2012 American College of Rheumatology Guidelines for ... · 2012 American College of Rheumatology Guidelines for ... Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches

2012 American College of RheumatologyGuidelines for Management of Gout. Part 1:Systematic Nonpharmacologic and PharmacologicTherapeutic Approaches to HyperuricemiaDINESH KHANNA,1 JOHN D. FITZGERALD,2 PUJA P. KHANNA,1 SANGMEE BAE,2 MANJIT K. SINGH,3

TUHINA NEOGI,4 MICHAEL H. PILLINGER, SHRADDHA PRAKASH,2

MARIAN KALDAS,2 9

FREDERIC LIOTE,10

SANFORD KAPLAN, STEVEN A. YAROWS,15

BLAKE ROESSLER,1 DANIEL E. FURST,2

N. LAWRENCE EDWARDS, MARK ROBBINS,22

NEIL WENGER,2 AND

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) areintended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determi-nation regarding their application to be made by the physician in light of each patient’s individual circumstances.Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guaranteeany specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodicrevision as warranted by the evolution of medical knowledge, technology, and practice.

The American College of Rheumatology is an independent, professional, medical and scientific society which doesnot guarantee, warrant, or endorse any commercial product or service.

IntroductionGout is a disorder that manifests as a spectrum of clinicaland pathologic features built on a foundation of an excessbody burden of uric acid, manifested in part by hyperuri-cemia, which is variably defined as a serum urate level

greater than either 6.8 or 7.0 mg/dl (1,2). Tissue depositionof monosodium urate monohydrate crystals in supersatu-rated extracellular fluids of the joint, and certain other

Supported by a research grant from the American Collegeof Rheumatology and by the National Institute of Arthritisand Musculoskeletal and Skin Diseases, NIH (grant K24-AR-063120).

1Dinesh Khanna, MD, MSc, Puja P. Khanna, MD, MPH,Blake Roessler, MD: University of Michigan, Ann Arbor;2John D. FitzGerald, MD, Sangmee Bae, MD, ShraddhaPrakash, MD, Marian Kaldas, MD, Maneesh Gogia, MD,Daniel E. Furst, MD, Neil Wenger, MD: University of Cali-fornia, Los Angeles; 3Manjit K. Singh, MD: Rochester Gen-eral Health System, Rochester, New York; 4Tuhina Neogi,MD, PhD, FRCPC, Hyon Choi, MD, DrPH: Boston UniversityMedical Center, Boston, Massachusetts; 5Michael H. Pillinger,MD: VA Medical Center and New York University School ofMedicine, New York; 6Joan Merill, MD: Oklahoma MedicalResearch Foundation, Oklahoma City; 7Susan Lee, MD,Robert Terkeltaub, MD: VA Healthcare System and Univer-sity of California, San Diego; 8Fernando Perez-Ruiz, MD,PhD: Hospital Universitario Cruces, Vizcaya, Spain; 9Will

Taylor, PhD, MBChB: University of Otago, Wellington, New´, MD, PhD: Universite Paris

Diderot, Sorbonne Paris Cite, and Hopital Lariboisiere,Paris, France; 11Jasvinder A. Singh, MBBS, MPH: VA Med-ical Center and University of Alabama, Birmingham;12Nicola Dalbeth, MD, FRACP: University of Auckland,Auckland, New Zealand; 13Sanford Kaplan, DDS: Oral andMaxillofacial Surgery, Beverly Hills, California; 14VandanaNiyyar, MD, Danielle Jones, MD, FACP: Emory University,Atlanta, Georgia; 15Steven A. Yarows, MD, FACP, FASH:IHA University of Michigan Health System, Chelsea; 16GailKerr, MD, FRCP(Edin): Veterans Affairs Medical Center,Washington, DC; 17Charles King, MD: North MississippiMedical Center, Tupelo; 18Gerald Levy, MD, MBA: South-ern California Permanente Medical Group, Downey; 19N.Lawrence Edwards, MD: University of Florida, Gainesville;20Brian Mandell, MD, PhD: Cleveland Clinic, Cleveland,Ohio; 21H. Ralph Schumacher, MD: VA Medical Center andUniversity of Pennsylvania, Philadelphia; 22Mark Robbins,MD, MPH: Harvard Vanguard Medical Associates/AtriusHealth, Somerville, Massachusetts.

Arthritis Care & ResearchVol. 64, No. 10, October 2012, pp 1431–1446DOI 10.1002/acr.21772© 2012, American College of Rheumatology

SPECIAL ARTICLE

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sites, mediates most of the clinical and pathologic featuresof gout. Typically, the disease initially presents as acuteepisodic arthritis. Gout also can manifest as chronic arthri-tis of 1 or more joints (1,2). Tophi, mainly found in artic-ular, periarticular, bursal, bone, auricular, and cutaneoustissues, are a pathognomonic feature of gout, and are de-tectable by physical examination and/or by imaging ap-proaches and pathology examination (3–5). Renal manifes-tations of gout include urolithiasis, typically occurringwith an acidic urine pH (1,2). Chronic interstitial nephrop-athy, mediated by monosodium urate monohydrate crystaldeposition in the renal medulla, can occur in severe dis-ease, but is currently considered to be an uncommon clin-ical manifestation of gout.

Gout is one of the most common rheumatic diseases ofadulthood, with a self-reported prevalence in the US re-cently estimated at 3.9% of adults (�8.3 million people)(6). The prevalence of gout has risen in many countries(e.g., New Zealand) and especially in the US over the lastfew decades, mediated by factors such as an increasedprevalence of comorbidities that promote hyperuricemia,including hypertension, obesity, metabolic syndrome,type 2 diabetes mellitus, and chronic kidney disease (CKD)(7–10). Other factors in the rising prevalence of gout in-clude certain dietary trends and widespread prescriptionsof thiazide and loop diuretics for cardiovascular diseases(11). Many gout patients, including the growing subset ofelderly patients affected with gout, have complex comor-bidities and medication profiles that complicate overallmanagement (12). Long-term morbidity and impairment of

Drs. Dinesh Khanna, FitzGerald, and Puja P. Khanna con-tributed equally to this work.

Dr. Dinesh Khanna has received consultant fees, speakingfees, and/or honoraria (less than $10,000 each) from No-vartis and Ardea and (more than $10,000 each) from Takedaand Savient, and has served as a paid investment consultantfor Guidepoint. Dr. Puja P. Khanna has received speakingfees (less than $10,000) from Novartis and (more than$10,000) from Takeda, and has served on the advisory boardfor Novartis. Dr. Pillinger has received speaking fees and/orhonoraria (less than $10,000 each) from the RA InvestigatorNetwork, NY Downtown Hospital, Winthrop Hospital,and Einstein College of Medicine. Dr. Perez-Ruiz has re-ceived consultant fees, speaking fees, and/or honoraria (lessthan $10,000 each) from Novartis, Menarini, and Savient,and (more than $10,000) from Ardea. Dr. Liote has receivedconsultant fees, speaking fees, and/or honoraria (lessthan $10,000 each) from Novartis Global, Novartis France,and Ipsen, and has served as a paid investment consultantfor Gerson Lehrman Group. Dr. Choi has served on theadvisory boards (less than $10,000 each) for Takeda, URL,

and Savient. Dr. Singh has received consultant fees,speaking fees, and/or honoraria (less than $10,000 each)from Ardea, Savient, Allergan, and Novartis, and (morethan $10,000) from Takeda, and has received investigator-initiated grants from Takeda and Savient. Dr. Dalbeth hasreceived consultant fees, speaking fees, and/or honoraria(less than $10,000 each) from Takeda, Ardea, and Novartis,has received research funding from Fonterra, and holds apatent from Fonterra for milk products for gout. Dr. Niyyarhas received honoraria (less than $10,000) from the Amer-ican Society of Nephrology. Dr. Kerr has served as a studyinvestigator (more than $10,000 each) for Savient and Nuon.Dr. Edwards has received consultant fees, speaking fees,and/or honoraria (less than $10,000 each) from Savient,Takeda, Ardea, and Regeneron, and (more than $10,000)from Novartis, and has given expert testimony for Novartis.Dr. Mandell has received consultant fees, speaking fees,and/or honoraria (less than $10,000 each) from Savient,Novartis, and Pfizer. Dr. Schumacher has received consul-tant fees (less than $10,000 each) from Pfizer, Regeneron,West-Ward, and Ardea, and (more than $10,000) from No-vartis. Dr. Terkeltaub has received consultant fees (less than$10,000 each) from Takeda, Savient, Ardea, BioCryst, URL,Regeneron, Pfizer, Metabolex, Nuon, Chugai, EnzymeRx,Ajanta, Anadys, Celgene, Isis, and Prescription Solutions, and(more than $10,000) from Novartis, has received grant sup-port from the VA San Diego Healthcare System and the NIH,and has served as a paid investment consultant for LeerinkSwann, Medacorp, and Guidepoint.

Address correspondence to Robert Terkeltaub, MD, VAHealthcare System/University of California, San Diego,111K, 3350 La Jolla Village Drive, San Diego, CA 92161.E-mail: [email protected].

Submitted for publication January 9, 2012; accepted inrevised form June 15, 2012.

Significance & Innovations● Patient education on diet, lifestyle, treatment ob-

jectives, and management of comorbidities is arecommended core therapeutic measure in gout.

● Xanthine oxidase inhibitor (XOI) therapy with ei-ther allopurinol or febuxostat is recommended asthe first-line pharmacologic urate-lowering ther-apy (ULT) approach in gout.

● Serum urate level should be lowered sufficientlyto durably improve signs and symptoms of gout,with the target �6 mg/dl at a minimum, and often�5 mg/dl.

● The starting dosage of allopurinol should be nogreater than 100 mg/day and less than that in mod-erate to severe chronic kidney disease (CKD), fol-lowed by gradual upward titration of the mainte-nance dose, which can exceed 300 mg daily evenin patients with CKD.

● Prior to initiation of allopurinol, rapid polymerasechain reaction–based HLA–B*5801 screeningshould be considered as a risk management com-ponent in subpopulations where both the HLA–B*5801 allele frequency is elevated and the HLA–B*5801–positive subjects have a very high hazardratio (“high risk”) for severe allopurinol hypersen-sitivity reaction (e.g., Koreans with stage 3 orworse CKD and all those of Han Chinese and Thaidescent).

● Combination oral ULT with 1 XOI agent and 1uricosuric agent is appropriate when the serumurate target has not been met by appropriate dos-ing of an XOI.

● Pegloticase is appropriate for patients with severegout disease burden and refractoriness to, or intol-erance of, appropriately dosed oral ULT options.

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health-related quality of life are now better appreciated inmany gout patients, particularly those with multiple co-morbidities and/or chronic gouty arthritis (13,14). Despiteadvanced understanding of the molecular bases of hyper-uricemia and gouty inflammation and the extensive prac-tice experience of many providers, substantial quality ofcare gaps exist in gout management (15). Moreover, signif-icant shortfalls in patient education and adherence havebeen identified in gout (16).

On behalf of the American College of Rheumatology(ACR), we were charged with developing systematic non-pharmacologic and pharmacologic recommendations foreffective treatments in gout with an acceptable risk/benefitratio. Our assignment was to focus on 4 specific domainsin gout management. Two of these domains are addressedherein, i.e., urate-lowering therapy (ULT) and chronicgouty arthritis with tophaceous disease detected on phys-ical examination (designated by the ACR with the termi-nology “chronic tophaceous gouty arthropathy” [CTGA]and specifically represented in the fundamental case sce-narios 7–9 described herein). The remaining 2 domains(analgesic and antiinflammatory management of acutegouty arthritis and pharmacologic antiinflammatory pro-phylaxis of attacks of gouty arthritis) are addressed in part2 of the guidelines as a separate article (17).

There are multiple lines of epidemiologic and experi-mental evidence that hyperuricemia, via the effects ofexcess soluble urate, may play a role in some human renal,cardiovascular, and metabolic comorbidities also fre-quently associated with gout (7–10). We did not addresspharmacologic management of asymptomatic hyperurice-mia due to a paucity of prospective, randomized, con-trolled human research trials in that area (18).

We were charged by the ACR with developing goutrecommendations based on evidence as available, at aninternational level, for rheumatologists and other healthcare providers, including other subspecialists, primarycare practitioners, nurse practitioners, physician assis-tants, and allied health professionals. The ACR requestedthat we apply the established RAND/University of Califor-nia at Los Angeles (UCLA) Appropriateness Method (19) togenerate recommendations, and we engaged a diverse in-ternational panel of experts. Creating a novel classificationof gout as a disease, new gout diagnostic criteria, or adefinition of treatment outcomes was beyond the scope ofthis work. Instead, we generated multifaceted case scenar-ios to elucidate decision making based primarily on clin-ical and laboratory test–based data that can be obtained ona gout patient in an office practice setting.

Guidelines for gout management have been generated inthe last decade, at the national or multinational societylevel and independent of industry sponsorship, by theEuropean League Against Rheumatism (EULAR) (20,21),the Dutch College of General Practitioners (22), the Japa-nese Society of Gout and Nucleic Acid Metabolism (23),and the British Society for Rheumatology (BSR) (24).Moreover, the National Institute for Health and ClinicalExcellence single technology appraisal process has beenapplied to ULT in gout patients receiving febuxostat (25).New guidelines were requested by the ACR, since theunderstanding of gout risk factors has been greatly aug-

mented by recent clinical research (12). Moreover, ULToptions recently increased via clinical development anddrug regulatory agency approval of new pharmacologicagents (febuxostat and the biologic drug pegloticase)(26,27). New imaging approaches for gout that can detectradiographic changes of early disease not visualized byplain radiography (e.g., high-resolution ultrasound, dual-energy computed tomography [CT]) (28,29) are being in-vestigated for impact on gout diagnosis, assessment ofdisease burden and severity, and choices and effectivenessof management. Developments such as these are consid-ered in the work of this committee, which was built onseveral key assumptions (Table 1).

The ACR gout guidelines are designed to emphasizesafety and quality of therapy and to reflect best practice, asevaluated by a diverse group of experts that examined thelevel of evidence available at the time. Importantly, soci-etal cost of health care and cost and cost-effectivenessdifferences between therapies are excluded from analysisby the RAND/UCLA Appropriateness Method (19) (Table1). Individual results of this work are designated as “rec-ommendations” rather than guidelines, in order to reflectthe nonprescriptive nature of decision making evaluatedby experts and based on available evidence at the time.The recommendations cannot substitute for individual-

Table 1. Key assumptions in the process applied todevelop the recommendations

1. Recommendations were developed using the RAND/University of California at Los Angeles methodology,which assesses level of evidence and safety andquality, but does not take comparisons of cost andcost-effectiveness of therapies into consideration.

2. The guidelines focused on clinically-based decisionmaking in common scenarios and not on rare casepresentations.

3. Multiple scenarios were developed for acute treatmentand chronic gout for voting purposes and are NOTmeant to be disease classification criteria for gout.

4. The project did not list specific drug choices,contraindications, and dosing in the presence ofcomorbidities associated with gout or with potentialdrug–drug interaction. These decisions are left withthe practitioner, based on evaluation of the risk/benefitratio when prescribing each therapy, the drug dosingand safety labeling, and other widely availabledatabases and accessible sources of general medicalinformation about potential drug-related adverse

5. When a particular drug is not recommended, it doesnot imply that it is contraindicated. Similarly, if ahierarchy or sequence of a treatment is recommended,it does not necessarily imply that an agent lower in

6. It is assumed that the diagnosis of gout was correctbefore initiation of any management option.

7. It is not always possible for the task force panel toreach a consensus on a case scenario (seeSupplemental Figure 3 for examples of votingscenarios, available in the online version of this articleat http://onlinelibrary.wiley.com/journal/10.1002/

ACR Guidelines for Gout Management: Part 1 1433

ized direct assessment of the patient, coupled with clinicaldecision making by a competent health care practitioner.Treatment recommendations also assume appropriate at-tention to potential drug interactions (e.g., with anticoag-ulants, azathioprine, amoxicillin) and effects of comor-bidities such as diabetes mellitus and renal, cardiac,gastrointestinal, and hepatic disease (Table 1). The moti-vation, financial circumstances, and preferences of thegout patient play a very important role. Moreover, therecommendations for gout management presented here arenot intended to limit or deny third party payor coverage ofhealth care costs for groups or individual patients withgout.

Materials and methods

Project design, development of recommendations, andgrading of evidence. The overall design of the project isschematized in Supplemental Figure 1 (available in theonline version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). The RAND/UCLAconsensus methodology, developed in the 1980s, incorpo-rates both Delphi and nominal group methods (19,30), andwas successfully used to develop other guidelines com-missioned by the ACR. The purpose of this methodology isto reach a consensus among experts, with an understand-ing that published literature may not be adequate to pro-vide sufficient evidence for day-to-day clinical decisionmaking. The RAND/UCLA method requires 2 groups ofexperts: a core expert panel (CEP) that provides input intocase scenario development and preparation of a scientificevidence report, and a task force panel (TFP) that voteson these case scenarios. Our CEP consisted of leaders foreach domain (see Supplemental Figure 2, available inthe online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Pharmaco-logic approaches and diet, lifestyle, and nonpharmaco-logic measures (e.g., weight loss, exercise) were addressedwithin each domain. The CEP leaders communicated withan international panel of gout experts and the principalinvestigators (PIs; JDF, PPK, DK, RT) to develop initial casescenarios that reflect broad differences in severity of thedisease and its clinical manifestations. In addition, therewere weekly interactive teleconferences between the do-main leaders and PIs to refine case scenarios. Although aprevious systematic review for gout has been performed byEULAR, as a prime example, we performed our own sys-tematic review of pertinent literature. The resultant scien-tific evidence report was given to the TFP in conjunctionwith clinical scenarios representing differing degrees ofdisease activity. There were multiple questions of interestand alternative options presented for each case scenario.

By ACR mandate, the TFP had a majority of memberswithout a perceived potential conflict of interest (COI),and had diverse experience and expertise, as described indetail in Supplemental Figure 2 (available in the onlineversion of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). The TFP included 7rheumatologists (including 1 Chair of Internal Medicineand 1 Internal Medicine Residency Training Program Di-rector), 2 primary care physicians, a nephrologist, and a

patient representative. There were 2 rounds of ratings, thefirst anonymous, with the members of the TFP instructedto rank each of the potential elements of the guidelines ona risk/benefit basis ranging from 1–9 on a Likert scale usingthe Delphi process, followed by a face-to-face group dis-cussion and then revoting of the same scenarios. A vote of1–3 on the Likert scale was rated as inappropriate (risksclearly outweigh the benefits), a vote of 4–6 was consid-ered uncertain (risk/benefit ratio is uncertain), and a voteof 7–9 was rated as appropriate (benefits clearly outweighthe risks). Samples of votes taken and results are providedin Supplemental Figure 3 (available in the online versionof this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Votes on case scenarios weretranslated into recommendations if the median votingscore was graded 7–9 (appropriate) and if there was nosignificant disagreement, defined as no more than 1 of 3 ofthe votes graded as inappropriate for the scenario. Thefinal rating was done anonymously in a 2-day face-to-facemeeting, facilitated by an experienced moderator (NW).During the face-to-face TFP meeting, some case scenarioswere clarified for content or verbiage and revoted on by the

The level of evidence supporting each recommendationwas ranked based on previous methods used by the Amer-ican College of Cardiology (31) and applied to recent ACRrecommendations (32,33). Level A grading was assigned torecommendations supported by multiple (i.e., �1) ran-domized clinical trials or meta-analyses. Level B gradingwas assigned to the recommendations derived from a sin-gle randomized trial or nonrandomized studies. Level Cgrading was assigned to consensus opinion of experts, case

PubMed and the Cochrane CentralRegister of Controlled Trials from the 1950s to the presentwere searched to find articles on gout with the help of anexperienced librarian. We used a search strategy based onthe Cochrane Highly Sensitive Search Strategy for identi-fying randomized trials. The search was expanded to in-clude articles discussing research designs such as cohort,case–control, and cross-sectional studies. Limits includedEnglish language and the exclusion of “animal only” stud-ies. The exact terms, process, and results of the search aresummarized in Supplemental Figure 4 (available in theonline version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Clinical case descriptions. The TFP evaluated clinicalscenarios with differences in frequency of acute goutsymptoms and differences related to the presence or extentof chronic findings (tophi, synovitis) on physical exami-nation, similar to what a clinician might see in a busypractice. Scenarios were divided into mild, moderate, andsevere disease activity in each of 3 distinct “treatmentgroups” (Figures 1A and B). In generating these 9 funda-mental clinical case scenarios, mild disease activity levelsin each treatment group were meant to represent patientsat the lowest disease activity level for which most clini-cians would consider initiating or altering a specific med-

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ication regimen. Conversely, the severe disease activitylevel was intended to represent patients with disease ac-tivity greater than or equal to that of the “average” subjectstudied in a clinical trial. The case scenarios were notintended to serve as classification criteria. To allow theTFP to focus on management decisions, each case scenariohad the assumption that the diagnosis of gout was correct.In addition, it was assumed that there was some clinicalevidence of gout disease activity. This included intermit-tent symptoms of variable frequency, specifically pre-

sented to the TFP as episodes of acute gouty arthritis of atleast moderate to severe pain intensity (17). Other clinicalevidence of gout disease activity, presented to the TFP inspecific case scenarios, was tophi detected by physicalexamination, or alternatively, chronic symptomatic arthri-tis (i.e., “chronic arthropathy” or “synovitis”) due to gout,with or without confirmed joint damage (e.g., deformity,erosion due to gout on an imaging study) (Figure 2). Hy-peruricemia was defined here as a serum urate level �6.8mg/dl (2). We determined all aspects of case scenariodefinitions by a structured iterative process, using regulare-mail and teleconferences at least once per month. Mul-tiple revisions to the proposed parameters were carriedout, until accepted by the CEP domain leaders.

Definitions of pharmacologic therapeutic agents. Med-ication classes evaluated in the case scenarios were de-fined as follows: xanthine oxidase inhibitor (XOI) refersto allopurinol or febuxostat, and uricosuric agents weredefined to include agents available in the US (probene-cid and off-label use [as uricosuric therapy] of fenofi-brate and losartan), but did not include sulfinpyrazone orbenzbromarone. Other agents and modalities were self-explanatory. Evaluation by the TFP of effectiveness of agiven therapeutic option assumed that patients in the casescenarios received the maximum tolerated typical dose fora period of time sufficient to accurately assess therapeuticresponse, unless otherwise indicated.

Managing perceived potential COI. Perceived potentialCOI was managed in a prospective and structured manner.Specifically, all participants intellectually involved in theproject, whether authors or not, were required to fully andprospectively disclose relationships with pharmaceuticalcompanies with a material interest in gout (see Supple-mental Figure 2 and Appendix A, available in the onlineversion of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Disclosures were up-dated every 6 months, and for the PIs, CEP, and TFP,updated just prior to the face-to-face meeting. A summarylisting of all perceived potential COI was disseminated toall participants in the project, and is available in Supple-mental Appendix A (available in the online version of thisarticle at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Based on the policies of the ACR,which are aligned with those of many medical societies,no more than 49% of the project participants could have aCOI at any given time. It was required that the project PI(JDF) remain without perceived potential COI prior to andduring the process.

Results

Primary principles of management for all gout casescenarios. The TFP generated recommendations for a sys-tematic nonpharmacologic and pharmacologic manage-ment approach intended to be applicable to all patientswith gout, which is summarized in Figure 3. This wasbased on the assumption that the diagnosis of gout wascorrect before initiation of management. The approachhighlighted patient education on the disease and treat-

Figure 1. Fundamental case scenarios evaluated by the task forcepanel (TFP). The TFP evaluated a broad spectrum of severity ofgout, with presenting clinical information comparable to thatencountered in practice. Scenarios were formulated iteratively bythe core expert panel, as described in the text, and were notintended to serve as disease classification criteria. All case sce-narios assumed that the diagnosis of gout was correct, and thatthere was some evidence of gout disease activity. Three distinct“treatment groups” for these recommendations, each with 3 casescenarios designed to succinctly represent clinically-based deci-sion making and totaling 9 in all, are shown. The treatment groupwith intermittent attacks of acute gout but no tophi detected onphysical examination was subdivided based on increasing yearlyfrequency of episodes of acute gouty arthritis of at least moderateto severe pain intensity (case scenarios 1–3;with clinically apparent high body urate burden was evaluated incase scenarios where there weretion, and either A, intermittently symptomatic acute gouty arthri-tis (case scenarios 4–6), or B, chronic joint symptoms due tosynovitis attributable to gout or articular tophus or tophi in casescenarios 7–9 (the domain termed chronic tophaceous gouty ar-thropathy [CTGA]). Severity of case scenarios in the CTGA do-main was distinguished by extent and characteristics of the tophiand chronic arthropathy, with variable inflammatory and deform-ing features detected on physical examination (see Figure 2).

ACR Guidelines for Gout Management: Part 1 1435

ments and their objectives, and initiation of diet and life-style recommendations, including the particular role ofuric acid excess in gout and as the key long-term treatmenttarget (evidence B) (34). The TFP also recommended, on acase-by-case basis, careful consideration of potential elim-ination of serum urate–elevating prescription medicationsthat might be nonessential for the optimal management ofcomorbidities (e.g., hypertension, hyperlipidemia, or ma-jor organ transplant) in a given patient. Prime examples ofurate-elevating medications are thiazide and loop diuret-ics, niacin, and calcineurin inhibitors (evidence C). How-ever, the TFP, without a specific vote, recognized the par-ticular benefits of thiazides for blood pressure control andoutcomes in many patients with hypertension. Althoughlow-dose acetylsalicylic acid (aspirin �325 mg daily) ele-vates serum urate, the TFP did not recommend discontin-

uation of this modality as cardiovascular disease prophy-laxis in gout patients. In discussion, without a specificvote, the TFP viewed the relative risks specifically attrib-utable to the modest effects of low-dose aspirin on serumurate as negligible in gout management.

The TFP recommended that clinicians consider causesof hyperuricemia for all gout patients, and recommended aspecific comorbidity checklist (evidence C) (Table 2). Indoing so, the TFP specially recommended consideration,and if indicated, medical evaluation of certain agents anddisorders that cause uric acid underexcretion or overpro-duction, which thereby could merit laboratory investiga-tions such as urinalysis, renal ultrasound, a completeblood cell count with differential cell count, or urine uricacid quantification, as indicated. In this context, the TFPspecifically recommended screening for uric acid overpro-

Figure 2. Detailed pictorial representations of chronic arthropathy in chronic tophaceous gouty arthropathy (CTGA) case scenariospresented to the task force panel (TFP). A core element of our approach was to present the TFP and the readership with specifically detailedsummaries of the CTGA case scenarios (case scenarios 7–9 in Figure 1B), including pictorial examples, to allow focus on clinicalinformation that prompts management decisions. The photograph on the top left was provided by Dr. Robert Terkeltaub; the photographson the top and bottom right were provided by Dr. Fernando Perez-Ruiz.

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Figure 3. Baseline recommendations and overall strategic plan for patients with gout.This algorithm summarizes overall treatment strategies and flow of management deci-sions for gout. Certain elements, including nonpharmacologic and pharmacologic mea-sures, the approach to refractory disease, and treatment and antiinflammatory prophy-laxis of acute gout attacks, are developed further in Tables 2–4 and Figures 4 and 5, andin part 2 of the guidelines, as referenced in the figure. Evidence grades (A–C, as indicated)are summarized for each task force panel (TFP) recommendation, and the text discussesin detail each aspect of clinical decision making. ULT � urate-lowering therapy; CKD �chronic kidney disease; CrCl � creatinine clearance.

ACR Guidelines for Gout Management: Part 1 1437

duction (by urine uric acid evaluation) in patient subsetswith gout clinical disease onset before age 25 years (evi-dence C) or a history of urolithiasis (evidence C).

The TFP provided guidance for referral to a specialist,with caution to avoid appearing self-serving. Althoughlimited by the absence of outcomes data on potential ben-efits of referral, the TFP recommended that gout case sce-narios including any of the following should be amongthose where referral to a specialist is considered (evidenceC for all): 1) unclear etiology of hyperuricemia; 2) refrac-tory signs or symptoms of gout; 3) difficulty in reaching thetarget serum urate level, particularly with renal impair-ment and a trial of XOI treatment; and 4) multiple and/orserious adverse events from pharmacologic ULT.

Clinical evaluation of gout disease activity and burden.The TFP recommended clinical evaluation of gout diseasesymptom severity and burden in individual patients byhistory and a thorough physical examination for symp-toms of arthritis and signs such as tophi and acute andchronic synovitis (evidence C). To be actionable by clini-cians, the authors without a specific TFP vote suggestedthat clinicians can work with patients to record and esti-mate the number per year and severity (17) of acute attacksof gouty arthritis per year.

Core recommendations for nonpharmacologic ULTmeasures in gout. The TFP recommended certain diet andlifestyle measures for the majority of patients with gout(evidence B and C for individual measures) (Figure 4).Many of the diet and lifestyle measures were recom-mended for decreasing the risk and frequency of acute goutattacks (12) and lowering serum urate levels, but the pri-mary emphasis of the TFP recommendations in Figure 4

was on diet and lifestyle choices for promotion and main-tenance of ideal health and prevention and optimal man-agement of life-threatening comorbidities in gout patients,including coronary artery disease (35,36) and obesity, met-abolic syndrome, diabetes mellitus, hyperlipidemia, andhypertension.

Dietary recommendations were grouped into 3 simplequalitative categories, termed “avoid,” “limit,” or “encour-age” (Figure 4). This approach, with rare exceptions(37,38), reflected a general lack of specific evidence fromprospective, blinded, randomized clinical intervention tri-als that linked consumed quantities of individual dietarycomponents to changes in either serum urate levels or goutoutcomes. Notably, the replication of hazardous lifestylerisk factors in a conventional clinical research trial wouldpotentially pose both design and ethical difficulties. Assuch, the TFP deliberated on evidence regarding the im-pact of exposures to alcohol or purine-rich foods in a shorttimeframe. The evidence sources were epidemiologicstudies of hyperuricemia and incident gout, includinglong-term prospective analyses (39–42) and internet-based case-crossover studies of specific exposures (43,44).The TFP recommended that gout patients limit their con-sumption of purine-rich meat and seafood (evidence B)(44) as well as high fructose corn syrup–sweetened softdrinks and energy drinks (evidence C), and encouraged theconsumption of low-fat or nonfat dairy products (evidenceB) (43) (Figure 4). The TFP voted to encourage vegetableintake in gout patients (evidence C) (Figure 4), havingconsidered evidence in healthy subjects for lowered serumurate levels and urine urolithiasis risk factors associatedwith dietary vegetable intake (43,45). However, there wasno specific TFP vote on the question of avoidance of excesspurine intake from food sources other than meat and sea-food, such as vegetables and legumes, in gout patients (44).The TFP recommended reduced consumption of alcohol(particularly beer, but also wine and spirits) and avoidanceof alcohol overuse in all gout patients (evidence B) (Figure4). The TFP further recommended abstinence from alcoholconsumption for gout patients during periods of activearthritis, especially with inadequate medical control of thedisorder and in CTGA (evidence C) (46). Significantly, indiscussion by the TFP, without a specific vote, the TFPrecognized that diet and lifestyle measures alone providetherapeutically insufficient serum urate–lowering effectsand/or gout attack prophylaxis for a large fraction of indi-viduals with gout (12). For example, some clinical trials ondiet and fitness have reported only an �10–18% decreasein serum urate (43). In further discussion by the TFP, againwithout a specific vote, the TFP viewed this degree ofserum urate level lowering as beneficial for all case sce-narios, but insufficient to achieve an effective serum uratetarget in those with sustained hyperuricemia substantiallyabove 7 mg/dl.

Core recommendations for pharmacologic ULT, includ-ing the serum urate target. Here, and with all other rec-ommendations for drug therapy in parts 1 and 2 of the2012 ACR guidelines for gout, the recommendations as-sumed a lack of contraindications, intolerance, seriousadverse events, or drug–drug interactions for given agents.

Table 2. Specific recommendation of a comorbiditychecklist for gout patients

Appropriate to consider in the clinical evaluation, and ifclinically indicated, to evaluate (evidence C for all)*

Obesity, dietary factorsExcessive alcohol intakeMetabolic syndrome, type 2 diabetes mellitusHypertension†Hyperlipidemia, modifiable risk factors for coronary

artery disease or strokeSerum urate–elevating medications†History of urolithiasisChronic kidney, glomerular, or interstitial renal disease

(e.g., analgesic nephropathy, polycystic kidney disease)In selected cases, potential genetic or acquired cause of

uric acid overproduction (e.g., inborn error of purinemetabolism or psoriasis, myeloproliferative, orlymphoproliferative disease, respectively)

Lead intoxication

* Evidence grades for recommendations: level Amultiple (i.e., �1) randomized clinical trials or meta-analyses; levelB � derived from a single randomized trial or nonrandomizedstudies; level C � consensus opinion of experts, case studies, orstandard of care.† The task force panel, without a specific vote, recognized theparticular benefits of thiazide diuretics for blood pressure controland outcomes in many patients with hypertension.

1438 Khanna et al

The TFP recommended gout with CKD stage 2–5 or end-stage renal disease as an appropriate indication, by itself,for pharmacologic ULT (evidence C) in patients with priorgout attacks and current hyperuricemia. In pharmacologicULT, certain treatment choices (e.g., probenecid) and drugdosing decisions (e.g., allopurinol) are impacted by thecreatinine clearance. The TFP, without a direct vote, dis-cussed and recognized the clinical value of accurate mea-surement of creatinine clearance, not simply the serumcreatinine, in ascertaining the degree of renal impairment.However, the scope of the project did allow for detailedprescriptive recommendations regarding specific ULTdrug doses, usage of individual agents in the presence of agiven degree of either renal impairment, or other comor-bidities such as hepatic impairment.

TFP recommendations for pharmacologic ULT, showngraphically in Figure 3, included recommendation of XOItherapy with either allopurinol or febuxostat as the first-line pharmacologic approach (evidence A). The panel didnot preferentially recommend either XOI over the otherXOI drug. In doing so, the TFP weighed the lack of pub-lished safety data for febuxostat in the setting of stage 4 orworse CKD. Probenecid was recommended as an alterna-tive first-line pharmacologic ULT option in the setting ofcontraindication or intolerance to at least 1 XOI agent(evidence B). However, the TFP did not recommend pro-benecid as a first-line ULT monotherapy in those with acreatinine clearance below 50 ml/minute.

The TFP recommended that pharmacologic ULT couldbe started during an acute gout attack, provided that effec-

Figure 4. Specific task force panel (TFP) recommendations on general health, diet, and lifestyle measures for gout patients. The TFPrecommendations on nonpharmacologic measures for gout patients are shown, including a program of broad diet and lifestyle measures.The recommendations encompass measures not only for decreasing the risk and frequency of acute gout attacks and lowering serum urate,but also with a major emphasis on maintenance of ideal health and prevention and best practice management of cardiovascular andmetabolic diseases. Dietary recommendations were grouped into 3 simple qualitative categories, termed “avoid,” “limit,” and “encourage,”reflecting a general lack of specific evidence from prospective, blinded, randomized clinical intervention trials linking consumedquantities of individual dietary components to changes in either serum urate or to gout signs and symptoms. Specific TFP votes on dietarycomponents resulting in a “lack of consensus” are also cited. BMI � body mass index.

ACR Guidelines for Gout Management: Part 1 1439

tive antiinflammatory management has been instituted(evidence C). The TFP recommended regular monitoringof serum urate (every 2–5 weeks) during ULT titration,including continuing measurements once the serum uratetarget is achieved (every 6 months; evidence C). The TFPweighed this measure as particularly useful to monitoradherence, given that poor adherence to ULT is a commonproblem in gout patients (16).

The TFP recommended that the goal of ULT is to achievea serum urate level target at a minimum of �6 mg/dl in allgout case scenarios (evidence A). Moreover, the TFP rec-ommended that the target serum urate level should belowered sufficiently to durably improve signs and symp-toms of gout, including palpable and visible tophi detectedby physical examination, and that this may involve ther-apeutic serum urate level lowering to below 5 mg/dl (evi-dence B).

Recommendations specific to allopurinol dosing andpharmacogenetics. TFP recommendations for use of allo-purinol in gout are summarized in Table 3. Importantly,the TFP recommended that the starting dosage of allopuri-nol should be no greater than 100 mg per day (evidence B)(47), consistent with prior Food and Drug Administration(FDA) and EULAR guidelines (21). The rationale of theTFP was partly that a low allopurinol starting dose couldreduce early gout flares after ULT initiation (26), andpartly as a component of risk management with respect tothe potential for severe hypersensitivity reaction to allo-purinol (47), discussed in further detail below. The TFPrecommended gradual upward titration of the allopurinolmaintenance dose every 2–5 weeks to an appropriate max-imum dose for gout, in order to treat to the serum uratetarget appropriate for the individual patient (evidence C).

The TFP weighed robust evidence that allopurinolmonotherapy at doses of 300 mg or less daily failed toachieve the serum urate level target of�5 mg/dl (48,49) in more than half of the subjects withgout. The TFP reviewed small studies in which the allo-purinol dose was titrated above 300 mg daily in gout withoverall success in achieving the serum urate target (49,50).Importantly, in doing so, the TFP also recommended thatthe maintenance dosage of allopurinol can be raised above300 mg per day, even in those with renal impairment,provided there is adequate patient education and regularmonitoring for drug hypersensitivity and other adverseevents, such as pruritis, rash, and elevated hepatictransaminases, as well as attention to potential develop-ment of eosinophilia (evidence B).

The TFP next considered the issue of measures to reducethe incidence of severe allopurinol hypersensitivity reac-tions, here termed allopurinol hypersensitivity syndrome(AHS). TFP discussion recognized the potential for hospi-talization and severe morbidity and the reported mortalityrate of 20–25% in AHS (51,52). The estimated incidence ofAHS is �1:1,000 in the US, and its spectrum includes notonly Stevens-Johnson syndrome and toxic epidermalnecrolysis, but also systemic disease with a clinical con-stellation of features such as eosinophilia, vasculitis, rash,and major end-organ disease (53). Concurrent thiazide useand renal impairment have been implicated as risk factors

for AHS (50,54,55). A widely employed risk managementstrategy has been a non–evidence-based algorithm for al-lopurinol maintenance dosing, calibrated to renal impair-ment (evidence C) (56); importantly, the TFP did not rec-ommend this strategy.

In their evaluation of the allopurinol starting dose as acomponent of risk management strategy, the TFP firstweighed evidence that the highest risk of severe allopuri-nol hypersensitivity reaction is in the first few months oftherapy. A recent case–controlled retrospective analysis ofAHS and allopurinol starting dose (47) further supportedthe aforementioned recommendation by the TFP of a start-ing dose of allopurinol of no more than 100 mg daily, andthe TFP recommendation of an even lower starting dose ofallopurinol (50 mg daily) in stage 4 or worse CKD (evi-dence B).

Table 3. Core recommendations in the use of allopurinoland uricosuric ULT in gout*

AllopurinolStarting dosage should be no greater than 100 mg/day

for any patient, and start at 50 mg/day in stage 4 orworse CKD (evidence B)

Gradually titrate maintenance dose upward every 2–5weeks to appropriate maximum dose in order totreat to chosen SUA target (evidence C)

Dose can be raised above 300 mg daily, even withrenal impairment, as long as it is accompanied byadequate patient education and monitoring for drugtoxicity (e.g., pruritis, rash, elevated hepatictransaminases; evidence B)

Prior to initiation, consider HLA–B*5801 in selectedpatients, specifically in subpopulations at higherrisk for severe allopurinol hypersensitivity reaction(e.g., Koreans with stage 3 or worse CKD, and HanChinese and Thai irrespective of renal function;

Probenecid is the first choice among uricosuric agentsfor ULT monotherapy (evidence B)

In gout patients with a creatinine clearance �50 ml/minute, probenecid is not recommended as first-lineULT monotherapy (evidence C)

Use of agents other than probenecid with clinicallysignificant uricosuric effects, such as fenofibrate andlosartan, can be therapeutically useful ascomponents of a comprehensive ULT strategy

History of urolithiasis contraindicates first-lineuricosuric urate-lowering monotherapy (evidence C)

Urinary uric acid should be measured before initiation

Elevated urine uric acid indicative of uric acidoverproduction contraindicates uricosuric ULT

Continue to monitor urinary uric acid during

Consider urine alkalinization (e.g., with potassiumcitrate) with monitoring of urine pH, in addition toincreased fluid intake, as a risk management strategy

� chronic kidney disease;

1440 Khanna et al

Figure 5. Case scenario–specific escalation of pharmacologic urate-lowering therapy (ULT) in gout, including approach to refractorydisease. The figure, which accompanies Table 4, shows task force panel (TFP) recommendations for patients with continuing gout diseaseactivity and focuses on escalating pharmacologic ULT measures, particularly for refractory disease. Each of the fundamental case scenariosis considered. Case scenario numbering of 1–9 refers to those gout clinical scenarios specifically detailed in Figures 1A and B above. Thechronic tophaceous gouty arthropathy (CTGA) case scenarios numbered 7–9 are additionally shown in photographs in Figure 2. Theserecommendations specifically assume that for each case scenario: 1) the serum urate target needed to achieve improved gout signs andsymptoms has not yet been achieved, 2) appropriate nonpharmacologic ULT measures have been applied, and 3) appropriate treatment andantiinflammatory prophylaxis are employed for attacks of acute gouty arthritis. Evidence grades for individual TFP votes to recommendthat are shown here are summarized in the text. In the figure, the decision-making symbol indicates therapeutic appropriateness, with �indicative of either a therapeutically inappropriate measure or one with uncertain risk:benefit ratio. The decision-making symbol �indicates that the TFP recommended this therapeutic measure as appropriate only in specific conditions in a clinical scenario, marked bythe symbol § or ¶ that refers to particular circumstances described below the figure. CKD chronic kidney disease; ESRD � end-stage renaldisease; XOI � xanthine oxidase inhibitor.

Table 4. Summary of recommendations for case scenarios of refractory disease in gout (Figure 5), including combination oralULT and use of pegloticase*

Attempt upward dose titration of 1 XOI to respective maximum appropriate dose (evidence A)Febuxostat can be substituted for allopurinol or vice versa in the event of drug intolerance and adverse events, and such a

substitution should be considered after initial failure of upward dose titration of 1 XOI (evidence C)†Effective therapeutic options include addition of a uricosuric agent (e.g., probenecid, fenofibrate, or losartan) to an XOI drug

(evidence B) or vice versa (evidence C)Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, conventional and

appropriately dosed ULT (evidence A)‡Pegloticase therapy is not recommended as first-line ULT agent for any case scenariosLACK OF CONSENSUS: appropriate duration of pegloticase therapy relative to intended and achieved decrease in symptoms

and signs of gout, including decrease in tophus size

* ULT � urate-lowering therapy; XOI � xanthine oxidase inhibitor.† Important drug label information includes that febuxostat and allopurinol should not be used in combination with each other.‡ Important drug label information includes that pharmacologic oral ULT agents should be discontinued during the course of pegloticase therapy toavoid masking the loss of a pegloticase serum urate–lowering effect associated with an increased risk of pegloticase infusion reactions.

ACR Guidelines for Gout Management: Part 1 1441

The TFP also weighed the rapidly emerging area ofpharmacogenetics to screen for AHS (53,57,58), and rec-ommended that, prior to initiation of allopurinol, HLA–B*5801 testing should be considered in select patient sub-populations at an elevated risk for AHS (evidence A).Those with HLA–B*5801 and of Korean descent with stage3 or worse CKD (HLA–B*5801 allele frequency �12%), orof Han Chinese or Thai extraction irrespective of renalfunction (HLA–B*5801 allele frequency �6–8%), havebeen highlighted in the literature as prime examples ofsubjects at high risk for AHS, marked by HLA–B*5801hazard ratios of several hundred (59–61). Such high-riskindividuals were recommended to be prescribed an alter-native to allopurinol if HLA–B*5801 positive (evidence A).The TFP recommended that the HLA–B*5801 screening bedone by the rapid, widely available polymerase chain re-action (PCR)–based approach (evidence A) that, in only�10% of tests, requires more cumbersome followup HLA–B*5801 sequencing for inconclusive results. Significantly,the TFP did not recommend universal HLA–B*5801 allo-purinol screening. Current evidence informing this TFPdecision included that whites with an HLA–B*5801 prev-alence of �2% had a substantially lower HLA–B*5801hazard ratio and negative predictive value of the test thanin the aforementioned Asian subpopulations (53,58,62).

Recommendations specific to primary uricosuric urate-lowering monotherapy.suric monotherapy was employed as a primary ULT mo-dality (Table 3), probenecid was recommended by the TFPas the first choice among uricosuric drugs currently avail-able in the US (evidence B). The TFP recommended that ahistory of urolithiasis contraindicates first-line use of apotent uricosuric agent for ULT (evidence C), given thatprobenecid (and benzbromarone, which is unavailable inthe US) was associated with anasis (63,64). Specific TFP recommendations for risk man-agement in uricosuric ULT also included initial measure-ment and monitoring of urine uric acid, and that anelevated urine uric acid level indicative of uric acid over-production contraindicates uricosuric ULT. There was noTFP consensus on assay of undissociated urine uric acid,or use of Simkin’s Index and similar calculation on spoturine, in risk management in uricosuric therapy (63). TheTFP did recommend that when initiating uricosuric ULT,patients should also be instructed to increase fluid intakeand consider urine alkalinization (e.g., with potassiumcitrate; evidence C for all) (63), but no quantitative param-eters were voted on for these measures, in view of lack ofevidence.

Recommendations on pharmacologic ULT decisionmaking in gout, including case scenarios with mild, mod-erate, or severe disease activity or CTGA. The TFP votedon clinical decision making in each of the 9 case scenarioswhen the serum urate target had not yet been met andunder circumstances where gout remained symptomatic(i.e., where there were 1 or more continuing clinical signsand symptoms of gout, such as recent acute gout attacks,tophi, and chronic gouty arthritis) (Figure 5 and Table 4).

In doing so, the TFP, in limited voting scenarios, firstconsidered the potential role of imaging in the evaluationof disease burden and clinical decision making on ULTgout. The TFP recommended the utility of high-resolutionultrasound, CT, or dual-energy CT (evidence B) to detecttophi, and the utility of plain radiographic findings con-sistent with tophi (such as characteristic bone erosion;evidence C). The TFP also voted that the ultrasound “dou-ble contour sign” was consistent with nontophaceousurate crystal deposition on the surface of articular cartilage(evidence B). However, the TFP did not recommend use ofthe double contour sign as a sufficient indicator for initi-ating or increasing the intensity of ULT, given that the signwas detected in joints of �25% subjects with asymptom-atic hyperuricemia in a recent study (65). Conversely, in arecent study, the double contour sign was not universally

33% of subjects in an ultra-sound survey of multiple joints in each subject) in patientswith early gout not receiving ULT (66).

For all 9 case scenarios when the serum urate target hasnot been met, the TFP recommended upward dose titra-tion of 1 XOI (allopurinol or febuxostat) to the respectivemaximum appropriate dose for the individual patient (ev-idence A) (Figure 5 and Table 4). The maximum FDA-approved dose of allopurinol is 800 mg daily, and forfebuxostat is 80 mg daily. Given the request for an inter-national frame of the gout guidelines by the ACR, the TFPrecommended increasing febuxostat up to 120 mg daily, adose approved in many countries outside the US, in thespecific scenario of active disease refractory to appropri-ately dosed oral ULT (evidence A). The TFP further rec-ommended, and broadly so in the 9 case scenarios, that ifupward titration of the initial XOI agent was not toleratedor did not achieve the serum urate target, substitution ofanother XOI was an appropriate first-line option (evidence

Notably, the TFP recommended probenecid and otheragents with clinically significant uricosuric effects, such asfenofibrate and losartan, as therapeutically useful in acomprehensive ULT program in refractory disease (evi-dence B). Specifically, the TFP recommended a combina-tion oral ULT approach (i.e., 1 XOI agent [allopurinol orfebuxostat] and 1 uricosuric agent [probenecid, fenofi-brate, or losartan being the currently available agents inthe US]) as an option when the serum urate target has notbeen met across the 9 case scenarios (evidence B) (67–69)(Figure 5 and Table 4).

Last, the TFP recommended pegloticase as appropriateonly in the case scenarios with severe gout disease burdenand refractoriness to, or intolerance of, appropriatelydosed oral ULT options (evidence A) (Figure 5 and Table4). In 2 large placebo-controlled randomized clinical trials,pegloticase 8 mg every 2 weeks was effective in reducingthe serum uric acid level to �6 mg/dl in 42% of patientsversus 0% in the placebo group at 6 months (27). In addi-tion, 45% of patients receiving pegloticase 8 mg every 2weeks had complete resolution of 1 or more tophi versus8% in the placebo group, with significant improvement inchronic arthropathy and health-related quality of life. Im-portantly, the TFP did not recommend pegloticase as afirst-line ULT for any case scenarios. The TFP also did not

1442 Khanna et al

achieve consensus on the appropriate duration of pegloti-case therapy once decreased symptoms and signs of gout,including decrease in size (or resolution) of tophi on clin-ical examination, had been achieved.

DiscussionWe present the first ACR evidence- and consensus-basedpharmacologic and nonpharmacologic management rec-ommendations for gout, the product of a formal groupconsensus process. The thorough systematic review ofthe literature essential to this project was timely. Compa-rable gout guidelines independently (i.e., not developedwith pharmaceutical company support) assembled at thelevel of national and multinational rheumatology societiesin the last decade by EULAR and the BSR did not com-prehensively evaluate newer evidence and therapies, in-cluding febuxostat and pegloticase (21,24). The ACR-sponsored work presented here in part 1 of the guidelinesfocused on systematic disease management and urate-lowering measures in all gout patients and in refractorydisease, including CTGA. The work first addressed coreaspects of patient education, which includes discussionwith the patient of the role of uric acid excess in gout andas key long-term treatment target, and impacts heavily onULT treatment adherence and ultimate efficacy (34). Basedon the existing evidence in patients with gout, the TFP wasable to generate a set of diet and lifestyle recommendationsfor gout, but the recommendations are dominated or su-perseded, for good reason, by diet and lifestyle recommen-dations for life-threatening comorbidities common in goutpatients, such as atherosclerosis, diabetes mellitus, andhypertension. There was only limited advice on specificserving sizes and quantities, as was the case for prior goutrecommendations of this nature (21). Clearly, more re-search is needed in diet and lifestyle modifications forgout, especially for direct intervention studies (34).

The TFP also recommended that all gout patients have athorough clinical evaluation of disease activity and bur-den, and appropriate attention to possible etiologies ofhyperuricemia in each patient, with potential modificationof secondary causes of hyperuricemia such as comorbidi-ties and specific medications that elevate serum urate.However, the TFP did not vote on specific indications foremploying imaging studies to assess disease burden ortreatment responses in gout. This issue should be updatedin the next few years, as more studies appear on the use ofhigh-resolution ultrasound and dual-energy CT that mayinform disease classification and prognosis in gout, and asmore outcomes data emerge on ULT-induced alterations inimaging findings of gout (70).

Specific TFP recommendations on indications for phar-macologic ULT initiation were accompanied by novel TFPrecommendations that either allopurinol or febuxostat isappropriate as the first line of pharmacologic ULT, al-though the issue of allopurinol nontitration in comparisonto clinical trial designs for these agents was recognized.Probenecid was recommended as an alternative first-linetherapy if at least 1 XOI drug was contraindicated or nottolerated, but probenecid monotherapy was not recom-mended as a first-line approach in those with a creatinineclearance less than 50 ml/minute. In discussion, TFP res-

ervations on probenecid included lack of data on long-term safety and efficacy in stage 3 CKD (given that creati-nine clearance �50 ml/minute was an exclusion criterionin some studies [48,69]). Reservations also included mul-tiple drug interactions, the �9% risk of urolithiasis, andthe complexity of risk management in dose escalation ofprobenecid ULT as a monotherapy. There was an unex-pected lack of TFP consensus on ideal approaches to mon-itor uric acid excretion to lessen the risk of urolithiasis riskmanagement during probenecid ULT as monotherapy.

Treating to a serum urate target was evaluated in detail.The TFP consolidated previous EULAR and BSR recom-mendations (21,24), here recommending that serum urateshould be lowered in patients with gout to achieve, at aminimum, a serum urate level �6 mg/dl. In those withgreater disease severity and urate burden, such as thosewith tophi detected on physical examination and withCTGA, the TFP recommended that the serum urate levelmay need to be lowered below 5 mg/dl to achieve better

Dosing, efficacy, and safety of allopurinol were ad-dressed at length, since allopurinol is the most commonlyprescribed ULT worldwide. First, TFP recommendationsreinforced both the previous EULAR guidelines (21) andFDA guidance for risk management to initiate allopurinolat no more than 100 mg daily, and to start allopurinol at 50mg daily in patients with stage 4 or worse CKD. Second,the TFP recommended steady upward titration of allopuri-nol soon after initiation, accompanied by adequate patienteducation and monitoring for drug toxicity. Recent clinicaltrial evidence that allopurinol doses of 300 mg or less dailyfail to achieve target serum urate in the majority of goutpatients informed the TFP recommendation that, with ap-propriate risk management, allopurinol can be advancedabove 300 mg daily to achieve the serum urate target,including in patients with CKD. The TFP, for all degrees ofrenal impairment, did not recommend the AHS risk man-agement strategy of Hande et al (56), in which a non–evidence-based algorithm for allopurinol maintenancedosing had been calibrated to renal impairment. However,the authors, without a specific TFP vote, are concernedabout the lack of long-term safety data for allopurinoldosing above 300 mg daily, particularly with significantrenal impairment, which is associated with increased al-lopurinol toxicity (50,71).

The TFP also made the novel recommendation thatrapid PCR-based HLA–B*5801 screening should be con-sidered as a risk management component in subpopula-tions where both the HLA–B*5801 allele frequency is el-evated and the HLA–B*5801–positive subjects have a veryhigh hazard ratio (“high risk”) for severe allopurinol hy-persensitivity reaction (e.g., Koreans with stage 3 [orworse] CKD and all those of Han Chinese and Thai de-scent). It is anticipated that additional high-risk subpopu-lations for AHS will be identified in future studies.

The TFP recommended uricosuric therapy as a valuablecomponent of comprehensive urate-lowering strategies.Specific novel TFP recommendations on appropriatenessof use of combination XOI and uricosuric ULT as a second-line approach in refractory disease across the case scenar-ios studied here reinforce BSR recommendations on such

ACR Guidelines for Gout Management: Part 1 1443

a combination therapy (24). Significantly, for combinationwith an XOI drug, the TFP recommended not simply pro-benecid, but also as alternatives, other medications withless marked uricosuric effects (fenofibrate and losartan).However, the authors recognize that the published data arelimited. The authors believe that ongoing and further stud-ies will help understand how to optimize combinations ofuricosuric agents with XOI therapy to decrease the risk ofuricosuric-induced urolithiasis, while increasing the ve-locity of size reduction of body urate stores and tophi (67).

Based on results of placebo-controlled trials in studypopulations with particularly severe gout, the TFP recom-mended pegloticase as a third-line agent in distinct casescenarios of refractory disease with failure of appropri-ately dosed oral ULT, including in CTGA. Clinical trialsdirectly comparing pegloticase to appropriate maximallydosed first- and second-line oral medication regimens ofthe agents recommended here would be of interest insevere gout, including CTGA.

Limitations of the ACR gout guidelines include the qual-ity and quantity of evidence evaluated. For part 1 of thegout guidelines, the majority of evidence reviewed, uponwhich recommendations were based, was level C, withless than 20% level A evidence. For ULT clinical trials,study designs comparing allopurinol to febuxostat, whereboth agents are titrated to attempt to achieve the serumurate target, would be more informative than past trials(26,72,73). Another issue was variability in end points andoutcome measures (e.g., gout attack frequency, serumurate, tophus size reduction, and health-related quality oflife) in the clinical trials reviewed. Moreover, there arelikely differences in “real-world” patients compared tothose in most large industry-sponsored clinical trials.Clearly, further studies are needed in both the ULT andCTGA domains of gout.

The RAND/UCLA methodology utilized for this projectdid not allow us to address the important clinical practiceand societal implications of treatment costs, which clearlyimpact patient and provider preferences for gout manage-ment options recommended by the TFP as effective. Forexample, the authors recognize the potential cost issues ofthe ULT recommendations presented, since, for example,febuxostat is substantially more expensive than allopuri-nol or probenecid. We note that a recent single technologyappraisal with cost analysis done by an independent evi-dence review group of the National Institute for Health andClinical Excellence concluded that febuxostat should berecommended for ULT in gout only in patients with con-traindications or intolerance to allopurinol (25). Con-versely, PCR-based HLA–B*5801 pharmacogeneticsscreening for allopurinol is a one-time test and relativelyinexpensive, but raises new questions about the addedcosts to gout management, particularly for populationswhere the risk of AHS is low (53,57,58). Last, third-lineULT with pegloticase is an expensive biologic therapyapproach for gout, and additional biologic agents for gouttherapy are currently being developed and investigated.Cost-effectiveness trials and analyses are particularlytimely for emerging therapies in gout.

The ACR guidelines for ULT in gout presented herein,and for treatment and antiinflammatory prophylaxis of

gouty arthritis presented in a separate article (part 2 of theguidelines) (17), will require updating as new evidenceemerges for appropriate evaluation and management ofgout advances and new medications achieve regulatoryagency approval. Increased comparative studies of gout-specific health-related quality of life impairment anddisease activity outcomes for ULT agents and regimensevaluated here will be of particular interest, given cost,long-term safety, and other considerations such as cardio-vascular disease outcomes. It is hoped that publication ofthese guidelines, along with effective patient education ingout treatments and the objectives and safety issues ofmanagement, will improve patient adherence, quality ofcare, and outcomes in management of gout.

Therapies that were approved after theoriginal literature review, or diet and lifestyle measuresstudied after the original literature review, are not in-

We thank Ms Amy Miller and Ms Regina Parker of the ACRfor administrative support and guidance. Drs. JenniferGrossman (UCLA), Michael Weinblatt (Brigham and Wom-en’s Hospital, Harvard Medical School), Ken Saag (Univer-sity of Alabama, Birmingham), and Ted Ganiats (Univer-sity of California, San Diego) provided valuable guidanceon the objectives and process. Rikke Ogawa (UCLA) pro-vided greatly appreciated service as a medical research

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors ap-proved the final version to be published. Dr. Terkeltaub had fullaccess to all of the data in the study and takes responsibility forthe integrity of the data and the accuracy of the data analysis.

Dinesh Khanna, Fitzgerald, Puja P.Khanna, Bae, Neogi, Pillinger, Merill, Lee, Prakash, Perez-Ruiz,Choi, Jasvinder A. Singh, Dalbeth, Kaplan, Mandell, Schumacher,

Dinesh Khanna, Fitzgerald, Puja P. Khanna,Bae, Manjit K. Singh, Pillinger, Lee, Prakash, Gogia, Taylor, Choi,Kaplan, Kerr, King, Edwards, Mandell, Wenger, Terkeltaub.Analysis and interpretation of data. Dinesh Khanna, Fitzgerald,Puja P. Khanna, Bae, Manjit K. Singh, Neogi, Merill, Lee, Prakash,Kaldas, Liote, Choi, Kaplan, Niyyar, Jones, Yarows, Roessler, Kerr,King, Levy, Furst, Mandell, Schumacher, Robbins, Wenger,Terkeltaub.

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2012 American College of RheumatologyGuidelines for Management of Gout. Part 2:Therapy and Antiinflammatory Prophylaxis ofAcute Gouty ArthritisDINESH KHANNA,1 PUJA P. KHANNA,1 JOHN D. FITZGERALD,2 MANJIT K. SINGH,3 SANGMEE BAE,2

TUHINA NEOGI,4 MICHAEL H. PILLINGER, SHRADDHA PRAKASH,2

MARIAN KALDAS,2 9

FREDERIC LIOTE,10

SANFORD KAPLAN, STEVEN A. YAROWS,15

BLAKE ROESSLER,1 DANIEL E. FURST,2

N. LAWRENCE EDWARDS, MARK ROBBINS,22

NEIL WENGER,2 AND

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) areintended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determi-nation regarding their application to be made by the physician in light of each patient’s individual circumstances.Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guaranteeany specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodicrevision as warranted by the evolution of medical knowledge, technology, and practice.

The American College of Rheumatology is an independent, professional, medical and scientific society which doesnot guarantee, warrant, or endorse any commercial product or service.

IntroductionIn response to a request for proposal from the AmericanCollege of Rheumatology (ACR), our group was chargedwith developing nonpharmacologic and pharmacologicguidelines for treatments in gout that are safe and effective,i.e., with an acceptable risk/benefit ratio. These guidelines

for the management and antiinflammatory prophylaxis ofacute attacks of gouty arthritis complement our article on

Supported by a research grant from the American Collegeof Rheumatology and by the National Institute of Arthritisand Musculoskeletal and Skin Diseases, NIH (grant K24-AR-063120).

1Dinesh Khanna, MD, MSc, Puja P. Khanna, MD, MPH,Blake Roessler, MD: University of Michigan, Ann Arbor;2John D. FitzGerald, MD, Sangmee Bae, MD, ShraddhaPrakash, MD, Marian Kaldas, MD, Maneesh Gogia, MD,Daniel E. Furst, MD, Neil Wenger, MD: University of Cali-fornia, Los Angeles; 3Manjit Singh, MD: Rochester GeneralHealth System, Rochester, New York; 4Tuhina Neogi, MD,PhD, FRCPC, Hyon Choi, MD, DrPH: Boston University Med-ical Center, Boston, Massachusetts; 5Michael H. Pillinger,MD: VA Medical Center and New York University School ofMedicine, New York; 6Joan Merill, MD: Oklahoma MedicalResearch Foundation, Oklahoma City; 7Susan Lee, MD,

Robert Terkeltaub, MD: VA Healthcare System and Univer-Fernando Perez-Ruiz, MD,

PhD: Hospital Universitario Cruces, Vizcaya, Spain; 9WillTaylor, PhD, MBChB: University of Otago, Wellington, NewZealand; 10Frederic Liote, MD, PhD: Universite ParisDiderot, Sorbonne Paris Cite, and Hopital Lariboisiere,Paris, France; 11Jasvinder A. Singh, MBBS, MPH: VAMedical Center and University of Alabama, Birmingham;12Nicola Dalbeth, MD, FRACP: University of Auckland,Auckland, New Zealand; 13Sanford Kaplan, DDS: Oral andMaxillofacial Surgery, Beverly Hills, California; 14VandanaNiyyar, MD, Danielle Jones, MD, FACP: Emory University,Atlanta, Georgia; 15Steven A. Yarows, MD, FACP, FASH:IHA University of Michigan Health System, Chelsea; 16GailKerr, MD, FRCP(Edin): Veterans Affairs Medical Center,Washington, DC; 17Charles King, MD: North MississippiMedical Center, Tupelo; 18Gerald Levy, MD, MBA: South-ern California Permanente Medical Group, Downey; 19N.Lawrence Edwards, MD: University of Florida, Gainesville;20Brian Mandell, MD, PhD: Cleveland Clinic, Cleveland,Ohio; 21H. Ralph Schumacher, MD: VA Medical Center and

Arthritis Care & ResearchVol. 64, No. 10, October 2012, pp 1447–1461DOI 10.1002/acr.21773© 2012, American College of Rheumatology

SPECIAL ARTICLE

1447

guidelines to treat hyperuricemia in patients with evi-dence of gout (or gouty arthritis) (1).

Gout is the most common cause of inflammatory arthri-tis in adults in the US. Clinical manifestations in jointsand bursa are superimposed on local tissue deposition ofmonosodium urate crystals. Acute gout characteristicallypresents as a self-limited attack of synovitis (also called“gout flare”). Acute gout attacks account for a major com-ponent of the reported decreased health-related quality oflife in patients with gout (2,3). Acute gout attacks can bedebilitating and are associated with decreased work pro-ductivity (4,5).

Urate-lowering therapy (ULT) is a cornerstone in themanagement of gout (1) and, when effective in loweringserum urate, is associated with a decreased risk of acutegouty attacks (6). However, during the initial phase ofULT, there is an early increase in acute gout attacks, whichhas been hypothesized due to remodeling of articular uratecrystal deposits as a result of rapid and substantial lower-ing of ambient urate concentrations (7). Acute gout attacksattributable to the initiation of ULT may contribute tononadherence in long-term gout treatment, as reported in

In order to systematically evaluate management of acutegouty arthritis, we generated multifaceted case scenariosto elucidate decision making based primarily on clinicaland laboratory test–based data that can be obtained from agout patient by both nonspecialist and specialist healthcare providers in an office practice setting. This effort wasnot intended to create a novel classification system of goutor new gout diagnostic criteria, since such endeavors are

Prior gout recommendations and guidelines, at the in-dependent (i.e., non–pharmaceutical industry sponsored)national or multinational rheumatology society level, have

Significance & Innovations● An acute gouty arthritis attack should be treated

with pharmacologic therapy, initiated within 24hours of onset.

● Established pharmacologic urate-lowering therapyshould be continued, without interruption, duringan acute attack of gout.

● Nonsteroidal antiinflammatory drugs (NSAIDs),corticosteroids, or oral colchicine are appropriatefirst-line options for treatment of acute gout, andcertain combinations can be employed for severeor refractory attacks.

● Pharmacologic antiinflammatory prophylaxis isrecommended for all gout patients when pharma-cologic urate lowering is initiated, and should becontinued if there is any clinical evidence of con-tinuing gout disease activity and/or the serumurate target has not yet been achieved.

● Oral colchicine is an appropriate first-line goutattack prophylaxis therapy, including with appro-priate dose adjustment in chronic kidney diseaseand for drug interactions, unless there is a lack oftolerance or medical contraindication.

● Low-dose NSAID therapy is an appropriate choicefor first-line gout attack prophylaxis, unless thereis a lack of tolerance or medical contraindication.

fees, speaking fees, and/or honoraria (less than $10,000each) from Novartis, Takeda, and Ardea, has received re-search funding from Fonterra, and holds a patent fromFonterra for milk products for gout. Dr. Niyyar has receivedhonoraria (less than $10,000) from the American Society ofNephrology. Dr. Kerr has served as a study investigator(more than $10,000 each) for Savient and Nuon. Dr. Ed-wards has received consultant fees, speaking fees, and/orhonoraria (less than $10,000 each) from Savient, Takeda,Ardea, and Regeneron, and (more than $10,000) from No-vartis, and has given expert testimony for Novartis. Dr.Mandell has received consultant fees, speaking fees, and/orhonoraria (less than $10,000 each) from Savient, Novartis,and Pfizer. Dr. Schumacher has received consultant fees(less than $10,000 each) from Pfizer, Regeneron, West-Ward,and Ardea, and (more than $10,000) from Novartis. Dr.Terkeltaub has received consultant fees (less than $10,000each) from Takeda, Savient, Ardea, BioCryst, URL, Regen-eron, Pfizer, Metabolex, Nuon, Chugai, EnzymeRx, Ajanta,Anadys, Celgene, Isis, and Prescription Solutions, and(more than $10,000) from Novartis, has received grant sup-port from the VA San Diego Healthcare System and the NIH,and has served as a paid investment consultant for LeerinkSwann, Medacorp, and Guidepoint.

Address correspondence to Robert Terkeltaub, MD, VAHealthcare System/University of California, San Diego,111K, 3350 La Jolla Village Drive, San Diego, CA 92161.E-mail: [email protected].

Submitted for publication January 9, 2012; accepted inrevised form June 15, 2012.

University of Pennsylvania, Philadelphia;MD, MPH: Harvard Vanguard Medical Associates/AtriusHealth, Somerville, Massachusetts.

Drs. Dinesh Khanna, Puja P. Khanna, and FitzGerald con-tributed equally to this work.

Dr. Dinesh Khanna has received consultant fees, speakingfees, and/or honoraria (less than $10,000 each) from No-vartis and Ardea and (more than $10,000 each) from Takedaand Savient, and has served as a paid investment consultantfor Guidepoint. Dr. Puja P. Khanna has received speakingfees (less than $10,000) from Novartis and (more than$10,000) from Takeda, and has served on the advisory boardfor Novartis. Dr. Pillinger has received speaking fees and/orhonoraria (less than $10,000 each) from the RA InvestigatorNetwork, NY Downtown Hospital, Winthrop Hospital, andEinstein College of Medicine. Dr. Perez-Ruiz has receivedconsultant fees, speaking fees, and/or honoraria (less than$10,000 each) from Novartis, Menarini, and Savient, and(more than $10,000) from Ardea. Dr. Liote has receivedconsultant fees, speaking fees, and/or honoraria (less than$10,000 each) from Novartis Global, Novartis France, andIpsen, and has served as a paid investment consultant forGerson Lehrman Group. Dr. Choi has served on the advisoryboards (less than $10,000 each) for Takeda, URL, and Savi-ent. Dr. Singh has received consultant fees, speaking fees,and/or honoraria (less than $10,000 each) from Ardea, Savi-ent, Allergan, and Novartis, and (more than $10,000) fromTakeda, and has received investigator-initiated grants fromTakeda and Savient. Dr. Dalbeth has received consultant

1448 Khanna et al

been published by the European League Against Rheuma-tism (EULAR) (9,10), the Dutch College of General Practi-tioners (11), and the British Society for Rheumatology(BSR) (12). The ACR requested new guidelines in view ofthe increasing prevalence of gout (13), the clinical com-plexity of management of gouty arthritis imposed bycomorbidities common in patients with gout (14), andincreasing numbers of treatment options via clinical de-velopment of agents (15–17). The ACR charged us to de-velop these guidelines to be useful for both rheumatolo-gists and other health care providers on an internationallevel. As such, this process and resultant recommenda-tions involved a diverse and international panel of experts.

In this article, we concentrate on 2 of the 4 gout domains(1) that the ACR requested for evaluation of pharmacologicand nonpharmacologic management approaches: analge-sic and antiinflammatory management of acute attacks ofgouty arthritis and pharmacologic antiinflammatory pro-phylaxis of acute attacks of gouty arthritis. Part 1 of theguidelines focused on systematic nonpharmacologic mea-sures (patient education, diet and lifestyle choices, iden-tification and management of comorbidities) that impacthyperuricemia, and made recommendations on pharmaco-logic ULT in a range of case scenarios of patients withdisease activity manifested by acute and chronic forms ofgouty arthritis, including chronic tophaceous gouty ar-thropathy (1). Each individual and specific statement isdesignated as a “recommendation,” in order to reflect thenonprescriptive nature of decision making for the hypo-thetical clinical scenarios.

So that the voting panel could focus on gout treatmentdecisions, a number of key assumptions were made, asdescribed in part 1 of the guidelines (1). Importantly, eachproposed recommendation assumed that correct diagnosesof gout and acute gouty arthritis attacks had been made forthe voting scenario in question. For treatment purposes,it was also assumed that treating clinicians were com-petent, and considered underlying medical comorbidities(including diabetes mellitus, gastrointestinal disease,hypertension, and hepatic, cardiac, and renal disease)and potential drug toxicities and drug–drug interactionswhen making both treatment choices and dosing deci-sions on chosen pharmacologic interventions. The RAND/University of California at Los Angeles (UCLA) methodol-ogy used here emphasizes the level of evidence, safety,and quality of therapy, and excludes analyses of societalcost of health care. As such, the ACR gout guidelines aredesigned to reflect best practice, supported either by levelof evidence or consensus-based decision making. Theseguidelines cannot substitute for individualized direct as-sessment of the patient, coupled with clinical decisionmaking by a competent health care practitioner. The mo-tivation, financial circumstances, and preferences of thegout patient also need to be considered in clinical practice,and it is incumbent on the treating clinician to weigh theissues not addressed by this methodology, such as treat-ment costs, when making management decisions. Last, theguidelines for gout management presented herein were notdesigned to determine eligibility for health care cost cov-erage by third party payors.

Materials and methodsUtilizing the RAND/UCLA methodology (18), we con-ducted a systematic review, generated case scenarios, de-veloped recommendations, and graded the evidence.

Design: RAND/UCLA Appropriateness Method over-view. The RAND/UCLA method of group consensus wasdeveloped in the 1980s, incorporates both Delphi andnominal group methods (18), and has been successfullyused to develop other guidelines commissioned by theACR. The purpose of this methodology is to reach a con-sensus among experts, with an understanding that pub-lished literature may not be adequate to provide sufficientevidence for day-to-day clinical decision making. TheRAND/UCLA method requires 2 groups of experts: a coreexpert panel (CEP) that provides input into case scenariodevelopment, and a task force panel (TFP) that votes onthe case scenarios (1). A systematic review of pertinentliterature was performed concurrently, and a scientificevidence report was generated. This evidence report wasthen given to the TFP, in conjunction with a variety ofclinical scenarios and clinical decision-making questions

The diverse TFP, totaling 11 people, consisted of rheu-matologists in a community private practice (CK), a healthmaintenance organization practice (GL), and a VeteransAffairs practice (GK); a rheumatology physician–scientistinflammation researcher (BR); a rheumatologist with ex-pertise in clinical pharmacology (DEF); a rheumatologistgout expert that is an Internal Medicine Residency Direc-tor (NLE); a rheumatologist gout expert that is a Chair ofInternal Medicine (BM); 2 primary care internal medicinephysicians (DJ, SAY); a nephrologist (VN); and a patientrepresentative (SK) (1). There were 2 rounds of ratings, thefirst anonymous, with the members of the TFP instructedto rank each potential element of the guidelines on arisk/benefit Likert scale ranging from 1–9, followed by aface-to-face group discussion with revoting. A vote of 1–3on the Likert scale was scored as inappropriate, whererisks clearly outweigh the benefits; a vote of 4–6 was

(“lack of consensus”), where the risk/benefit ratio is uncertain; and a vote of 7–9 was scored as

, where benefits clearly outweigh the risks.Case scenarios were translated into recommendations,where the median voting scores were 7–9 on the Likertscale (“appropriate”), and if there was no significant dis-agreement, defined as no more than one-third of the TFPvoting below the Likert scale level of 7 in the question. Thefinal rating was done anonymously in a 2-day face-to-facemeeting led by an experienced internal medicine physi-cian moderator (NW).

Systematic review. PubMed and the Cochrane CentralRegister of Controlled Trials (CENTRAL) were searched tofind all articles on gout with the help of an experiencedlibrarian. PubMed is a database of medical literature fromthe 1950s to the present. CENTRAL includes referencesfrom PubMed, Embase, and the Cochrane Review Groups’specialized registers of controlled trials and hand searchresults. We used search terminology (hedge) based on theCochrane Highly Sensitive Search Strategy for identifying

ACR Guidelines for Gout Management: Part 2 1449

randomized trials. The hedge was expanded to includearticles discussing research design, cohort, case–control,and cross-sectional studies. Limits added to the hedgeinclude English language and the exclusion of “animalonly” studies. The searches for all 4 domains were con-ducted simultaneously and therefore included terms forhyperuricemia and other gout-related issues. Conductedon September 25, 2010, the search retrieved 5,830 articlesfrom PubMed and CENTRAL. The review was divided into3 stages: titles, abstracts from manuscripts, and entiremanuscripts. At each stage, each title, abstract, or manu-script was included or excluded using prespecified rules,as described (1). Of the 5,830 titles, 192 duplicate titlesand 82 non-English titles were excluded, with an addi-tional 3,729 titles excluded based on exclusion criteria,leaving 1,827 titles, of which another 1,699 were excludedin the abstract phase. A total of 128 manuscripts remainedthat were further categorized into pharmacologic and non-pharmacologic studies (1). Subsequently, we updated oursystematic review by repeating the search with the samecriteria to include any articles that were published be-tween September 25, 2010 and March 31, 2011, and wehand searched recent meeting abstracts from the ACR andEULAR for any randomized controlled trials that were yetto be published. The supplemental search resulted in 4additional manuscripts and 5 meeting abstracts on phar-macologic agents, some of which were subsequently pub-lished and then reevaluated for evidence grade. Finally,there were 41 manuscripts on nonpharmacologic modali-ties (such as diet, alcohol, exercise, etc.) that included bothretrospective and prospective studies, but all were ex-cluded, since none were randomized controlled studies oninterventions in gout patients. There were 87 manuscriptson pharmacologic agents for the treatment of patients withgout. Of these, 47 were randomized controlled trials andincluded in the evidence report, whereas the remaining 40uncontrolled trials were excluded. A total of 21 manu-scripts on ULT were separately addressed (1).

For this article (part 2 of the guidelines), a total of 30manuscripts and 5 meeting abstracts were assessed, with26 manuscripts and 2 meeting abstracts on acute gout and4 manuscripts and 3 meeting abstracts on prophylaxisincluded in the evidence report and evaluated by the TFP.

Case scenarios. Through an interactive, iterative pro-cess, the CEP developed unique case scenarios of acutegouty attacks with varied treatment options, and the typeof attack by severity, duration, and extent of the attack.The objective was to represent a broad spectrum of attacksthat a clinician might see in a busy practice. For the casescenarios, the severity of acute gout differed based onself-reported worst pain on a 0–10 visual analog scale(VAS) (19,20). Pain �4 was considered mild, 5–6 wasconsidered moderate, and �7 was considered severe(19,20). Case scenarios also varied by duration of the acutegout attack; we divided this into early (�12 hours), wellestablished (12–36 hours), and late (�36 hours). Case sce-narios also varied in the number of active joints involved:1 or a few small joints, 1 or 2 large joints (ankle, knee,wrist, elbow, hip, or shoulder), and polyarticular involve-

ment (defined as either acute arthritis involving 3 separatelarge joints, or acute arthritis of 4 or more joints, witharthritis involving more than 1 “region” of joints). Jointregions were defined as: forefoot (metatarsal joints andtoes), midfoot (tarsal joints), ankle/hindfoot, knee, hip,fingers, wrist, elbow, shoulder, or other (Figure 1). Themanagement strategies presented were developed for casescenarios involving gouty arthritis, but the intent was thatacute bursal inflammation due to gout (e.g., in the prepa-tellar or olecranon bursa) and small joint involvementwould have comparable recommendations for overallmanagement strategies.

Developing recommendations from votes by the TFPand grading the evidence. A priori recommendationswere derived from only positive results (median Likert

7). In the text below, all recommendations derivedfrom TFP votes are denoted by an accompanying evi-dence grade. In addition to TFP vote results, the panelprovided some statements based on discussion (not votes).Such statements are specifically described as discus-sion items (rather than TFP-voted recommendations) inthe Results. We also comment on specific circumstanceswhere the TFP did not vote a particularly important clin-ical decision-making item as appropriate (i.e., the median

6 or there was a wide dispersion of votes7). Samples of voting scenarios

and results are shown in Supplemental Figure 1 (availablein the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

The level of evidence supporting each recommendationwas ranked based on previous methods used by the Amer-ican College of Cardiology (21) and applied to other recentACR recommendations (22,23): level A grading was as-signed to recommendations supported by more than 1randomized clinical trial, or 1 or more meta-analyses; levelB grading was assigned to the recommendations derivedfrom a single randomized trial, or nonrandomized studies;and level C grading was assigned to consensus opinion ofexperts, case studies, or standard of care.

Managing perceived potential conflict of interest (COI).Potential COI was managed in a prospective and struc-tured manner (1). All of the participants intellectuallyinvolved in the project, whether authors or not, were re-quired to fully disclose their relationships with any of thecompanies with a material interest in gout, listed in Sup-plemental Appendix A (available in the online versionof this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Disclosures were identifiedat the start of the project and updated every 6 months. Asummary listing of all perceived potential COI is availablein Supplemental Appendix A (available in the onlineversion of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Based on the policies of the ACR, no more than 49% ofthe project participants were permitted to have COI at anygiven time, and a majority of the TFP was required to haveno perceived potential COI. It was further required that theproject principal investigator (JDF) remain without per-

1450 Khanna et al

ceived potential COI during the guideline developmentprocess, and for an additional 12 months afterward.

Results

General principles for treatment of the acute attack ofgouty arthritis (“acute gout” management).marizes the overall recommendations on treatment of anacute gouty arthritis attack. The TFP recommended that anacute gouty arthritis attack should be treated with phar-macologic therapy (evidence C), and that treatment shouldbe preferentially initiated within 24 hours of onset of anacute gout attack (evidence C). The latter recommendationwas based on consensus that early treatment leads to betterpatient-reported outcomes. The TFP also recommendedcontinuing established pharmacologic ULT without inter-ruption during an acute attack of gout (evidence C), i.e., donot stop ULT therapy during an acute attack. The TFP alsorecommended patient education, not simply on dietaryand other triggers of acute gout attacks, but also providingthe patients with instruction so that they can initiate treat-ment upon signs and symptoms of an acute gout attack,without the need to consult their health care practitionerfor each attack (evidence B) (24). Moreover, fundamentalpatient education includes discussion that gout is causedby body excess of uric acid, and that only effective ULT ispotentially “curative” (evidence B) (24).

Initial pharmacologic treatment of the acute attack ofThe TFP recommended that the choice of

pharmacologic agent should be based upon severity ofpain and the number of joints involved (Figure 2). Forattacks of mild/moderate gout severity (�6 of 10 on a 0–10pain VAS) particularly those involving 1 or a few smalljoints or 1 or 2 large joints, the TFP recommended thatinitiating monotherapy was appropriate, with recom-mended options being oral nonsteroidal antiinflammatorydrugs (NSAIDs), systemic corticosteroids, or oral colchi-cine (evidence A for all therapeutic categories) (25–28)(Figure 2). The TFP also voted that combination therapywas an appropriate option to consider when the acute goutattack was characterized by severe pain, particularly in anacute polyarticular gout attack or an attack involving 1–2large joints (evidence C) (Figure 2). The TFP did not rankone therapeutic class over another. Therefore, it is at thediscretion of the prescribing physicians to choose the mostappropriate monotherapy based on the patient’s prefer-ence, prior response to pharmacologic therapy for an acutegout attack, and associated comorbidities. Recommenda-tions for appropriate combination therapy options arehighlighted in Table 1 and discussed below. The TFP didnot vote on case scenarios for specific renal or hepaticfunction impairment–adjusted dosing and individual con-traindications or drug–drug interactions with pharmaco-logic therapies (29–31).

Figure 1. Case scenarios for defining acute gouty arthritis attack features. These case scenarios were generated by the core expert panel,and therapeutic decision-making options for these scenarios were voted on by the task force panel.

ACR Guidelines for Gout Management: Part 2 1451

Figure 2. Overview of management of an acute gout attack. This algorithm summarizes the recommendations by the task force panel onthe overall approach to management of an acute attack of gouty arthritis, with further details, as expanded in other figures and tables,referenced in the figure and discussed in the text. ULT � urate-lowering therapy; NSAID � nonsteroidal antiinflammatory drug; COX-2 �cyclooxygenase 2; GI � gastrointestinal; IL-1 � interleukin-1.

1452 Khanna et al

NSAIDs. For NSAIDs, the TFP recommended full dos-ing at either the Food and Drug Administration (FDA)– orEuropean Medical Agency–approved antiinflammatory/analgesic doses used for the treatment of acute pain and/or treatment of acute gout (evidence A–C) (27,28,32–34)(Figure 3A). The FDA has approved naproxen (evidence A)(34,35), indomethacin (evidence A) (27,28,32,33), andsulindac (evidence B) (36) for the treatment of acute gout.However, analgesic and antiinflammatory doses of otherNSAIDs may be as effective (evidence B and C). For cyclo-oxygenase 2 (COX-2) inhibitors, as an option in patientswith gastrointestinal contraindications or intolerance toNSAIDs, published randomized controlled trials supportthe efficacy of etoricoxib (evidence A) and lumiracoxib(evidence B) (25,37,38), but these agents are not availablein the US, and lumiracoxib has been withdrawn from usein several countries due to hepatotoxicity. A randomizedcontrolled trial of a single comparison of celecoxib versusindomethacin (39) suggested effectiveness of a high-dosecelecoxib regimen (800 mg once, followed by 400 mg onday 1, then 400 mg twice daily for a week) in acute gout.The TFP recommended this celecoxib regimen as an op-tion for acute gout in carefully selected patients with con-traindications or intolerance to NSAIDs (evidence B),keeping in mind that the risk/benefit ratio is not yet clearfor celecoxib in acute gout.

The TFP did not reach a consensus to preferentiallyrecommend any one specific NSAID as first-line treatment.The TFP did recommend continuing the initial NSAIDinhibitor treatment regimen at the full dose (if appropriate)until the acute gouty attack completely resolved (evidenceC). The option to taper the dose in patients with multiplecomorbidities/hepatic or renal impairment was reinforcedby the TFP, without specific TFP voting or more prescrip-tive guidance. Last, there was no TFP consensus on the useof intramuscular ketorolac or topical NSAIDs for the treat-ment of acute gout.

Colchicine. The TFP recommended oral colchicine asone of the appropriate primary modality options to treatacute gout, but only for gout attacks where the onset wasno greater than 36 hours prior to treatment initiation (ev-idence C) (Figure 3B). The TFP recommended that acutegout can be treated with a loading dose of 1.2 mg ofcolchicine followed by 0.6 mg 1 hour later (evidence B)(10), and this regimen can then be followed by gout attackprophylaxis dosing 0.6 mg once or twice daily (unless doseadjustment is required) 12 hours later, until the gout attackresolves (evidence C) (26). For countries where 1.0 mg or0.5 mg rather than 0.6 mg tablets of colchicine are avail-able, the TFP recommended, as appropriate, 1.0 mg col-chicine as the loading dose, followed by 0.5 mg 1 hourlater, and then followed, as needed, after 12 hours, bycontinued colchicine (up to 0.5 mg 3 times daily) until theacute attack resolves (evidence C). In doing so, the TFPrationale was informed by pharmacokinetics of the low-dose colchicine regimen, where the exposure to the drugin plasma becomes markedly reduced �12 hours afteradministration in healthy volunteers (26). The TFP alsoevaluated prior EULAR recommendations on a colchicinedosing regimen for acute gout (0.5 mg 3 times daily) andthe BSR-recommended maximum dosage for acute gout of

The algorithm in Figure 3B outlines recommendationsfor colchicine based on FDA labeling and TFP delibera-tions and votes, including specific recommendations forpatients already receiving colchicine acute gout attack pro-phylaxis. For more specific prescriptive guidance, practi-tioners should consult the FDA-approved drug labeling,including recommended dosing reduction in moderate tosevere chronic kidney disease (CKD) (40,41), and colchi-cine dose reduction (or avoidance of colchicine use) withdrug interactions with moderate to high potency inhibitorsof cytochrome P450 3A4 and of P-glycoprotein; major col-chicine drug interactions include those with clarithromy-cin, erythromycin, cyclosporine, and disulfiram (30,31).Last, the TFP did not vote on use of intravenous colchi-cine, since the formulation is no longer available in theUS, due to misuse and associated severe toxicity.

Systemic and intraarticular corticosteroids and adre-nocorticotropic hormone (ACTH). When selecting corti-costeroids as the initial therapy, the TFP recommended tofirst consider the number of joints with active arthritis. Forinvolvement of 1 or 2 joints, the TFP recommended the useof oral corticosteroids (evidence B); the TFP additionallyrecommended the option of intraarticular corticosteroidsfor acute gout of 1 or 2 large joints (evidence B) (42) (Figure3C). For intraarticular corticosteroid therapy in acutegouty arthritis, it was recommended that dosing be basedon the size of the involved joint(s), and that this modalitycould be used in combination (Table 1) with oral cortico-steroids, NSAIDs, or colchicine (evidence B) (42). Specificdoses for intraarticular corticosteroid therapy in specificjoints were not considered during TFP voting.

Where intraarticular joint injection is impractical (e.g.,polyarticular joint involvement, patient preference, or in-jection of the involved joint site is not in the scope of theprovider’s usual practice), the TFP recommended oral cor-

Table 1. Task force panel (TFP) recommendations forcombination therapy approach to acute gouty arthritis

Initial combination therapy is an appropriate optionfor an acute, severe gout attack, particularly withinvolvement of multiple large joints or polyarticulararthritis (evidence C)

Acceptable combination therapy approaches includethe initial simultaneous use of full doses (or, whereappropriate, prophylaxis doses) of either: 1) colchicineand nonsteroidal antiinflammatory drugs (NSAIDs),2) oral corticosteroids and colchicine, or 3) intra-articular steroids with all other modalities (evidence C)

For patients not responding adequately to initialpharmacologic monotherapy, adding a secondappropriate agent is an acceptable option (evidence C)*

The TFP was not asked to vote on use of NSAIDs andsystemic corticosteroids in combination, given coreexpert panel concerns about synergistic gastrointestinaltract toxicity

* Assumes that the initial diagnosis of acute gout was correct, andthat the lack of adequate response of acute gout was to an appro-priate first-line therapy option.

ACR Guidelines for Gout Management: Part 2 1453

ticosteroids, prednisone, or prednisolone at a starting dos-age of at least 0.5 mg/kg per day for 5–10 days, followed bydiscontinuation (evidence A) (28,43), or alternately, 2–5

days at the full dose, followed by tapering for 7–10 days,and then discontinuation (evidence C). Acknowledgingcurrent prevalence of usage, the TFP recommended, as an

Figure 3. Recommendations for the individual pharmacologic monotherapy options for an acute gouty arthritis attack. The figure isseparated into distinct parts that schematize use of the first-line therapy options (A, nonsteroidal antiinflammatory drugs [NSAIDs],B, colchicine, and C, corticosteroids), and specific recommendations by the task force panel (TFP). COX-2 � cyclooxygenase 2; FDA �Food and Drug Administration; EMA � European Medical Agency; EULAR � European League Against Rheumatism; IM � intramuscular.

1454 Khanna et al

appropriate option according to provider and patient pref-erence, the use of an oral methylprednisolone dose packfor initial treatment of an acute attack of gout (evidence C).

The TFP also recommended, as appropriate in each casescenario, an alternative regimen of intramuscular single-dose (60 mg) triamcinolone acetonide, followed by oralprednisone or prednisolone (evidence C). However, therewas no consensus by the TFP on the use of intramusculartriamcinolone acetonide as monotherapy. Last, the TFPvote also did not reach a consensus on use of ACTH(evidence A) for acute gout in patients able to take medi-cations orally, but did consider ACTH in separate voting,as described below, for patients unable to take oral anti-inflammatory medications.

Initial combination therapy for acute gout. For patientswith severe acute gout attack (�7 of 10 on a 0–10 painVAS) and patients with an acute polyarthritis or involve-ment of more than 1 large joint, the TFP recommended, asan appropriate option, the initial simultaneous use of fulldoses (or, where appropriate, a full dose of 1 agent andprophylaxis dosing of the other) of 2 of the pharmacologicmodalities recommended above. Specifically, the TFP rec-ommended the option to use combinations of colchicineand NSAIDs, oral corticosteroids and colchicine, or intra-articular steroids with any of the other modalities (evi-dence C). The TFP was not asked by the CEP to vote on useof NSAIDs and systemic corticosteroids in combination,

given CEP concerns about synergistic gastrointestinal tract

Inadequate response of an acute gout attack to initialThere is a lack of a uniform definition of an

inadequate response to the initial pharmacologic therapyfor an acute attack of gouty arthritis (2,26,44). Clinicaltrials in acute gout have defined variable primary endpoints for therapeutic response, such as percent improve-ment in pain on a Likert scale or VAS. To define inade-quate response for scenarios in this section, the CEP askedthe TFP to vote on various percent improvement defini-tions at time points such as 24, 48, or 72 hours. The TFPvoted that the following criteria would define an inade-quate response of acute gout to pharmacologic therapy incase scenarios: either �20% improvement in pain scorewithin 24 hours or �50% improvement in pain score �24hours after initiating pharmacologic therapy.

For the scenario of a patient with an acute attack ofgouty arthritis not responding adequately to initial phar-macologic monotherapy, the TFP advised, without a spe-cific vote, that alternative diagnoses to gout should beconsidered (Figure 2 and Table 1). For patients not re-sponding to initial therapy, the TFP also recommendedswitching to another monotherapy recommended above(evidence C) or adding a second recommended agent (ev-idence C). Use of a biologic interleukin-1 (IL-1) inhibitor(anakinra 100 mg subcutaneously daily for 3 consecutive

Figure 4. Acute gouty arthritis attack management in the nothing by mouth (NPO) patient. The figure schematizes options for managementof acute gout in the patient unable to take oral antiinflammatory medications, and specific recommendations by the task force panel ondecision making in this setting. ACTH intramuscular; NSAID � nonsteroidalantiinflammatory drug.

ACR Guidelines for Gout Management: Part 2 1455

days; evidence B) (44,45) or canakinumab 150 mg subcu-taneously (46,47) as an option for severe attacks of acutegouty arthritis refractory to other agents was graded asevidence A in the systematic review. Given a lack of ran-domized studies for anakinra (44,45) and the unclear risk/benefit ratio and lack of FDA approval for canakinumab(46,47) at the time this was written, the authors, indepen-dent of TFP discussion, assessed the role of IL-1 inhibitortherapy in acute gout as uncertain.

Case scenarios for the nothing by mouth (NPO) patient.Acute gout attacks are common in the in-hospital setting,where patients may be NPO due to different surgical andmedical conditions. In such a scenario, the TFP recom-mended intraarticular injection of corticosteroids for in-volvement of 1 or 2 joints (with the dose depending on thesize of the joint; evidence B) (42) (Figure 4). The TFP alsorecommended, as appropriate options, intravenous or in-tramuscular methylprednisolone at an initial dose at 0.5–2.0 mg/kg (evidence B) (48).

The TFP also recommended, as an appropriate alterna-tive for the NPO patient, subcutaneous synthetic ACTH atan initial dose of 25–40 IU (evidence A) (49), with repeatdoses as clinically indicated (for either ACTH or intrave-nous steroid regimens). There was no voting by the TFP onspecific followup ACTH or an intravenous steroid dosingregimen, given a lack of evidence. In the scenario of theNPO patient with acute gout, there was no consensus onthe use of intramuscular ketorolac or intramuscular triam-cinolone acetonide monotherapy. Biologic IL-1 inhibitiontherapy remains an FDA-unapproved modality for NPOpatients, without specific past evaluation in this popula-tion.

Critical drug therapy adverse event considerations inacute gout. It was not possible to evaluate every permuta-tion of gout treatment and comorbid disease, given theconstraints of the project. The treating clinician will needto carefully weigh the complexities of each unique patient.TFP discussions emphasized that potential drug toxicitiesdue to comorbidities and drug–drug interactions are con-siderable in treatment of acute gout (30,31). Some exam-ples include underlying moderate and severe CKD(NSAIDs, COX-2 inhibitors, colchicine), congestive heartfailure (NSAIDs, COX-2 inhibitors), peptic ulcer disease(NSAIDs, COX-2 inhibitors, corticosteroids), anticoagula-tion or antiplatelet aggregation therapy (NSAIDs), diabetesmellitus (corticosteroids), ongoing infection or high risk ofinfection (corticosteroids), and hepatic disease (NSAIDs,COX-2 inhibitors, colchicine) (30,31).

Complementary therapies for acute gout attack. TheTFP recommended topical ice application to be an appro-priate adjunctive measure to 1 or more pharmacologictherapies for acute gouty arthritis (evidence B) (50). TheTFP voted, as inappropriate, the use of a variety of oralcomplementary agents for the treatment of an acute at-tack (cherry juice or extract, salicylate-rich willow barkextract, ginger, flaxseed, charcoal, strawberries, black cur-rant, burdock, sour cream, olive oil, horsetail, pears, orcelery root).

Recommendations for pharmacologicantiinflammatory prophylaxis of attacks ofacute gout

The TFP recommended pharmacologic antiinflammatoryprophylaxis for all case scenarios of gout where ULT wasinitiated, given high gout attack rate frequencies in earlyULT (evidence A) (51–54) (Figure 5). For gout attack pro-phylaxis, the TFP recommended, as a first-line option, useof oral colchicine (evidence A) (54,55). The TFP also rec-ommended, as a first-line option (with a lower evidencegrade than for colchicine), the use of low-dose NSAIDs(such as naproxen 250 mg orally twice a day), with proton-pump inhibitor therapy or other effective suppressiontherapy for peptic ulcer disease and its complications,where indicated (evidence C) (54).

In their evaluation of colchicine evidence in gout attackprophylaxis, the TFP specifically recommended low-dosecolchicine (0.5 mg or 0.6 mg orally once or twice a day,with dosing further adjusted downward for moderate tosevere renal function impairment and potential drug–druginteractions) (30) as appropriate for gout attack prophy-laxis. The TFP did not vote on specific quantitative renalfunction impairment–adjusted dosing of oral colchicine.Since a pharmacokinetic analysis suggesting colchicinedose should be decreased by 50% below a creatinine clear-ance of 50 ml/minute is unpublished in peer-review form(41), specific quantitative colchicine dose adjustment inCKD is the decision of the treating clinician.

The TFP, in discussion without a specific vote, recog-nized the evidence that colchicine and low-dose NSAIDprophylaxis fail to prevent all gout attacks in patientpopulations after initiation of ULT (51–54). As an alter-native gout attack prophylaxis strategy in patients withintolerance or contraindication or refractoriness to bothcolchicine and NSAIDs, the TFP recommended use oflow-dosage prednisone or prednisolone (defined here as

10 mg/day) (evidence C). Nevertheless, concerns wereraised in discussion among the TFP and by the otherauthors regarding particularly sparse evidence for efficacyof this low-dose strategy. Given the known risks of pro-longed use of corticosteroids, the authors urge clinicians tobe particularly attentive in reevaluating the risk/benefitratio of continued corticosteroid prophylaxis as the risk ofacute gout attack decreases with time in conjunction witheffective ULT. The TFP voted the use of high daily doses(i.e., �10 mg daily) of prednisone or prednisolone for goutattack prophylaxis to be as inappropriate in most casescenarios, and there was a lack of TFP consensus for moresevere forms of chronic tophaceous gouty arthropathy.Last, there was a lack of TFP consensus on the risk/benefitratio for off-label use of biologic IL-1 inhibition (evidenceA) (56,57) for antiinflammatory gout attack prophylaxisin patients who previously failed or had intolerance orcontraindications to low doses of colchicine, NSAIDs, andprednisone or prednisolone for gout attack prophylaxis.

Duration of antiinflammatory prophylaxis of acute goutattacks. The TFP recommended to continue pharmaco-logic gout attack prophylaxis if there is any clinical evi-dence of continuing gout disease activity (such as 1 or

1456 Khanna et al

more tophi detected on physical examination, recent acutegout attacks, or chronic gouty arthritis), and/or the serumurate target has not yet been achieved (1). Specifically, theTFP voted to continue the prophylaxis for the greater of:

1) 6 months’ duration (evidence A) (51,53,54), 2) 3 monthsafter achieving the target serum urate level for the patientwithout tophi detected on physical examination (evidenceB), or 3) 6 months after achieving the target serum urate

Figure 5. Pharmacologic antiinflammatory prophylaxis of gout attacks and its relationship to pharmacologic urate-lowering therapy(ULT). The figure provides an algorithm for use of antiinflammatory prophylaxis agents to prevent acute gout attacks. The schematichighlights specific recommendations by the TFP on decision making on the initiation, options, and duration of prophylaxis relative topharmacologic ULT therapy, relative to achievement of the treatment objectives of ULT. NSAIDs � nonsteroidal antiinflammatory drugs.

ACR Guidelines for Gout Management: Part 2 1457

level, where there has been resolution of tophi previouslydetected on physical examination (evidence C) (Figure 5).

DiscussionAcute attacks of gout have a detrimental impact on thequality of life of the patient due to pain and dysfunction ofaffected joints, and acute gout can have a substantial eco-nomic and societal impact (58–60). Following a system-atic review of the literature and use of a formal groupassessment process, we provide the first ACR guidelinesfor the therapy and antiinflammatory prophylaxis of acutegout attacks.

The TFP recommended multiple modalities (NSAIDs,corticosteroids by different routes, and oral colchicine) asappropriate initial therapeutic options for acute gout at-tacks. The TFP was informed in part by recent directcomparison studies suggesting approximate equivalencyof oral systemic corticosteroids with NSAIDs (28,43). Es-sentially, the TFP concluded, without a specific vote, thatselection of treatment choice is that of the prescribingclinician, and to be based upon factors including patientpreference, the patient’s previous response to pharmaco-logic therapies, associated comorbidities and, in theunique case of colchicine, the time since onset of the acutegout attack. The dosing adjustments and relative and ab-solute contraindications for NSAIDs and colchicine due toassociated comorbidities (such as renal and hepatic im-pairment) and drug interactions were not addressed inthese guidelines. There is published literature addressingthese issues (30,31) such as quality indicators for safe useof NSAIDs (61–63), including ACR quality indicators fortreatment of gout (64).

The TFP recommended a novel set of strict limitationson colchicine doses for acute gout, starting with no morethan 1.8 mg over 1 hour in the first 12-hour period oftreatment (evidence B) (26), a paradigm shift from wide-spread prior use of this drug in clinical practice (10,12),but in accordance with FDA guidance. Prior EULAR andBSR recommendations on colchicine dosing for acute gout(10,12) and colchicine low-dose regimen pharmacokinet-ics (26) informed the TFP recommendation of low-dosecolchicine (at a maximum of 0.6 mg twice daily) as acontinuation option for an acute gout attack, if started atleast 12 hours following the initial low-dose regimen.

For patients with polyarticular joint involvement andsevere presentations of gout in 1 or 2 large joints, the TFPrecommended, as appropriate, certain first-line combina-tion therapy approaches. Although there is a lack of pub-lished randomized controlled trial data to support theserecommendations, a large survey of rheumatologists in theUS has shown that combination therapy for acute gout isoften employed (65).

With respect to antiinflammatory prophylaxis of acutegout attacks, low-dose colchicine or low-dose NSAIDswere recommended as acceptable first-line options by theTFP, with a higher evidence level for colchicine. The useof low-dose colchicine or an NSAID in gout attack prophy-laxis is also recommended by EULAR (10). To date, insmall clinical trials, low-dose daily oral colchicine waseffective in preventing acute gout attacks (3,55), with sup-portive post hoc analyses in ULT trials (54). The efficacy of

low-dose NSAIDs for gout attack prophylaxis also wasdescribed in the febuxostat clinical trial program (54);however, prophylaxis was not the primary focus of thetrials. Importantly, recent clinical trials of ULT agentshave shown substantial rates of acute gout attacks in thefirst 6 months after the initiation of ULT, even when pro-phylaxis with colchicine 0.6 mg daily or low-dose NSAIDtherapy is administered (51–54). It is noteworthy that theTFP recommended prednisone or prednisolone �10 mgdaily as a second-line option for acute gout prophylaxis,with the caveat that there is a lack of published robust datafor the use of low-dose oral prednisone for gout prophy-laxis. More investigation is needed to improve manage-ment for this clinical problem. Assessment of modulationof cardiovascular event risks by colchicine prophylaxis orby NSAIDs (66) in patients with gout would be particularly

Limitations of the recommendations presented in this30% were based on level A

evidence, with approximately half based on level C evi-dence; this indicates the need for more studies in theaspects of gout management considered here. The processused here was limited by the current trial designs forassessment of acute gout therapies and prophylaxis ofantiinflammatory pharmacologic agents in gout. For acutegout studies, most studies were on NSAIDs and involvedan active comparator and noninferiority trial design. How-ever, the majority of these studies failed to provide anoninferiority margin, which needs to be defined a priorito assess the validity of these trials. Although the majorityof studies assessed pain as the primary outcome for theacute gout trials, there is a lack of a single uniform measurethat precludes meta-analysis. Furthermore, there is a lackof consensus on what time period after initiation of ther-apy constitutes a primary response, since trials rangedfrom a few hours to 10 days. With the exception of recentanalyses of biologic IL-1 inhibitors (56,57), there was alack of robust clinical trials of gout attack prophylaxisusing antiinflammatory pharmacologic agents. Also, theprimary measure in these trials is the recurrence of self-reported acute gout attacks, an outcome that has not beenvalidated using Outcome Measures in Rheumatology cri-teria (67). Efforts are underway to precisely define acutegout attack in gout clinical trials (68). Last, the RAND/UCLA methodology did not address important societaland patient preference issues on treatment costs and cost-effectiveness comparisons between medication choices foracute gout and pharmacologic prophylaxis of acute goutattacks. This is already a pressing question with respect touse of agents, including colchicine and COX-2 selectiveinhibitors, and would be expected to emerge as a largerissue if biologic IL-1 inhibitors, in late-stage clinical de-velopment after phase III studies at the time this waswritten, obtain regulatory approval for acute gout treat-ment and prophylaxis.

In summary, these guidelines, the first from the ACRfor the management and antiinflammatory prophylaxisof acute attacks of gouty arthritis, have been developedto provide recommendations to clinicians treating pati-ents with gout. The ACR plans to update these guide-lines to capture future treatments or advances in the

1458 Khanna et al

management and prophylaxis of acute gout, and as therisk/benefit ratios of emerging therapies are further inves-tigated.

Addendum. Therapies that were approved after theoriginal literature review, or diet and lifestyle measuresstudied after the original literature review, are not in-cluded in these recommendations.

ACKNOWLEDGMENTSWe thank Ms Amy Miller and Ms Regina Parker of the ACRfor administrative support and guidance. Drs. JenniferGrossman (UCLA), Michael Weinblatt (Brigham and Wom-en’s Hospital, Harvard Medical School), Ken Saag (Univer-sity of Alabama, Birmingham), and Ted Ganiats (Univer-sity of California, San Diego) provided valuable guidanceon the objectives and process. Rikke Ogawa (UCLA) pro-vided greatly appreciated service as a medical researchlibrarian.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors ap-proved the final version to be published. Dr. Terkeltaub had fullaccess to all of the data in the study and takes responsibility forthe integrity of the data and the accuracy of the data analysis.Study conception and design.Fitzgerald, Bae, Neogi, Pillinger, Merill, Lee, Perez-Ruiz, Choi,Jasvinder A. Singh, Dalbeth, Kaplan, Roessler, Mandell,Schumacher, Robbins, Wenger, Terkeltaub.Acquisition of data. Dinesh Khanna, Puja P. Khanna, Fitzgerald,Manjit K. Singh, Bae, Pillinger, Lee, Prakash, Gogia, Taylor,Choi, Kaplan, Roessler, Kerr, King, Edwards, Mandell, Wenger,Terkeltaub.Analysis and interpretation of data.Khanna, Fitzgerald, Manjit K. Singh, Bae, Neogi, Merill, Lee,Kaldas, Liote, Choi, Kaplan, Niyyar, Jones, Yarows, Roessler, Kerr,King, Levy, Furst, Mandell, Schumacher, Robbins, Wenger,Terkeltaub.

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