REVIEW URRENT C OPINION
Evolution of management of gout: a comparison of recent guidelines Puja P. Khanna a and John FitzGerald b
Purpose of review There have been several guidelines on the management of gout over the last decade; however, inconsistencies between them create confusion for practitioners. This review highlights areas of agreement between guidelines and discusses data where disagreements exist. Recent findings For acute gout, the guidelines agree that anti-inflammatory treatment should start as soon as possible, preferably within 24 hours. Older guidelines preferred NSAIDs or colchicine over steroids, but newer ones leave the choice of agent to the physician. For colchicine, all guidelines recommend using low dose. Intraarticular, oral or intramuscular steroids are all described as effective. For management of hyperuricemia, indications for initiating urate-lowering therapy (ULT) have become more inclusive over the years by requiring lower burden of disease severity or including patient comorbidities. Probenecid has fallen out of favour with most guidelines favouring allopurinol over febuxostat. Although there is a disagreement about timing of initiation for ULT, guidelines recommend treating to target of serum urate (sUA) less than 6 mg/dl, and less than 5 mg/dl for patients with more severe disease. Concurrent anti-inflammatory prophylaxis has gained strong support over the years. Summary Most guidelines are in agreement with recommendations for management of gout and most changes have been directional and evolutionary. Keywords acute, advances in gout, chronic, imaging
INTRODUCTION There has been an increased effort in the last decade to improve management of the most common form of arthritis in rheumatology, gout, which for multiple reasons is inadequately treated. Management of gout can be complicated due to the episodic nature of the disease. This can be further confounded when initiating urate-lowering therapy (ULT) due to the increased risk of acute gout attacks upon initiation and various comorbidities of patients. Our review provides a review of the recommendations across various guidelines with updates from recent literature on the therapeutics and update on diagnostic modalities in gout.
EPIDEMIOLOGY OF GOUT AND ADHERENCE TO MEDICATIONS According to the National Health and Nutrition Examination Surveys from 2007 to 2010, half of all Americans with gout on ULT, and two-thirds
with an indication for ULT, have a serum urate (sUA) above target [1]. Most recent prevalence estimates from NHANES III showed that 3.9% of adults in the United States suffer from gout [2]. Another recent qualitative analysis in 43 African-American patients admitted to similar barriers in adherence to ULT [3]. Various rheumatologic societies have developed guidelines for management of gout [4–8]. All have emphasized patient education as the central theme for improving patient-related outcomes [9]. Despite published guidelines, there are significant disparities in approaches to gout management, a Division of Rheumatology, University of Michigan, Ann Arbor, Michigan and bDavid Geffen School of Medicine, UCLA, Los Angeles, California, USA
Correspondence to Puja P. Khanna, MD, MPH, Division of Rheumatology, Department of Internal Medicine, 300 North Ingalls, Ste. 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, 27:139–146 DOI:10.1097/BOR.0000000000000154
1040-8711 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Crystal deposition diseases
KEY POINTS Despite numerous different gout guidelines, there is more in common across the guidelines than different in recommendations for care. NSAIDs, COX-2 inhibitors, corticosteroids, colchicine and IL-1 inhibitors have strong evidence to suggest efficacy in the treatment of acute gout. A ‘treat-to-target’ strategy to achieve serum urate of at least 6 mg/dl or lower is agreed upon across all the guidelines. Imaging modalities such as ultrasound and DECT are promising technologies to aid in the diagnosis of gout.
most of the guidelines. EULAR, ACR and 3e initiative were all given very low marks for applicability, which by definition describes the following: ‘the guideline describes a) facilitators and barriers to its application, b) provides advice and/or tools on how the recommendations can be put into practice, c) the potential resource implications of applying the recommendations have been considered, and finally d) presents monitoring and/or auditing criteria’. The AGREE methodology is an important introduction into the development of guidelines development. Hopefully, future guidelines will take into account the domains outlined in the assessment as noted in the Table 1.
ACUTE GOUT THERAPIES prescribing patterns of providers and lack of uniform standard of care for chronic treatment of gout [4–6,8,10,11]. The latest systematic review of medication adherence in gout showed that less than 50% of gout patients in the real-world setting are adherent to their treatment [12 ]. In the last two decades, there have been five major international gout guidelines; see Tables 1–4 [13,14 ] for full list plus the 2014 British Society of Rheumatology (BSR), European League against Rheumatism, American College of Rheumatology (ACR), and 3e Initiative - Multinational Evidence, Exchange and Expertise group. EULAR update (available only as an abstract). It interesting to note how some of these recommendations have evolved over the years. A recent review [13] evaluated and rated the quality of the guidelines using AGREE II methodology across several domains [15]. See Table 1 for domains and scores for each guideline; results need to be interpreted with caution, as one of the two raters was also a senior author for one of the guidelines and self-rated his own guideline. However, the analysis highlights some important concerns about &
&
For treatment of acute gout, three guidelines, ACR [16], BSR [4] and 3e [6] initiative recommend NSAIDs, corticosteroids or oral colchicine to be similarly effective (Table 2). However, EULAR [7] recommended oral colchicine and/or NSAID as first-line agents over corticosteroids for the treatment of acute attacks. When selecting colchicine, all guidelines recommend using low-dose colchicine (1.8–2.0 mg, country-specific loading dose). The ACR recommended topical ice application to be an appropriate adjunctive measure to one or more pharmacologic therapies for acute gouty arthritis. For patients with severe disease (defined as >7 of 10 pain on a 0–10 VAS and/or acute polyarticular gout attack, or an attack involving at least one to two large joints), the ACR guidelines recommend initiating combination pharmacologic therapy and use of IL-1 inhibition in individuals with refractory attacks of acute gout or contraindications to all the three agents above. BSR, EULAR, and ACR all recommend combining pharmacological and nonpharmacological treatments such as rest or ice as add-on to single-drug treatment (monotherapy) for acute
Table 1. AGREE II quality score (%) Guidelines Domain
ACR
BSR
EULAR
3e initiative
Scope and purpose
66
89
66
72
Stakeholder involvement
50
78
28
44
Rigour of development
60
73
77
75
Clarity of presentation
61
94
78
83
Applicability
8
63
4
8
Editorial independence
83
75
42
83
Overall quality
50
70
60
60
3e, Multinational Evidence, Exchange and Expertise group; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; EULAR, European League against Rheumatism. Adapted with permission from [13].
140
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Evolution of management of gout Khanna and FitzGerald Table 2. Summary of recommendations and evidence on management of acute gout 2012 ACR Gout Guidelines, Part 1
2006 EULAR
2007 BSR
3e initiative
When to start Rx
Immediately after initiation of acute attack
Not addressed
Within 24 h of initiation of attack
Not addressed
Monotherapy
NSAIDs are the drugs of choice followed by colchicine
first-line oral lowdose colchicine or NSAIDs
No preference and can be colchicine, NSAIDs, or corticosteroids
No preference and can be colchicine, NSAIDs, or corticosteroids
Oral colchicine
0.5 mg 2–4 times daily
0.5 mg 3 times a day
1.8 mg first day followed by 0.6 mg once or twice daily until end of attack
Low-dose colchicine (up to 2 mg daily)
NSAIDS and coxibs
Fast-acting NSAIDs at a maximum dose are the drugs of choice; duration of therapy not addressed
Different NSAIDs are similarly effective; duration of therapy not addressed
NSAIDs or COX-2 is effective at FDA/ EMA-approved doses; duration for 1 week
NSAIDs or COX-2 is effective; duration of therapy not addressed
Intra-articular steroids
IA steroids for acute monoarticular gouty arthritis
Effective and well tolerated for acute gout
Recommends for acute gout in 1–2 large joints with acute gout
Effective for acute gout
Oral steroids
Effective if unable to tolerate NSAIDs or refractory gout; duration of therapy not addressed
Not addressed
Recommends oral steroids at 0.5 mg/kg for 5–10 days, or 2–5 days of full dose tapered over 7–10 days
Effective for acute gout; duration of therapy not addressed
IM steroids
Effective if unable to tolerate NSAIDs or refractory gout
Not addressed
Triamcinolone acetonide 60 mg once followed by oral prednisone. In patients who are NPO, initial methylprednisolone is 0.5– 2 mg/kg and repeated, as needed
Effective for acute gout
Combination therapy: with 2 pharmacologic agents
Not addressed
Not addressed
When the acute attack was characterized by severe pain; acute polyarticular gout attack or an attack involving 1–2 large joints
Not addressed
Nonpharmacologic
Recommends lifestyle modifications as well as ice in combination with pharmacologic therapy
Should be used in combination with pharmacologic therapy (i.e. ice)
Supplement first-line therapy with topical ice as needed
Not addressed
3e, Multinational Evidence, Exchange and Expertise group; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; EULAR, European League against Rheumatism; IA, intra-articular; IM, intramuscular; p.o., oral. & Adapted with permission from [14 ].
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Evolution of management of gout: a comparison of recent guidelines Puja P. Khanna a and John FitzGerald b
Purpose of review There have been several guidelines on the management of gout over the last decade; however, inconsistencies between them create confusion for practitioners. This review highlights areas of agreement between guidelines and discusses data where disagreements exist. Recent findings For acute gout, the guidelines agree that anti-inflammatory treatment should start as soon as possible, preferably within 24 hours. Older guidelines preferred NSAIDs or colchicine over steroids, but newer ones leave the choice of agent to the physician. For colchicine, all guidelines recommend using low dose. Intraarticular, oral or intramuscular steroids are all described as effective. For management of hyperuricemia, indications for initiating urate-lowering therapy (ULT) have become more inclusive over the years by requiring lower burden of disease severity or including patient comorbidities. Probenecid has fallen out of favour with most guidelines favouring allopurinol over febuxostat. Although there is a disagreement about timing of initiation for ULT, guidelines recommend treating to target of serum urate (sUA) less than 6 mg/dl, and less than 5 mg/dl for patients with more severe disease. Concurrent anti-inflammatory prophylaxis has gained strong support over the years. Summary Most guidelines are in agreement with recommendations for management of gout and most changes have been directional and evolutionary. Keywords acute, advances in gout, chronic, imaging
INTRODUCTION There has been an increased effort in the last decade to improve management of the most common form of arthritis in rheumatology, gout, which for multiple reasons is inadequately treated. Management of gout can be complicated due to the episodic nature of the disease. This can be further confounded when initiating urate-lowering therapy (ULT) due to the increased risk of acute gout attacks upon initiation and various comorbidities of patients. Our review provides a review of the recommendations across various guidelines with updates from recent literature on the therapeutics and update on diagnostic modalities in gout.
EPIDEMIOLOGY OF GOUT AND ADHERENCE TO MEDICATIONS According to the National Health and Nutrition Examination Surveys from 2007 to 2010, half of all Americans with gout on ULT, and two-thirds
with an indication for ULT, have a serum urate (sUA) above target [1]. Most recent prevalence estimates from NHANES III showed that 3.9% of adults in the United States suffer from gout [2]. Another recent qualitative analysis in 43 African-American patients admitted to similar barriers in adherence to ULT [3]. Various rheumatologic societies have developed guidelines for management of gout [4–8]. All have emphasized patient education as the central theme for improving patient-related outcomes [9]. Despite published guidelines, there are significant disparities in approaches to gout management, a Division of Rheumatology, University of Michigan, Ann Arbor, Michigan and bDavid Geffen School of Medicine, UCLA, Los Angeles, California, USA
Correspondence to Puja P. Khanna, MD, MPH, Division of Rheumatology, Department of Internal Medicine, 300 North Ingalls, Ste. 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, 27:139–146 DOI:10.1097/BOR.0000000000000154
1040-8711 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-rheumatology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Crystal deposition diseases
KEY POINTS Despite numerous different gout guidelines, there is more in common across the guidelines than different in recommendations for care. NSAIDs, COX-2 inhibitors, corticosteroids, colchicine and IL-1 inhibitors have strong evidence to suggest efficacy in the treatment of acute gout. A ‘treat-to-target’ strategy to achieve serum urate of at least 6 mg/dl or lower is agreed upon across all the guidelines. Imaging modalities such as ultrasound and DECT are promising technologies to aid in the diagnosis of gout.
most of the guidelines. EULAR, ACR and 3e initiative were all given very low marks for applicability, which by definition describes the following: ‘the guideline describes a) facilitators and barriers to its application, b) provides advice and/or tools on how the recommendations can be put into practice, c) the potential resource implications of applying the recommendations have been considered, and finally d) presents monitoring and/or auditing criteria’. The AGREE methodology is an important introduction into the development of guidelines development. Hopefully, future guidelines will take into account the domains outlined in the assessment as noted in the Table 1.
ACUTE GOUT THERAPIES prescribing patterns of providers and lack of uniform standard of care for chronic treatment of gout [4–6,8,10,11]. The latest systematic review of medication adherence in gout showed that less than 50% of gout patients in the real-world setting are adherent to their treatment [12 ]. In the last two decades, there have been five major international gout guidelines; see Tables 1–4 [13,14 ] for full list plus the 2014 British Society of Rheumatology (BSR), European League against Rheumatism, American College of Rheumatology (ACR), and 3e Initiative - Multinational Evidence, Exchange and Expertise group. EULAR update (available only as an abstract). It interesting to note how some of these recommendations have evolved over the years. A recent review [13] evaluated and rated the quality of the guidelines using AGREE II methodology across several domains [15]. See Table 1 for domains and scores for each guideline; results need to be interpreted with caution, as one of the two raters was also a senior author for one of the guidelines and self-rated his own guideline. However, the analysis highlights some important concerns about &
&
For treatment of acute gout, three guidelines, ACR [16], BSR [4] and 3e [6] initiative recommend NSAIDs, corticosteroids or oral colchicine to be similarly effective (Table 2). However, EULAR [7] recommended oral colchicine and/or NSAID as first-line agents over corticosteroids for the treatment of acute attacks. When selecting colchicine, all guidelines recommend using low-dose colchicine (1.8–2.0 mg, country-specific loading dose). The ACR recommended topical ice application to be an appropriate adjunctive measure to one or more pharmacologic therapies for acute gouty arthritis. For patients with severe disease (defined as >7 of 10 pain on a 0–10 VAS and/or acute polyarticular gout attack, or an attack involving at least one to two large joints), the ACR guidelines recommend initiating combination pharmacologic therapy and use of IL-1 inhibition in individuals with refractory attacks of acute gout or contraindications to all the three agents above. BSR, EULAR, and ACR all recommend combining pharmacological and nonpharmacological treatments such as rest or ice as add-on to single-drug treatment (monotherapy) for acute
Table 1. AGREE II quality score (%) Guidelines Domain
ACR
BSR
EULAR
3e initiative
Scope and purpose
66
89
66
72
Stakeholder involvement
50
78
28
44
Rigour of development
60
73
77
75
Clarity of presentation
61
94
78
83
Applicability
8
63
4
8
Editorial independence
83
75
42
83
Overall quality
50
70
60
60
3e, Multinational Evidence, Exchange and Expertise group; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; EULAR, European League against Rheumatism. Adapted with permission from [13].
140
www.co-rheumatology.com
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Evolution of management of gout Khanna and FitzGerald Table 2. Summary of recommendations and evidence on management of acute gout 2012 ACR Gout Guidelines, Part 1
2006 EULAR
2007 BSR
3e initiative
When to start Rx
Immediately after initiation of acute attack
Not addressed
Within 24 h of initiation of attack
Not addressed
Monotherapy
NSAIDs are the drugs of choice followed by colchicine
first-line oral lowdose colchicine or NSAIDs
No preference and can be colchicine, NSAIDs, or corticosteroids
No preference and can be colchicine, NSAIDs, or corticosteroids
Oral colchicine
0.5 mg 2–4 times daily
0.5 mg 3 times a day
1.8 mg first day followed by 0.6 mg once or twice daily until end of attack
Low-dose colchicine (up to 2 mg daily)
NSAIDS and coxibs
Fast-acting NSAIDs at a maximum dose are the drugs of choice; duration of therapy not addressed
Different NSAIDs are similarly effective; duration of therapy not addressed
NSAIDs or COX-2 is effective at FDA/ EMA-approved doses; duration for 1 week
NSAIDs or COX-2 is effective; duration of therapy not addressed
Intra-articular steroids
IA steroids for acute monoarticular gouty arthritis
Effective and well tolerated for acute gout
Recommends for acute gout in 1–2 large joints with acute gout
Effective for acute gout
Oral steroids
Effective if unable to tolerate NSAIDs or refractory gout; duration of therapy not addressed
Not addressed
Recommends oral steroids at 0.5 mg/kg for 5–10 days, or 2–5 days of full dose tapered over 7–10 days
Effective for acute gout; duration of therapy not addressed
IM steroids
Effective if unable to tolerate NSAIDs or refractory gout
Not addressed
Triamcinolone acetonide 60 mg once followed by oral prednisone. In patients who are NPO, initial methylprednisolone is 0.5– 2 mg/kg and repeated, as needed
Effective for acute gout
Combination therapy: with 2 pharmacologic agents
Not addressed
Not addressed
When the acute attack was characterized by severe pain; acute polyarticular gout attack or an attack involving 1–2 large joints
Not addressed
Nonpharmacologic
Recommends lifestyle modifications as well as ice in combination with pharmacologic therapy
Should be used in combination with pharmacologic therapy (i.e. ice)
Supplement first-line therapy with topical ice as needed
Not addressed
3e, Multinational Evidence, Exchange and Expertise group; ACR, American College of Rheumatology; BSR, British Society of Rheumatology; EULAR, European League against Rheumatism; IA, intra-articular; IM, intramuscular; p.o., oral. & Adapted with permission from [14 ].
1040-8711 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-rheumatology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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