Curr Rheumatol Rep (2014) 16:458 DOI 10.1007/s11926-014-0458-z
SURGERY AND PERIOPERATIVE CARE (CR MACKENZIE AND SM GOODMAN, SECTION EDITORS)
Inpatient Gout: A Review Mark C. Fisher & Michael H. Pillinger & Robert T. Keenan
Published online: 12 October 2014 # Springer Science+Business Media New York 2014
Keywords Gout, Inpatient . Hospitalization . Healthcare Burden
Introduction Gout is the most common inflammatory arthritis, currently affecting over 8 million people in the United States alone. Moreover, gout incidence has been rising for at least the last four decades [1•, 2]. Though gout is primarily considered an outpatient problem, acute gouty attacks are both a cause and a consequence of hospital admission, and gout—whether acute or chronic - can impact both morbidity and length of stay [3–5]. The purpose of this paper is to review the literature on inpatient gout, including diagnostic challenges, risk of flare associated with hospitalization, treatment, and its impact as a healthcare burden.
Methods Pubmed, EMBASE, and Ovid searches were performed using the terms gout and hospital, and gout and
This article is part of the Topical Collection on Surgery and Perioperative Care M. C. Fisher (*) Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, 2100 Yawkey 55 Fruit St., Boston, MA 02114, USA e-mail: [email protected] M. H. Pillinger Department of Medicine, New York University School of Medicine, New York, USA R. T. Keenan Division of Rheumatology and Immunology, Duke University School of Medicine, Durham, USA
inpatient. Only English-language publications were reviewed. A total of 1732 publications were identified, and, if the title suggested a possible inpatient component, abstracts were reviewed for relevance. We also reviewed the bibliographies of all relevant manuscripts to identify other pertinent studies.
Diagnostic Challenges In the inpatient setting, presentation of a single inflammed joint has a broad differential. Oligo-articular or polyarticular inflammatory arthritis, fever, or an elevated white blood cell count may further complicate the picture, making the diagnosis of acute joint pain more elusive. The possibility of a crystal-induced arthropathy may go unconsidered, resulting in unnecessary delay and/or waste of resources. In a review of 67 inpatient consults for possible crystalline arthropathy over 5 years, 41 patients were diagnosed with gout, and 2 with both gout and pseudogout [6]. Importantly, a quarter of these patients were noted to have experienced errors in diagnosis or treatment prior to rheumatology consultation: 11 patients had their gout diagnosis delayed, and 6 patients initially received inappropriate therapy. This analysis likely underrepresents the number of actual gout patients, however, as many patients with gout likely never underwent rheumatology consultation, and in at least some cases, the diagnosis was probably never even considered. In a retrospective review of 138 patients hospitalized with gout at a single center, only 79 (57 %) were seen by a rheumatologist during their hospital course [7]. Moreover—and despite consensus that synovial fluid polarizing microscopy examination for extracellular and intracellular monosodium urate crystals is the gold standard for gout diagnosis— many patients never underwent arthrocentesis [8]. Patients seen by a rheumatologist were much more likely to have
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had an arthrocentesis (51.9 vs. 18.6 %). Of the 52 patients who underwent arthrocentesis, monosodium urate crystals were identified in 96.2 % of fluid examinations; two patients seen by rheumatology with a negative arthrocentesis were nonetheless diagnosed with gout. Among the 88 patients who did not undergo arthrocentesis, the diagnosis was made by clinical impression (50.6 % of those seen by rheumatology, 81.4 % of those seen by other practitioners). Unfortunately, clinical impression is of limited utility, since an arthrocentesis performed after the clinical impression is made will often yield an alternative diagnosis. In a review of all patients undergoing arthrocentesis performed by a rheumatology service over 14 months (86 aspirations), a definitive diagnosis of gout was made in only 44 % [9]. Other diagnoses included septic arthritis (8 cases) and pseudogout (2 cases). These alternative diagnoses are also quite notable, as they should be included in the differential diagnosis of any patient who also would be evaluated for possible gout, and in the case of septic arthritis, delay in diagnosis could be catastrophic. An additional 25 patients were characterized as having an inflammatory fluid but were not assigned any diagnosis; it is likely that a significant percentage of these also had gout.
Risk of Flare Associated with Hospitalization Despite physician conviction that flare rates increase during hospitalization, only a few studies have formally examined this question. In one study of patients with a history of gout undergoing surgery, 302 patients were identified over a 10year period, 52 (17.2 %) of whom experienced a post-surgical gout flare [10]. In a review of patients undergoing bariatric surgery, 21 patients had a history of gout, and 7 (33 %) flared post-operatively, though in some cases the flare occurred postdischarge [11]. In a case–control study, Kang et al. examined 390 patients, comparing 323 subjects with a history of gout who did not flare post-surgery (82.8 %) versus 67 subjects who developed post-surgical gout (17.2 %) (out of 390 patients with a history of gout), noting that post-surgical gout tended to occur within 8 days post-operatively, and that prophylactic administration of colchicine was associated with decreased risk of gout flare [12]. Dubreuil et al. performed an online, case-crossover study to assess for triggers of recurrent gout attacks [13•]. As part of the authors’ assessment, they assessed the impact of hospitalization on risk of flare. Of 724 patients assessed, 614 met ACR criteria for gout. Over 1 year, 35 hospitalizations occurred. For two patients, the gout attack was the primary reason for the hospitalization; for all others, the gout attack occurred after hospital admission. Seven of the patients had their first-ever episode of gout. In
Curr Rheumatol Rep (2014) 16:458
a multivariate analysis, hospitalization increased the risk of gout attack 4-fold (OR 4.05, 95 % CI 1.78–9.19). Several theories have been proposed as to why hospitalization might lead to a gout flare. These include volume depletion or acidosis, both of which can impact renal urate handling and raise serum urate [14, 15]. Discontinuation of urate lowering therapy (in contradiction of the 2012 American College of Rheumatology Gout Treatment Guidelines) in patients with established gout is a common practice during hospitalizations and can lead to acute increases in serum urate [16••]. Conversely, over-hydration may lead to acute declines in serum urate, partial dissolution of urate deposits and release of urate crystals. Medications used during hospitalization, particularly diuretics, heparin, low dose aspirin, or beta blockers, may also predispose to gout attacks. In addition, in one study, surgery itself was associated with increased systemic inflammation and decreased serum urate, despite no increase in uric acid excretion in the urine [17]. Any of these alterations in uric acid concentration may promote acute formation or release (urate “stripping”) of urate crystals, triggering acute gouty arthritis. The presence of gout may also contribute to rates of hospitalization. Of note, up to 18 % of patients with gout are hospitalized annually, a number much higher than observed in the general population [4]. While some of these hospitalizations may reflect admission for a gout attack, in others, gout and/or hyperuricemia may be a marker for other comorbidities that may lead to admission, including hypertension, coronary artery disease, chronic kidney disease, and diabetes. These problems, and the risk of admission, may be compounded by poor outpatient gout management.
Management of Inpatient Gout Management of gout in the inpatient setting can be complicated, as most patients are admitted for other morbidities that may present relative or absolute contraindications to one or more standard gout therapies. A review of 575 gout patients showed that over 90 % have contraindications to NSAID use and/or glucocorticoid use, and about 50 % have relative or absolute contraindications to colchicine use [18]. The extent to which hospitalized gout patients may have similar or— possibly even more likely—increased rates of these contraindications has never been assessed. A 2-year, retrospective review at a 400-bed hospital identified 79 patients with acute gout diagnosed during their hospital course, from among 184 patients with a past history of the condition. Of these, 15 were admitted for gout, and 64 were admitted for other reasons [19]. Only 30 (of 79) of these admitted patients received rheumatology consultation during their hospital stay, and only 20 underwent diagnostic arthrocentesis (14 by rheumatology, 6 by orthopedics). Colchicine was prescribed to treat 53 % of patients, and NSAIDs
Curr Rheumatol Rep (2014) 16:458
to 51 %. Combination therapy was used in 52 % of patients. Among patients who also had renal failure, 36 were treated with colchicine, and 32 with NSAIDs, representing a potential contraindication. Despite being diagnosed with gout, only 27 % of the subjects had their serum uric acid assessed, either before or after their attack. A 20-month retrospective review of 134 patients suffering an acute attack of gout during admission to a tertiary referral center found that most (118, 88.1 %) had been admitted to a non-rheumatology service [20]. Over 50 % of patients had allopurinol discontinued during their hospital course, 19 % had their allopurinol dose increased, and 8 % had their allopurinol decreased. in contrast to ACR Gout Treatment Guidelines, which generally recommend maintaining a steady dose of urate-lowering drug during acute attacks. Upon admission, prophylactic medications were also frequently discontinued; colchicine was discontinued in 37 %, NSAIDs in 46 %, and prednisone in 21 % of patients. Among patients who received treatment for acute gout, 75 % received colchicine, 32 % oral NSAIDs, 28 % prednisone, 7 % intra-articular steroids, and 1 % received ACTH. More than 42 % required 2 or more of these treatments for their flare, and 16 % received 3 medications (typically colchicine, NSAID and corticosteroids, despite ACR recommendations that do not include the combining of NSAIDs and corticosteroids). By the authors’ analysis, 24.6 % of patients received inappropriately selected therapy. Allopurinol was started during the acute flare in 5.2 % of patients. Strikingly, in 9 % of patients, only analgesia was prescribed, without any anti-inflammatory or anti-gout medications. Of the 118 patients not on a rheumatology service diagnosed with gout (primarily presumptively), rheumatology was consulted for 40 patients (33.9 %). Patients seen by a rheumatologist were more likely to have their serum urate measured, have a synovial aspirate performed, and/or have imaging of the involved joints. Therapy for acute gout was often delayed, with 29 % of patients having a delay of 2 or more days before treatment was initiated. On review of 125 available discharge summaries, only 26 % had rheumatology follow-up planned. These studies illustrate shortcomings in inpatient gout management, both in terms of appropriate therapy for acute arthritis (frequent delays in therapy and inappropriate dosing), and in terms of chronic disease (mismanagement of urate lowering therapies in-hospital). Kamalaraj et al. attempted to implement a protocol for nonrheumatologists to follow for management of inpatient acute gout [21••]. The protocol included assessment of all patients with a history of gout upon admission, noting current medications for gout, and recommending continuation if at all possible. For all episodes of acute joint pain, gout was to be urgently considered with recommendation for aspiration and rheumatology consultation if the diagnosis was questionable. In all cases specific laboratories and studies were recommended, along with immediate implementation of therapy, for
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which several possibilities were listed based on possible comorbidities. If the diagnosis of gout was considered very likely, therapy could proceed without rheumatology consultation. However, rheumatology consultation was always available, and recommended for difficult diagnoses and/or therapeutic management. Totals of 118 pre-protocol and 89 postprotocol patients were compared. Allopurinol was much less likely to be discontinued (20 vs. 56.3 %) among subjects treated according to the protocol. Numbers were too small to assess the impact of the protocol on discontinuation of NSAIDs, colchicine or prednisone. Other benefits of protocolized care that were observed included decreases in: allopurinol initiations during acute attack (47.8 vs. 100 %); inappropriate use of high-dose colchicine (1.5 vs. 22.1 %); and inappropriate use of NSAIDs (30 vs. 40.6 %). Prednisone usage was increased on the protocol (22.6 vs. 8.7 %). Rheumatology consultation also increased, from 37.3 to 55.1 %. Treatment was initiated much more rapidly: median time to initiation of therapy from symptom onset went from 2 days to same day, and delays of 3 or more days went from 33 to 5.6 %. These data suggest that, for the inpatient setting at least, protocol-based treatment of gout may accelerate care and improve outcomes. In addition to conventional therapies, IL-1β inhibition has been used off-label for the treatment of acute gout in the hospital setting. A review of 26 patients, receiving a total of 40 courses of anakinra, noted marked improvement in 67 % by 24 h, and complete resolution in 5 days in 72.5 % [22]. Only 1 patient was completely refractory to anakinra, and there were no adverse events attributed to this drug. ACTH is also used off label for the treatment of gout, and has also been studied in the hospital setting [23]. A retrospective review of 181 patients showed 77.9 % improvement in pain one day post injection. Of the 40 non-responders, 82.85 % responded to a 2nd injection the next day. The side effects, risks, and costs of these medications do need to be considered when contemplating their usage.
Hospital Healthcare Burden In an assessment of the impact of gout among US military veterans, conducted from October 2006 to March 2008, 18.3 % of patients with gout underwent hospitalization, compared to 15.1 % of patients without gout [4]. In another study, a survey of 296 patients with gout revealed that 7.2 % required overnight hospitalization specifically for their gout [24]. In an assessment of gout admissions across an entire country (New Zealand) from 1999 to 2009, the number of gout admissions increased by 61 % over the 10 years, (approximately 5.5 % annually) [25]. These increases are roughly consistent with reported increases in overall prevalence during that period, and accounted for between 0.09 and 0.11 % of all
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hospital admissions annually. Patients with a history of gout admitted for other reasons accounted for an additional 0.38 % of all hospital admissions during that time, most commonly for heart failure (9 %), acute myocardial infarction (5 %), angina (4.5 %), cellulitis (4.3 %), and pneumonia (3.8 %). The authors were able to contrast these data to admissions for gout in England over the same period of time (0.021–0.031 % of all admissions annually), with the rate in England increasing by 86.6 % during the 10 years (approximately 7.2 % annually). The difference between the New Zealand and England rates most likely reflects the difference in gout prevalence in these two populations. These data show that the burden of inpatient acute gout is rising. The financial impact of an episode of gout during hospitalization is substantial. In an insurance database of about 300,000 patients with a prevalence of gout of about 0.47 %, gout was associated with increased annual hospitalization costs, on average US$1371 versus $615.26 [26]. These data did not discriminate whether the cost was due to hospitalization for gout or for other reasons, or if gout impacted a hospitalization that was for a different primary indication. In a retrospective review of 920 patients admitted with ischemic stroke, gout was associated with an increased length of stay (17.17 vs. 14.01 days) [27]. In another retrospective review of 77 patients who developed an episode of gout during their hospitalization, compared with matched control patients, patients with gout experienced a 6-day increase in length of stay (9 vs. 3 days) [28]. Gout severity also matters. Patients with refractory gout, defined as either 3–5 episodes or ≥6 episodes a year of acute gouty arthritis, were more likely to be hospitalized (OR for inpatient care 4.38 and 16.41, respectively), and hospitalizations among this cohort were associated with significantly higher costs for hospitalization (US$3056/year and US$8571, respectively) [29]. Interestingly, Wasserman et al. have reported that hyperuricemia is an independent predictor of mortality among patients admitted to the internal medicine wards of an academic hospital, regardless of the admission diagnosis [30]. Can the care and cost burdens of inpatient gout be modified? A case–control study comparing patients with gout requiring multiple hospitalizations for primary diagnosis of gout, matched with gout patients who did not require admission, found that medical comorbidity, particularly heart disease, hyperuricemia, and inadequate allopurinol dosing all increased the risk of admission specifically for gout [31]. This suggests that more active gout management can prevent admission for primary diagnosis of gout.
Conclusion Although often considered primarily an outpatient issue, acute gout represents a significant diagnostic challenge in the
Curr Rheumatol Rep (2014) 16:458
inpatient setting, often resulting in delayed or inappropriate treatment. Hospitalization is associated with a significantly increased risk of acute gout, and management in the inpatient setting is often complicated by underlying comorbid conditions. Moreover, inpatient gout is a significant contributor to both the management of other conditions, and to increased healthcare costs. Improvements in diagnosis and management would likely lead to decreased morbidity and cost associated with this diagnosis. Compliance with Ethics Guidelines Conflict of Interest Mark C. Fisher declares no conflict of interest. Michael H. Pillinger reports that he has served as a consultant for Savient, and for Crealta. He is the recipient of investigator-initiated grants from Takeda and Savient, and currently serves as a site investigator for a clinical study by Takeda, outside the submitted work. Robert T. Keenan reports that he has served as a consultant for Takeda, AstraZeneca, and Crealta, Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.• Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10): 3136–41. This paper illustrates the increasing prevalence of gout in the United States and discusses its significance. 2. Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol. 2002;29(11):2403–6. 3. Mandell BF, Edwards NL, Sundy JS, et al. Preventing and treating acute gout attacks across the clinical spectrum: a roundtable discussion. Cleve Clin J Med. 2010;77 Suppl 2:S2–25. doi:10.3949/ccjm. 77.s2.01. 4. Singh JA, Strand V. Gout is associated with more comorbidities, poorer health-related quality of life and higher healthcare utilisation in US veterans. Ann Rheum Dis. 2008;67(9):1310–6. 5. Saseen JJ, Agashivala N, Allen RR, et al. Comparison of patient characteristics and gout-related health-care resource utilization and costs in patients with frequent versus infrequent gouty arthritis attacks. Rheumatology (Oxford). 2012;51(11):2004–12. 6. Ho Jr G, DeNuccio M. Gout and pseudogout in hospitalized patients. Arch Intern Med. 1993;153(24):2787–90. 7. Barber C, Thompson K, Hanly JG. Impact of a rheumatology consultation service on the diagnostic accuracy and management of gout in hospitalized patients. J Rheumatol. 2009;36(8):1699– 704. 8. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20(3):895–900.
Curr Rheumatol Rep (2014) 16:458 9.
Chong YY, Fong KY, Thumboo J. The value of joint aspirations in the diagnosis and management of arthritis in a hospital-based rheumatology service. Ann Acad Med Singapore. 2007;36(2): 106–9. 10. Craig MH, Poole GV, Hauser CJ. Postsurgical gout. Am Surg. 1995;61(1):56–9. 11. Friedman JE, Dallal RM, Lord JL. Gouty attacks occur frequently in postoperative gastric bypass patients. Surg Obes Relat Dis. 2008;4(1):11–3. 12. Kang EH, Lee EY, Lee YJ, et al. Clinical features and risk factors of postsurgical gout. Ann Rheum Dis. 2008;67(9):1271–5. 13.• Dubreuil M, Neogi T, Chen CA, et al. Increased risk of recurrent gout attacks with hospitalization. Am J Med. 2013;126(12):1138– 41. This study illustrates the risk of gout flare associated with hospitalization. 14. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143(7):499–516. 15. Richette P, Bardin T. Purine-rich foods: an innocent bystander of gout attacks? Ann Rheum Dis. 2012;71(9):1435–6. 16.•• Khanna D, Khanna PP, Fitzgerald JD, et al. American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10):1447–61. This review discusses the evidence-based medicine and expert opinion for management of gout. 17. Waldron JL, Ashby HL, Razavi C, et al. The effect of the systemic inflammatory response, as provoked by elective orthopaedic surgery, on serum uric acid in patients without gout: a prospective study. Rheumatology (Oxford). 2013;52(4):676– 8. 18. Keenan RT, O'Brien WR, Lee KH, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011;124(2):155–63. 19. Petersel D, Schlesinger N. Treatment of acute gout in hospitalized patients. J Rheumatol. 2007;34(7):1566–8.
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Gnanenthiran SR, Hassett GM, Gibson KA, et al. Acute gout management during hospitalization: a need for a protocol. Intern Med J. 2011;41(8):610–7. 21.•• Kamalaraj N, Gnanenthiran SR, Kathirgamanathan T, et al. Improved management of acute gout during hospitalization following introduction of a protocol. Int J Rheum Dis. 2012;15(6):512– 20. This study illustrates how protocol driven therapy can improved gout outcomes during hospitalization. 22. Ghosh P, Cho M, Rawat G, et al. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken). 2013;65(8):1381–4. 23. Daoussis D, Antonopoulos I, Yiannopoulos G, et al. ACTH as first line treatment for acute gout in 181 hospitalized patients. Joint Bone Spine. 2013;80(3):291–4. 24. Singh JA, Sarkin A, Shieh M, et al. Health care utilization in patients with gout. Semin Arthritis Rheum. 2011;40(6):501–11. 25. Robinson PC, Merriman TR, Herbison P, et al. Hospital admissions associated with gout and their comorbidities in New Zealand and England 1999-2009. Rheumatology (Oxford). 2013;52(1):118–26. 26. Brook RA, Kleinman NL, Patel PA, et al. The economic burden of gout on an employed population. Curr Med Res Opin. 2006;22(7):1381–9. 27. Lin YH, Hsu HL, Huang YC, et al. Gouty arthritis in acute cerebrovascular disease. Cerebrovasc Dis. 2009;28(4):391–6. 28. Lee G, Roberts L. Healthcare burden of in-hospital gout. Intern Med J. 2012;42(11):1261–3. 29. Wu EQ, Forsythe A, Guérin A, et al. Comorbidity burden, healthcare resource utilization, and costs in chronic gout patients refractory to conventional urate-lowering therapy. Am J Ther. 2012;19(6):e157–66. 30. Wasserman A, Shnell M, Boursi B, et al. Prognostic significance of serum uric acid in patients admitted to the Department of Medicine. Am J Med Sci. 2010;339(1):15–21. 31. Hutton I, Gamble G, Gow P, et al. Factors associated with recurrent hospital admissions for gout: a case-control study. J Clin Rheumatol. 2009;15(6):271–4.
SURGERY AND PERIOPERATIVE CARE (CR MACKENZIE AND SM GOODMAN, SECTION EDITORS)
Inpatient Gout: A Review Mark C. Fisher & Michael H. Pillinger & Robert T. Keenan
Published online: 12 October 2014 # Springer Science+Business Media New York 2014
Keywords Gout, Inpatient . Hospitalization . Healthcare Burden
Introduction Gout is the most common inflammatory arthritis, currently affecting over 8 million people in the United States alone. Moreover, gout incidence has been rising for at least the last four decades [1•, 2]. Though gout is primarily considered an outpatient problem, acute gouty attacks are both a cause and a consequence of hospital admission, and gout—whether acute or chronic - can impact both morbidity and length of stay [3–5]. The purpose of this paper is to review the literature on inpatient gout, including diagnostic challenges, risk of flare associated with hospitalization, treatment, and its impact as a healthcare burden.
Methods Pubmed, EMBASE, and Ovid searches were performed using the terms gout and hospital, and gout and
This article is part of the Topical Collection on Surgery and Perioperative Care M. C. Fisher (*) Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, 2100 Yawkey 55 Fruit St., Boston, MA 02114, USA e-mail: [email protected] M. H. Pillinger Department of Medicine, New York University School of Medicine, New York, USA R. T. Keenan Division of Rheumatology and Immunology, Duke University School of Medicine, Durham, USA
inpatient. Only English-language publications were reviewed. A total of 1732 publications were identified, and, if the title suggested a possible inpatient component, abstracts were reviewed for relevance. We also reviewed the bibliographies of all relevant manuscripts to identify other pertinent studies.
Diagnostic Challenges In the inpatient setting, presentation of a single inflammed joint has a broad differential. Oligo-articular or polyarticular inflammatory arthritis, fever, or an elevated white blood cell count may further complicate the picture, making the diagnosis of acute joint pain more elusive. The possibility of a crystal-induced arthropathy may go unconsidered, resulting in unnecessary delay and/or waste of resources. In a review of 67 inpatient consults for possible crystalline arthropathy over 5 years, 41 patients were diagnosed with gout, and 2 with both gout and pseudogout [6]. Importantly, a quarter of these patients were noted to have experienced errors in diagnosis or treatment prior to rheumatology consultation: 11 patients had their gout diagnosis delayed, and 6 patients initially received inappropriate therapy. This analysis likely underrepresents the number of actual gout patients, however, as many patients with gout likely never underwent rheumatology consultation, and in at least some cases, the diagnosis was probably never even considered. In a retrospective review of 138 patients hospitalized with gout at a single center, only 79 (57 %) were seen by a rheumatologist during their hospital course [7]. Moreover—and despite consensus that synovial fluid polarizing microscopy examination for extracellular and intracellular monosodium urate crystals is the gold standard for gout diagnosis— many patients never underwent arthrocentesis [8]. Patients seen by a rheumatologist were much more likely to have
458, Page 2 of 5
had an arthrocentesis (51.9 vs. 18.6 %). Of the 52 patients who underwent arthrocentesis, monosodium urate crystals were identified in 96.2 % of fluid examinations; two patients seen by rheumatology with a negative arthrocentesis were nonetheless diagnosed with gout. Among the 88 patients who did not undergo arthrocentesis, the diagnosis was made by clinical impression (50.6 % of those seen by rheumatology, 81.4 % of those seen by other practitioners). Unfortunately, clinical impression is of limited utility, since an arthrocentesis performed after the clinical impression is made will often yield an alternative diagnosis. In a review of all patients undergoing arthrocentesis performed by a rheumatology service over 14 months (86 aspirations), a definitive diagnosis of gout was made in only 44 % [9]. Other diagnoses included septic arthritis (8 cases) and pseudogout (2 cases). These alternative diagnoses are also quite notable, as they should be included in the differential diagnosis of any patient who also would be evaluated for possible gout, and in the case of septic arthritis, delay in diagnosis could be catastrophic. An additional 25 patients were characterized as having an inflammatory fluid but were not assigned any diagnosis; it is likely that a significant percentage of these also had gout.
Risk of Flare Associated with Hospitalization Despite physician conviction that flare rates increase during hospitalization, only a few studies have formally examined this question. In one study of patients with a history of gout undergoing surgery, 302 patients were identified over a 10year period, 52 (17.2 %) of whom experienced a post-surgical gout flare [10]. In a review of patients undergoing bariatric surgery, 21 patients had a history of gout, and 7 (33 %) flared post-operatively, though in some cases the flare occurred postdischarge [11]. In a case–control study, Kang et al. examined 390 patients, comparing 323 subjects with a history of gout who did not flare post-surgery (82.8 %) versus 67 subjects who developed post-surgical gout (17.2 %) (out of 390 patients with a history of gout), noting that post-surgical gout tended to occur within 8 days post-operatively, and that prophylactic administration of colchicine was associated with decreased risk of gout flare [12]. Dubreuil et al. performed an online, case-crossover study to assess for triggers of recurrent gout attacks [13•]. As part of the authors’ assessment, they assessed the impact of hospitalization on risk of flare. Of 724 patients assessed, 614 met ACR criteria for gout. Over 1 year, 35 hospitalizations occurred. For two patients, the gout attack was the primary reason for the hospitalization; for all others, the gout attack occurred after hospital admission. Seven of the patients had their first-ever episode of gout. In
Curr Rheumatol Rep (2014) 16:458
a multivariate analysis, hospitalization increased the risk of gout attack 4-fold (OR 4.05, 95 % CI 1.78–9.19). Several theories have been proposed as to why hospitalization might lead to a gout flare. These include volume depletion or acidosis, both of which can impact renal urate handling and raise serum urate [14, 15]. Discontinuation of urate lowering therapy (in contradiction of the 2012 American College of Rheumatology Gout Treatment Guidelines) in patients with established gout is a common practice during hospitalizations and can lead to acute increases in serum urate [16••]. Conversely, over-hydration may lead to acute declines in serum urate, partial dissolution of urate deposits and release of urate crystals. Medications used during hospitalization, particularly diuretics, heparin, low dose aspirin, or beta blockers, may also predispose to gout attacks. In addition, in one study, surgery itself was associated with increased systemic inflammation and decreased serum urate, despite no increase in uric acid excretion in the urine [17]. Any of these alterations in uric acid concentration may promote acute formation or release (urate “stripping”) of urate crystals, triggering acute gouty arthritis. The presence of gout may also contribute to rates of hospitalization. Of note, up to 18 % of patients with gout are hospitalized annually, a number much higher than observed in the general population [4]. While some of these hospitalizations may reflect admission for a gout attack, in others, gout and/or hyperuricemia may be a marker for other comorbidities that may lead to admission, including hypertension, coronary artery disease, chronic kidney disease, and diabetes. These problems, and the risk of admission, may be compounded by poor outpatient gout management.
Management of Inpatient Gout Management of gout in the inpatient setting can be complicated, as most patients are admitted for other morbidities that may present relative or absolute contraindications to one or more standard gout therapies. A review of 575 gout patients showed that over 90 % have contraindications to NSAID use and/or glucocorticoid use, and about 50 % have relative or absolute contraindications to colchicine use [18]. The extent to which hospitalized gout patients may have similar or— possibly even more likely—increased rates of these contraindications has never been assessed. A 2-year, retrospective review at a 400-bed hospital identified 79 patients with acute gout diagnosed during their hospital course, from among 184 patients with a past history of the condition. Of these, 15 were admitted for gout, and 64 were admitted for other reasons [19]. Only 30 (of 79) of these admitted patients received rheumatology consultation during their hospital stay, and only 20 underwent diagnostic arthrocentesis (14 by rheumatology, 6 by orthopedics). Colchicine was prescribed to treat 53 % of patients, and NSAIDs
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to 51 %. Combination therapy was used in 52 % of patients. Among patients who also had renal failure, 36 were treated with colchicine, and 32 with NSAIDs, representing a potential contraindication. Despite being diagnosed with gout, only 27 % of the subjects had their serum uric acid assessed, either before or after their attack. A 20-month retrospective review of 134 patients suffering an acute attack of gout during admission to a tertiary referral center found that most (118, 88.1 %) had been admitted to a non-rheumatology service [20]. Over 50 % of patients had allopurinol discontinued during their hospital course, 19 % had their allopurinol dose increased, and 8 % had their allopurinol decreased. in contrast to ACR Gout Treatment Guidelines, which generally recommend maintaining a steady dose of urate-lowering drug during acute attacks. Upon admission, prophylactic medications were also frequently discontinued; colchicine was discontinued in 37 %, NSAIDs in 46 %, and prednisone in 21 % of patients. Among patients who received treatment for acute gout, 75 % received colchicine, 32 % oral NSAIDs, 28 % prednisone, 7 % intra-articular steroids, and 1 % received ACTH. More than 42 % required 2 or more of these treatments for their flare, and 16 % received 3 medications (typically colchicine, NSAID and corticosteroids, despite ACR recommendations that do not include the combining of NSAIDs and corticosteroids). By the authors’ analysis, 24.6 % of patients received inappropriately selected therapy. Allopurinol was started during the acute flare in 5.2 % of patients. Strikingly, in 9 % of patients, only analgesia was prescribed, without any anti-inflammatory or anti-gout medications. Of the 118 patients not on a rheumatology service diagnosed with gout (primarily presumptively), rheumatology was consulted for 40 patients (33.9 %). Patients seen by a rheumatologist were more likely to have their serum urate measured, have a synovial aspirate performed, and/or have imaging of the involved joints. Therapy for acute gout was often delayed, with 29 % of patients having a delay of 2 or more days before treatment was initiated. On review of 125 available discharge summaries, only 26 % had rheumatology follow-up planned. These studies illustrate shortcomings in inpatient gout management, both in terms of appropriate therapy for acute arthritis (frequent delays in therapy and inappropriate dosing), and in terms of chronic disease (mismanagement of urate lowering therapies in-hospital). Kamalaraj et al. attempted to implement a protocol for nonrheumatologists to follow for management of inpatient acute gout [21••]. The protocol included assessment of all patients with a history of gout upon admission, noting current medications for gout, and recommending continuation if at all possible. For all episodes of acute joint pain, gout was to be urgently considered with recommendation for aspiration and rheumatology consultation if the diagnosis was questionable. In all cases specific laboratories and studies were recommended, along with immediate implementation of therapy, for
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which several possibilities were listed based on possible comorbidities. If the diagnosis of gout was considered very likely, therapy could proceed without rheumatology consultation. However, rheumatology consultation was always available, and recommended for difficult diagnoses and/or therapeutic management. Totals of 118 pre-protocol and 89 postprotocol patients were compared. Allopurinol was much less likely to be discontinued (20 vs. 56.3 %) among subjects treated according to the protocol. Numbers were too small to assess the impact of the protocol on discontinuation of NSAIDs, colchicine or prednisone. Other benefits of protocolized care that were observed included decreases in: allopurinol initiations during acute attack (47.8 vs. 100 %); inappropriate use of high-dose colchicine (1.5 vs. 22.1 %); and inappropriate use of NSAIDs (30 vs. 40.6 %). Prednisone usage was increased on the protocol (22.6 vs. 8.7 %). Rheumatology consultation also increased, from 37.3 to 55.1 %. Treatment was initiated much more rapidly: median time to initiation of therapy from symptom onset went from 2 days to same day, and delays of 3 or more days went from 33 to 5.6 %. These data suggest that, for the inpatient setting at least, protocol-based treatment of gout may accelerate care and improve outcomes. In addition to conventional therapies, IL-1β inhibition has been used off-label for the treatment of acute gout in the hospital setting. A review of 26 patients, receiving a total of 40 courses of anakinra, noted marked improvement in 67 % by 24 h, and complete resolution in 5 days in 72.5 % [22]. Only 1 patient was completely refractory to anakinra, and there were no adverse events attributed to this drug. ACTH is also used off label for the treatment of gout, and has also been studied in the hospital setting [23]. A retrospective review of 181 patients showed 77.9 % improvement in pain one day post injection. Of the 40 non-responders, 82.85 % responded to a 2nd injection the next day. The side effects, risks, and costs of these medications do need to be considered when contemplating their usage.
Hospital Healthcare Burden In an assessment of the impact of gout among US military veterans, conducted from October 2006 to March 2008, 18.3 % of patients with gout underwent hospitalization, compared to 15.1 % of patients without gout [4]. In another study, a survey of 296 patients with gout revealed that 7.2 % required overnight hospitalization specifically for their gout [24]. In an assessment of gout admissions across an entire country (New Zealand) from 1999 to 2009, the number of gout admissions increased by 61 % over the 10 years, (approximately 5.5 % annually) [25]. These increases are roughly consistent with reported increases in overall prevalence during that period, and accounted for between 0.09 and 0.11 % of all
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hospital admissions annually. Patients with a history of gout admitted for other reasons accounted for an additional 0.38 % of all hospital admissions during that time, most commonly for heart failure (9 %), acute myocardial infarction (5 %), angina (4.5 %), cellulitis (4.3 %), and pneumonia (3.8 %). The authors were able to contrast these data to admissions for gout in England over the same period of time (0.021–0.031 % of all admissions annually), with the rate in England increasing by 86.6 % during the 10 years (approximately 7.2 % annually). The difference between the New Zealand and England rates most likely reflects the difference in gout prevalence in these two populations. These data show that the burden of inpatient acute gout is rising. The financial impact of an episode of gout during hospitalization is substantial. In an insurance database of about 300,000 patients with a prevalence of gout of about 0.47 %, gout was associated with increased annual hospitalization costs, on average US$1371 versus $615.26 [26]. These data did not discriminate whether the cost was due to hospitalization for gout or for other reasons, or if gout impacted a hospitalization that was for a different primary indication. In a retrospective review of 920 patients admitted with ischemic stroke, gout was associated with an increased length of stay (17.17 vs. 14.01 days) [27]. In another retrospective review of 77 patients who developed an episode of gout during their hospitalization, compared with matched control patients, patients with gout experienced a 6-day increase in length of stay (9 vs. 3 days) [28]. Gout severity also matters. Patients with refractory gout, defined as either 3–5 episodes or ≥6 episodes a year of acute gouty arthritis, were more likely to be hospitalized (OR for inpatient care 4.38 and 16.41, respectively), and hospitalizations among this cohort were associated with significantly higher costs for hospitalization (US$3056/year and US$8571, respectively) [29]. Interestingly, Wasserman et al. have reported that hyperuricemia is an independent predictor of mortality among patients admitted to the internal medicine wards of an academic hospital, regardless of the admission diagnosis [30]. Can the care and cost burdens of inpatient gout be modified? A case–control study comparing patients with gout requiring multiple hospitalizations for primary diagnosis of gout, matched with gout patients who did not require admission, found that medical comorbidity, particularly heart disease, hyperuricemia, and inadequate allopurinol dosing all increased the risk of admission specifically for gout [31]. This suggests that more active gout management can prevent admission for primary diagnosis of gout.
Conclusion Although often considered primarily an outpatient issue, acute gout represents a significant diagnostic challenge in the
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inpatient setting, often resulting in delayed or inappropriate treatment. Hospitalization is associated with a significantly increased risk of acute gout, and management in the inpatient setting is often complicated by underlying comorbid conditions. Moreover, inpatient gout is a significant contributor to both the management of other conditions, and to increased healthcare costs. Improvements in diagnosis and management would likely lead to decreased morbidity and cost associated with this diagnosis. Compliance with Ethics Guidelines Conflict of Interest Mark C. Fisher declares no conflict of interest. Michael H. Pillinger reports that he has served as a consultant for Savient, and for Crealta. He is the recipient of investigator-initiated grants from Takeda and Savient, and currently serves as a site investigator for a clinical study by Takeda, outside the submitted work. Robert T. Keenan reports that he has served as a consultant for Takeda, AstraZeneca, and Crealta, Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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