DCGP
2012
ACR
Lifestyle modifications included
Table 1. Comparison of guidelines for the treatment of gout
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chronic diseases that are routinely managed by a primary care provider that included diabetes, hypertension, hyperlipidemia, osteoporosis, and hypothyroidism. Nonadherence to therapy is exceedingly common despite the fact that patients require lifelong ULT and is linked directly to achieving target serum uric acid levels [17,18]. Several studies [19–23] have shown that up to more than half of gout patients on ULT are nonadherent, with especially poor compliance among younger patients, patients of low socioeconomic status, and those without other comorbidities. Much of the difficulty with patient adherence can likely be tied to poor understanding of the disease process, the necessity to adhere to ULT in the absence of symptoms, and lack of trust in the effectiveness of medications [24 ,25 ]. Patient– provider miscommunication has been cited as a cause of poor adherence with patients feeling overwhelmed by the lifestyle changes and confusion over the role of various medications [26]. Lifestyle changes are often infrequently discussed, and many patients report not being counseled on diet, weight loss, and alcohol use [27]. Not surprisingly, patients who report a better understanding of the disease process were more likely to remain adherent to therapy and reported less severe symptoms [28]. &
&&
Strategies to improve management and care of the patient There is room for improvement in the medical management, and several interventions have been suggested to improve adherence to ULT, including regular monitoring of uric acid levels in gout patients, stressing the importance of escalating allopurinol doses, and ultimately referral to a rheumatologist if control of gout symptoms cannot be achieved [29,30 ]. Gout patients who are referred to a rheumatologist are much less likely to discontinue ULT and are more likely to reach a target uric acid level [31]. The importance of monitoring serum urate levels every few weeks after initiating ULT until a target uric acid level is reached should be stressed [9,30 ]. Equally important is stressing the importance of prophylaxis with colchicine or NSAIDs when starting ULT [31]. Small studies [32,33 ] have shown that intensive programs to manage uric acid therapy in gout patients can be effective in achieving target uric acid levels and suggest that there may be a role for further interventions to achieve target levels. The choice of urate-lowering agents is generally agreed upon in each of the guidelines with all five advising allopurinol at 50–100 mg starting dose as a first option. One of the more controversial recommendations in the most recent 2012 ACR &
guidelines has been the recommendation that febuxostat can be also used as a first-line agent [9]. The initial trials comparing febuxostat with allopurinol were designed as noninferiority trials that demonstrated the efficacy of febuxostat [34]. Subsequent trials suggested that febuxostat is likely superior compared with allopurinol for reaching target uric acid levels [35,36]. A recent Cochrane meta-analysis was generally in agreement with these findings and found that febuxostat was especially effective at higher doses as compared with allopurinol [37 ]. The recommendation to use febuxostat as an option for a first-line therapy is somewhat controversial because of the significant cost difference between allopurinol and febuxostat, although there is some evidence that is ultimately cost-effective [38]. Aside from greater reductions in uric acid levels, febuxostat also has the advantage of being an option in patients with chronic kidney disease, and although allopurinol may be safely used in patients with renal insufficiency, febuxostat may provide an alternative for providers who have concerns over allopurinol toxicity. Unique to the 2012 ACR guidelines was also the emphasis on starting prophylaxis simultaneously with the introduction of ULT as gout attacks are often worsened by changes in serum uric acid levels. The guidelines offer colchicine, NSAIDs, or corticosteroids for 2 weeks as potential options for prophylaxis during this time. A systematic review that included two placebo-controlled trials with colchicine supports a use of prophylaxis at the time of starting ULT [37 ]. Despite this, a recent study [25 ] found that the use of prophylaxis remains low with fewer than half of patients receiving it at the time of starting allopurinol. Another study [39] of the use of colchicine for prophylaxis of gout attacks showed wide discrepancies and inappropriate use of colchicine that likely reflects confusion at the level of the provider about proper usage. There is some evidence that interleukin-1 inhibitors such as anakinra may be of benefit in this scenario as well, although that was not addressed in the guidelines [37 ]. &
&
&&
&
&
&
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Impact of the gout guidelines The guidelines were purported to shift the current paradigm of treatment and change outcomes for gout patients. The purpose of these guidelines is to change practice patterns of providers so that they initiate ULT early in the management of chronic gout. However, it appears that with each set of new guidelines sufficient time needs to elapse before we can gauge the response to them. It also requires a set of tools that can measure the effectiveness of these recommendations. Historically, it takes anywhere from 3 to 5 years prior to the acceptance of any Volume 27 Number 3 May 2015
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The impact of gout guidelines Wise and Khanna
guidelines for mainstream practitioners to incorporate them in their day-to-day practice. However, a classic example that demonstrates this fact is the American College of Cardiology/American Heart Association’s cholesterol guidelines from 2013, which caution that despite significantly changing the providers’ prescribing patterns for secondary prevention, there is lack of evidence particularly for primary prevention of cardiovascular disease [40]. The gout guidelines are intended to set a mark of care once disseminated to the target audience and leads to improvement of quality of care. The gaps in care can be analyzed using these benchmarks, and as a result there have been a significantly large number of publications and abstracts presented at various society meetings. This has created an opportunity to study implementation and testing of quality measures in gout. As a result, the ACR has developed quality measures that are undergoing endorsement in the United States by the National Quality Forum for utilization as performance measures by Centers for Medicaid and Medicare. Guidelines by nature are meant to be advisory and not prescriptive. To make the best evidence-based healthcare decisions, a triad of information is needed: clinical state and circumstances, population values and preferences, and finally research evidence. To truly assess the impact of the current recommendations it is important to consider the knowledge, beliefs, and treatment practices of physicians [13,14 ]. Implementation strategies suggest that a multidisciplinary group with various educational levels and backgrounds should be approached, such as physicians, nurse practitioners, physicians’ assistants, and nurses, so as to involve all stakeholders who are critical for patient care. This approach seems to address several barriers identified by providers in accepting the guidelines such as lack of familiarity, agreement, self-efficacy, outcome expectancy, and inertia of previous and current practices. It is essential to also gauge the patients’ knowledge, beliefs, and behaviors such as resistance to new medications along with comorbidities, personal limitations, and access to care. The guidelines need to be incorporated as part of a comprehensive quality assessment system and should include both patient and physician education that can be audited during incentive processing. The quality measures developed by ACR can then be utilized as performance measures in day-to-day practice, thus making them standard of care. However, one of the critical facts is in order to succeed in changing the paradigm of treatment of gout; it is an absolute must to drill home the point that gout is a chronic disease. The perception that gout is only an acute flare-up appears to be the underlying reason for &
delay in care and inadequate choices made by both patients and physicians. It would be beneficial to include primary care providers and specialty societies as well in the conversation to integrate guidelines when there are coexisting comorbidities such as hypertension or diabetes. Pilot interventions with targeted audiences relaying simple statements about management of gout and continuing medical education both formal and curbside from specialists are the cornerstone of changing the perceptions of this disease and lead to a higher expectation about how to appropriately manage gout.
CONCLUSION Recently published gout guidelines are intended and projected to significantly impact and change practice patterns of primary care providers in the management of gout and provide comprehensive recommendations that are data driven. The impact of guidelines in day-to-day practice is difficult to gauge because of a variety of factors such as short timespan after recent release of guidelines, barriers such as patient adherence to treatment, lack of measurement tools to assess the change brought upon by the introduction of guidelines, and finally a lack of education in primary care providers of the appropriate use of uric acid-lowering therapies. Concerted effort is needed to develop tools to better assist primary care providers with implementing these recommendations from gout guidelines in order to improve patient compliance with medications and change long-term outcomes in gout. However, a major turnaround in management of gout can be foreseen in the upcoming future with the now available comprehensive set of guidelines. Acknowledgements None. Financial support and sponsorship P.P.K. is supported by research grants from the ACR and AstraZeneca. E.W. has no financial disclosures. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey. Arthritis Rheum 2011; 63:3136–3141. 2. Wertheimer A, Morlock R, Becker MA. A revised estimate of the burden of illness of gout. Curr Ther Res Clin Exp 2013; 75:1–4.
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Clinical therapeutics 3. Dalbeth N, House ME, Horne A, et al. Prescription and dosing of uratelowering therapy, rather than patient behaviours, are the key modifiable factors associated with targeting serum urate in gout. BMC Musculoskelet Disord 2012; 13:174. 4. Romeijnders AC, Gorter KJ. Summary of the Dutch College of General Practitioners’ ‘Gout’ Standard. Ned Tijdschr Geneeskd 2002; 146:309– 313. 5. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007; 46:1372–1374. 6. Zhang W, Doherty M, Bardin T, 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; 65:1312–1324. 7. Sivera F, Andres M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis 2014; 73:328–335. 8. Yamanaka H. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids 2011; 30:1018–1029. 9. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64:1431–1446. 10. Sacks JJ, Luo YH, Helmick CG. Prevalence of specific types of arthritis and other rheumatic conditions in the ambulatory healthcare system in the United States. Arthritis Care Res (Hoboken) 2010; 62:460–464. 11. Doghramji PP, Edwards NL, McTigue J. Managing gout in the primary care setting: what you and your patients need to know. Am J Med 2010; 123:S2. 12. Cottrell E, Crabtree V, Edwards JJ, Roddy E. Improvement in the management of gout is vital and overdue: an audit from a UK primary care medical practice. BMC Fam Pract 2013; 14:170. 13. Harrold LR, Mazor KM, Negron A, et al. Primary care providers’ knowledge, beliefs and treatment practices for gout: results of a physician questionnaire. Rheumatology (Oxford) 2013; 52:1623–1629. 14. Oderda GM, Shiozawa A, Walsh M, et al. Physician adherence to ACR gout & treatment guidelines: perception versus practice. Postgrad Med May 2014; 126:257–267. This article demonstrates the true acceptance of guidelines in the physician community. 15. Jennings CG, Mackenzie IS, Flynn R, et al. Up-titration of allopurinol in patients && with gout. Semin Arthritis Rheum 2014; 44:25–30. This publication emphasizes the need to titrate the dose of allopurinol to achieve target urate levels. 16. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy 2008; 28:437–443. 17. Halpern R, Fuldeore MJ, Mody RR, et al. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol 2009; 15:3–7. 18. Solomon DH, Avorn J, Levin R, Brookhart MA. Uric acid lowering therapy: prescribing patterns in a large cohort of older adults. Ann Rheum Dis 2008; 67:609–613. 19. Riedel AA, Nelson M, Joseph-Ridge N, et al. Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol 2004; 31:1575–1581.
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20. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther 2009; 11:R46. 21. Horsburgh S, Norris P. Ethnicity and access to prescription medicines. N Z Med J 2013; 126:7–11. 22. Zandman-Goddard G, Amital H, Shamrayevsky N, et al. Rates of adherence and persistence with allopurinol therapy among gout patients in Israel. Rheumatology (Oxford) 2013; 52:1126–1131. 23. Reach G. Treatment adherence in patients with gout. Joint Bone Spine 2011; 78:456–459. 24. van Onna M, Hinsenveld E, de Vries H, Boonen A. Health literacy in patients & dealing with gout: a qualitative study. Clin Rheumatol 2014. Patient perspective is emphasized in this publication. 25. Singh JA. Challenges faced by patients in gout treatment: a qualitative study. && J Clin Rheumatol 2014; 20:172–174. This article provides hones in patient barriers. 26. Harrold LR, Andrade SE, Briesacher B, et al. The dynamics of chronic gout treatment: medication gaps and return to therapy. Am J Med 2010; 123:54– 59. 27. Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007; 3:443–449. 28. Dalbeth N. Gout in 2010: progress and controversies in treatment. Nat Rev Rheumatol 2011; 7:77–78. 29. Rashid N, Coburn BW, Wu YL, et al. Modifiable factors associated with allopurinol adherence and outcomes among patients with gout in an integrated healthcare system. J Rheumatol 2014. 30. Mead T, Arabindoo K, Smith B. Managing gout: there’s more we can do. J Fam & Pract 2014; 63:707–713. This article provides strategies to better manage gout. 31. Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis 2009; 68:1265–1270. 32. Lim AY, Shen L, Tan CH, et al. Achieving treat to target in gout: a clinical practice improvement project. Scand J Rheumatol 2012; 41:450–457. 33. Goldfien RD, Ng MS, Yip G, et al. Effectiveness of a pharmacist-based gout & care management programme in a large integrated health plan: results from a pilot study. BMJ Open 2014; 4:e003627. This article is another strategy to improve adherence in medication use in gout. 34. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353:2450–2461. 35. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008; 59:1540–1548. 36. Hatoum H, Khanna D, Lin SJ, et al. Achieving serum urate goal: a comparative effectiveness study between allopurinol and febuxostat. Postgrad Med 2014; 126:65–75. 37. Kydd AS, Seth R, Buchbinder R, et al. Urate-lowering therapy for the & management of gout: a summary of 2 Cochrane reviews. J Rheumatol Suppl 2014; 92:33–41. This publication is a succinct summary of the evidence on urate-lowering agents. 38. Jutkowitz E, Choi HK, Pizzi LT, Kuntz KM. Cost-effectiveness of allopurinol and febuxostat for the management of gout. Ann Intern Med 2014; 161:617–626. 39. George M, Pullman-Mooar S, Hussain F, Schumacher HR. Evaluating appropriate use of prophylactic colchicine for gout flare prevention. Arthritis Care Res (Hoboken) 2014; 66:1258–1262. 40. Weinberger Y, Han BH. Statin treatment for older adults: the impact of the 2013 ACC/AHA Cholesterol Guidelines. Drugs Aging 2015; 32:87–93.
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The impact of gout guidelines Eric Wise and Puja P. Khanna
Purpose of review This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. Recent findings Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. Summary Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care. Keywords gout, guidelines, impact
INTRODUCTION Gout is currently the most common inflammatory arthritis in the United States and affects over 8 million Americans [1]. Acute episodes of gout typically manifest as attacks of intense joint pain resulting from an inflammatory response which is precipitated by uric acid crystal deposition in the synovial tissue surrounding synovial joints. Gout causes significant morbidity and is an economic burden with annual costs exceeding 6 billion dollars annually in direct costs and lost worker productivity [2]. Hyperuricemia is the single most identifiable parameter for the development of gout, and this risk of a gout attack increases with the degree of hyperuricemia. The management of gout focuses on the treatment of acute attacks as well as the underlying hyperuricemia to prevent future episodes. Treating hyperuricemia in gout with urate-lowering therapies (ULTs) is widely regarded as the principal strategy for preventing new attacks [3]. Multiple guidelines for the treatment and prevention of gout flares have been put forth, including those from the Dutch College of General Practitioners in 2002 [4], the British Society of
Rheumatology (BSR) in 2007 [5], the European League Against Rheumatism (EULAR) in 2006 [6], the Multinational Evidence, Expertise, Exchange Initiative (3e) in 2013 [7], the Japanese Society of Gout and Nucleic Acid Metabolism in 2011 [8], the American College of Rheumatology (ACR) in 2012 [9], and the updated EULAR set in 2014. Each of these guidelines contains recommendations for pharmacologic therapy as well as lifestyle modifications for treating both acute gout attacks along with recommendations for prophylaxis against further gout attacks. The respective guidelines are comparable in that all make similar recommendations for treating acute flares and for starting ULT after a second attack (Table 1). The ACR, 3e, and EULAR Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA Correspondence to Puja P. Khanna, MD, MPH, Assistant Professor, Division of Rheumatology, Department of Internal Medicine, 300 North Ingalls Street, Suite 7C27, Ann Arbor, MI 48109-5422, USA. Tel: +1 734 763 9151; fax: +1 734 763 1253; e-mail: [email protected] Curr Opin Rheumatol 2015, 27:225–230 DOI:10.1097/BOR.0000000000000168
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Clinical therapeutics
KEY POINTS Over the last decade, multiple guidelines have been developed to assist providers in the appropriate management of gout. The purpose of these guidelines is to change practice patterns of providers so that they initiate ULT early in the management of chronic gout. Adherence to these recommendations by both providers and patients remains poor because of variety of barriers. There are several initiatives in place to impact adherence and thus improve quality of care given to gout patients.
primary care providers on proper management [11]. Several studies, including a recent physician survey of primary care providers, have pointed to ongoing suboptimal treatment of gout in the primary care setting. A recent medical record review performed in the United Kingdom, for example, found that despite recommendations for the use of ULTs, only a minority of patients with a diagnosis of gout was actually taking uric acid-lowering agents [12]. Another survey of primary care providers’ gout management practices showed that only about half of the providers surveyed reported back management that was in accordance with current guidelines [13]. Even rheumatologists, who presumably are well aware of the guidelines, did only slightly better in a chart review of 350 patient records of gout patients seeking care in either a primary care provider’s office or a rheumatologist’s office [14 ]. Uptitration of ULT after initiation of any agent in order to achieve target serum urate levels in particular remains a significant barrier. A study [15 ] of a subset of 400 patients from the Febuxostat versus Allopurinol Streamline Trial (FAST) trial in the United Kingdom showed that with proper uptitration of a uric acid-lowering agent, 97% of patients could reach a target uric acid level of less than 6 mg/ dL. Yet, in this study, only 36% of patients were actually at a target level. Interestingly, the average number on uptitration was only slightly greater than one with most patients being controlled on 100–200 mg of allopurinol, although other studies have suggested that a significant number of patients need doses of allopurinol greater than 300 mg to achieve target uric acid levels. This finding suggests that majority of patients should be able to reach a target uric acid level without significant difficulty, though that is not happening at the present time. Monitoring of uric acid levels is also a significant barrier to achieving control. Only 22% of gout patients in a recent UK survey of primary care providers had a uric acid level recorded in the chart in the last year [12]. It is not clear whether provider concerns over the use of allopurinol, including liver toxicity, drug interactions, use in renal failure, and especially incidents of allopurinol-induced hypersensitivity syndrome, contribute to the unwillingness of primary care providers to uptitrate allopurinol. &
guidelines all recommend a target of 6 mg/dL, whereas the BSR guidelines recommend a target of 5 mg/dL. With the exception of the 3e guidelines, all recommend starting allopurinol 100 mg daily (50 mg in the presence of kidney disease) and uptitrating the dose to achieve the target serum uric acid. The guidelines each differ in subtle ways though. The BSR guidelines, for example, date from 2007 and recommend COX-2 inhibitors as a firstline therapy for acute gout or prophylaxis, whereas the newer guidelines do not and instead recommend equal efficacy for colchicine, steroids, and NSAIDs. The ACR and BSR are both aimed at assisting primary care providers and hospital physicians. The BSR guidelines include extensive diet recommendations, and the ACR guidelines are put forth in a flowchart format to assist decision making and contain a variety of scenarios such as treatment recommendations for patients who are unable to take oral medications. The Japanese Society guidelines are the only guidelines that contain a recommendation for treating asymptomatic hyperuricemia. The ACR guidelines, which are the newest, are also unique in that febuxostat is specifically recommended as a viable first-line therapy and also recommend the use of pegloticase, an intravenous recombinant uricase, for the treatment of refractory tophaceous gout.
Utilization of gout guidelines in the primary care setting: physician adherence Gout is primarily seen by primary care providers, and was responsible for over 2 million annual primary care visits in the years 2001 to 2005 [10]. Despite the availability of multiple guidelines, one of the biggest challenges of implementing strategies to prevent gout flares has been educating the 226
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&&
Patient adherence Patient adherence to their prescribed regimen is equally problematic. A study [16] of patient medication adherence to gout medications that involved over 1.3 million patients demonstrated that adherence rates for gout are among the lowest of common Volume 27 Number 3 May 2015
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2013
2006
2011
3E
EULAR
JSGNM
Yes
Yes
Yes
Yes
Yes
Yes
NSAIDS first, then colchicine, then corticosteroids
Colchicine or NSAIDs
NSAIDS, colchicine also an option
Colchicine NSAIDs
NSAIDs, coxibs, or colchicine
NSAIDs, corticosteroids, or colchicine
First line for acute attack
Not addressed
6 mg/dl (360 mmol/l)
6 mg/dl (360 mmol/l)
6 mg/dl (360 mmol/l)
5 mg/dl (300 mmol/l)
6 mg/dl (360 mmol/l)
Target uric acid level
N
Yes >8 with lifestyle, >9 with medications
N
N
N
N
Treatment of asymptomatic hyperuricemia
Not addressed
Not addressed
Not addressed
Renal impairment
Not addressed
First-line option
Febuxostat
Option as first-line therapy
Option as a first-line therapy
Second line
Second line
Second line
Second line or in combination
Use of uricosuric agents
Recommended for high uric acid excretors
50 mg starting dose
100 mg starting dose, decrease in renal impairment
Decrease dose in renal impairment
100 mg, may uptitrate to up to 900 mg
Start at 100 mg, may uptitrate beyond 300 mg
Allopurinol dose recommendations
Colchicine maintenance not advised
Colchicine recommended
Colchicine ‘reasonable’, less evidence for NSAIDs
Colchicine should be considered or else NSAIDs, steroids if contraindications are present
Colchicine/NSAIDs/ coxibs for 6 months
Colchicine/NSAIDs recommended for all patients
Prophylaxis when starting allopurinol
Losartan and fenofibrate when appropriate
Opiates as an adjunctive
Pegloticase for refractory cases
Other
3E, the Multinational Evidence, Exchange and Expertise Initiative; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; DCGP, Dutch College of General Practitioners; EULAR, the European League Against Rheumatism; JSGNM, Japanese Society of Gout and Nucleic Acid Metabolism.
2002
2007
BSR
DCGP
2012
ACR
Lifestyle modifications included
Table 1. Comparison of guidelines for the treatment of gout
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chronic diseases that are routinely managed by a primary care provider that included diabetes, hypertension, hyperlipidemia, osteoporosis, and hypothyroidism. Nonadherence to therapy is exceedingly common despite the fact that patients require lifelong ULT and is linked directly to achieving target serum uric acid levels [17,18]. Several studies [19–23] have shown that up to more than half of gout patients on ULT are nonadherent, with especially poor compliance among younger patients, patients of low socioeconomic status, and those without other comorbidities. Much of the difficulty with patient adherence can likely be tied to poor understanding of the disease process, the necessity to adhere to ULT in the absence of symptoms, and lack of trust in the effectiveness of medications [24 ,25 ]. Patient– provider miscommunication has been cited as a cause of poor adherence with patients feeling overwhelmed by the lifestyle changes and confusion over the role of various medications [26]. Lifestyle changes are often infrequently discussed, and many patients report not being counseled on diet, weight loss, and alcohol use [27]. Not surprisingly, patients who report a better understanding of the disease process were more likely to remain adherent to therapy and reported less severe symptoms [28]. &
&&
Strategies to improve management and care of the patient There is room for improvement in the medical management, and several interventions have been suggested to improve adherence to ULT, including regular monitoring of uric acid levels in gout patients, stressing the importance of escalating allopurinol doses, and ultimately referral to a rheumatologist if control of gout symptoms cannot be achieved [29,30 ]. Gout patients who are referred to a rheumatologist are much less likely to discontinue ULT and are more likely to reach a target uric acid level [31]. The importance of monitoring serum urate levels every few weeks after initiating ULT until a target uric acid level is reached should be stressed [9,30 ]. Equally important is stressing the importance of prophylaxis with colchicine or NSAIDs when starting ULT [31]. Small studies [32,33 ] have shown that intensive programs to manage uric acid therapy in gout patients can be effective in achieving target uric acid levels and suggest that there may be a role for further interventions to achieve target levels. The choice of urate-lowering agents is generally agreed upon in each of the guidelines with all five advising allopurinol at 50–100 mg starting dose as a first option. One of the more controversial recommendations in the most recent 2012 ACR &
guidelines has been the recommendation that febuxostat can be also used as a first-line agent [9]. The initial trials comparing febuxostat with allopurinol were designed as noninferiority trials that demonstrated the efficacy of febuxostat [34]. Subsequent trials suggested that febuxostat is likely superior compared with allopurinol for reaching target uric acid levels [35,36]. A recent Cochrane meta-analysis was generally in agreement with these findings and found that febuxostat was especially effective at higher doses as compared with allopurinol [37 ]. The recommendation to use febuxostat as an option for a first-line therapy is somewhat controversial because of the significant cost difference between allopurinol and febuxostat, although there is some evidence that is ultimately cost-effective [38]. Aside from greater reductions in uric acid levels, febuxostat also has the advantage of being an option in patients with chronic kidney disease, and although allopurinol may be safely used in patients with renal insufficiency, febuxostat may provide an alternative for providers who have concerns over allopurinol toxicity. Unique to the 2012 ACR guidelines was also the emphasis on starting prophylaxis simultaneously with the introduction of ULT as gout attacks are often worsened by changes in serum uric acid levels. The guidelines offer colchicine, NSAIDs, or corticosteroids for 2 weeks as potential options for prophylaxis during this time. A systematic review that included two placebo-controlled trials with colchicine supports a use of prophylaxis at the time of starting ULT [37 ]. Despite this, a recent study [25 ] found that the use of prophylaxis remains low with fewer than half of patients receiving it at the time of starting allopurinol. Another study [39] of the use of colchicine for prophylaxis of gout attacks showed wide discrepancies and inappropriate use of colchicine that likely reflects confusion at the level of the provider about proper usage. There is some evidence that interleukin-1 inhibitors such as anakinra may be of benefit in this scenario as well, although that was not addressed in the guidelines [37 ]. &
&
&&
&
&
&
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Impact of the gout guidelines The guidelines were purported to shift the current paradigm of treatment and change outcomes for gout patients. The purpose of these guidelines is to change practice patterns of providers so that they initiate ULT early in the management of chronic gout. However, it appears that with each set of new guidelines sufficient time needs to elapse before we can gauge the response to them. It also requires a set of tools that can measure the effectiveness of these recommendations. Historically, it takes anywhere from 3 to 5 years prior to the acceptance of any Volume 27 Number 3 May 2015
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The impact of gout guidelines Wise and Khanna
guidelines for mainstream practitioners to incorporate them in their day-to-day practice. However, a classic example that demonstrates this fact is the American College of Cardiology/American Heart Association’s cholesterol guidelines from 2013, which caution that despite significantly changing the providers’ prescribing patterns for secondary prevention, there is lack of evidence particularly for primary prevention of cardiovascular disease [40]. The gout guidelines are intended to set a mark of care once disseminated to the target audience and leads to improvement of quality of care. The gaps in care can be analyzed using these benchmarks, and as a result there have been a significantly large number of publications and abstracts presented at various society meetings. This has created an opportunity to study implementation and testing of quality measures in gout. As a result, the ACR has developed quality measures that are undergoing endorsement in the United States by the National Quality Forum for utilization as performance measures by Centers for Medicaid and Medicare. Guidelines by nature are meant to be advisory and not prescriptive. To make the best evidence-based healthcare decisions, a triad of information is needed: clinical state and circumstances, population values and preferences, and finally research evidence. To truly assess the impact of the current recommendations it is important to consider the knowledge, beliefs, and treatment practices of physicians [13,14 ]. Implementation strategies suggest that a multidisciplinary group with various educational levels and backgrounds should be approached, such as physicians, nurse practitioners, physicians’ assistants, and nurses, so as to involve all stakeholders who are critical for patient care. This approach seems to address several barriers identified by providers in accepting the guidelines such as lack of familiarity, agreement, self-efficacy, outcome expectancy, and inertia of previous and current practices. It is essential to also gauge the patients’ knowledge, beliefs, and behaviors such as resistance to new medications along with comorbidities, personal limitations, and access to care. The guidelines need to be incorporated as part of a comprehensive quality assessment system and should include both patient and physician education that can be audited during incentive processing. The quality measures developed by ACR can then be utilized as performance measures in day-to-day practice, thus making them standard of care. However, one of the critical facts is in order to succeed in changing the paradigm of treatment of gout; it is an absolute must to drill home the point that gout is a chronic disease. The perception that gout is only an acute flare-up appears to be the underlying reason for &
delay in care and inadequate choices made by both patients and physicians. It would be beneficial to include primary care providers and specialty societies as well in the conversation to integrate guidelines when there are coexisting comorbidities such as hypertension or diabetes. Pilot interventions with targeted audiences relaying simple statements about management of gout and continuing medical education both formal and curbside from specialists are the cornerstone of changing the perceptions of this disease and lead to a higher expectation about how to appropriately manage gout.
CONCLUSION Recently published gout guidelines are intended and projected to significantly impact and change practice patterns of primary care providers in the management of gout and provide comprehensive recommendations that are data driven. The impact of guidelines in day-to-day practice is difficult to gauge because of a variety of factors such as short timespan after recent release of guidelines, barriers such as patient adherence to treatment, lack of measurement tools to assess the change brought upon by the introduction of guidelines, and finally a lack of education in primary care providers of the appropriate use of uric acid-lowering therapies. Concerted effort is needed to develop tools to better assist primary care providers with implementing these recommendations from gout guidelines in order to improve patient compliance with medications and change long-term outcomes in gout. However, a major turnaround in management of gout can be foreseen in the upcoming future with the now available comprehensive set of guidelines. Acknowledgements None. Financial support and sponsorship P.P.K. is supported by research grants from the ACR and AstraZeneca. E.W. has no financial disclosures. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey. Arthritis Rheum 2011; 63:3136–3141. 2. Wertheimer A, Morlock R, Becker MA. A revised estimate of the burden of illness of gout. Curr Ther Res Clin Exp 2013; 75:1–4.
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20. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther 2009; 11:R46. 21. Horsburgh S, Norris P. Ethnicity and access to prescription medicines. N Z Med J 2013; 126:7–11. 22. Zandman-Goddard G, Amital H, Shamrayevsky N, et al. Rates of adherence and persistence with allopurinol therapy among gout patients in Israel. Rheumatology (Oxford) 2013; 52:1126–1131. 23. Reach G. Treatment adherence in patients with gout. Joint Bone Spine 2011; 78:456–459. 24. van Onna M, Hinsenveld E, de Vries H, Boonen A. Health literacy in patients & dealing with gout: a qualitative study. Clin Rheumatol 2014. Patient perspective is emphasized in this publication. 25. Singh JA. Challenges faced by patients in gout treatment: a qualitative study. && J Clin Rheumatol 2014; 20:172–174. This article provides hones in patient barriers. 26. Harrold LR, Andrade SE, Briesacher B, et al. The dynamics of chronic gout treatment: medication gaps and return to therapy. Am J Med 2010; 123:54– 59. 27. Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007; 3:443–449. 28. Dalbeth N. Gout in 2010: progress and controversies in treatment. Nat Rev Rheumatol 2011; 7:77–78. 29. Rashid N, Coburn BW, Wu YL, et al. Modifiable factors associated with allopurinol adherence and outcomes among patients with gout in an integrated healthcare system. J Rheumatol 2014. 30. Mead T, Arabindoo K, Smith B. Managing gout: there’s more we can do. J Fam & Pract 2014; 63:707–713. This article provides strategies to better manage gout. 31. Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis 2009; 68:1265–1270. 32. Lim AY, Shen L, Tan CH, et al. Achieving treat to target in gout: a clinical practice improvement project. Scand J Rheumatol 2012; 41:450–457. 33. Goldfien RD, Ng MS, Yip G, et al. Effectiveness of a pharmacist-based gout & care management programme in a large integrated health plan: results from a pilot study. BMJ Open 2014; 4:e003627. This article is another strategy to improve adherence in medication use in gout. 34. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353:2450–2461. 35. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008; 59:1540–1548. 36. Hatoum H, Khanna D, Lin SJ, et al. Achieving serum urate goal: a comparative effectiveness study between allopurinol and febuxostat. Postgrad Med 2014; 126:65–75. 37. Kydd AS, Seth R, Buchbinder R, et al. Urate-lowering therapy for the & management of gout: a summary of 2 Cochrane reviews. J Rheumatol Suppl 2014; 92:33–41. This publication is a succinct summary of the evidence on urate-lowering agents. 38. Jutkowitz E, Choi HK, Pizzi LT, Kuntz KM. Cost-effectiveness of allopurinol and febuxostat for the management of gout. Ann Intern Med 2014; 161:617–626. 39. George M, Pullman-Mooar S, Hussain F, Schumacher HR. Evaluating appropriate use of prophylactic colchicine for gout flare prevention. Arthritis Care Res (Hoboken) 2014; 66:1258–1262. 40. Weinberger Y, Han BH. Statin treatment for older adults: the impact of the 2013 ACC/AHA Cholesterol Guidelines. Drugs Aging 2015; 32:87–93.
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![[Hyperuricemia and gout: The impact of ultrasonography].](/assets/img/hold.png)
