Gout

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In medicine, gout is a "hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi."[1]

Etiology /cause

Calcium channel blockers and losartan are associated with a lower risk of gout as compared to other medications for hypertension. [2]

Diagnosis

Accuracy of diagnostic criteria for gout among patients who had synovial fluid analysis [3]
  Criteria Sensitivity Specificity
ARA (ACR) 6 of 12 criteria 70% 79%
Rome 2 of 4 criteria:
• Painful joint swelling, abrupt onset, Clearing in 1-2 weeks initially
• Serum uric acid: >7 in males; >6 in females
• Presence of tophi
• Urate crystals in synovial fluid or tissues
70% 83%
New York 2 of 5 criteria:
• 2 attacks of painful limb joint swelling
• Abrupt onset and remission in 1—2 weeks initially
• First MTP attack
• Presence of a tophus
• Response to colchicine-major reduction in inflammation within 48 h
67% 89%

Several sets of diagnostic criteria exit (see table).[3]

The serum uric acid level during an attack of gout[4][5]
  Sensitivity Specificity
> 5.88 mg/dl[4] 95% 53%
≥ 6 mg/dl[5] 86%  ?
≥ 8 mg/dl[5] 68% ?

A clinical prediction rule (online link) found that the following predicted urate crystals by aspiration:[4]

  • Male
  • Onset within one day
  • Joint redness
  • First metatarsaophalangeal joint
  • Previous arthritis attack per patient
  • History of hypertension or 1 or more cardiovascular diseases
  • Serum uric acid level > 5.88 mg/dl

However, among patients with high scores, 20% did not have crystals. Only one of 381 patients had bacterial arthritis.

Treatment

Clinical practice guidelines address treatment.[6][7][8] However, trials comparing glucocorticoids (steroids) and non-steroidal anti-inflammatory agents (NSAIDs) were not published till after the guidelines.

Regarding medications, if there are no mitigating factors in choosing a drug, glucocorticoids, non-steroidal anti-inflammatory agents (NSAIDs), and colchicine all work; however, colchicine consistently causes drug toxicity.

A combination treatment is ice four times a day with oral prednisone 30 mg orally tapered over 6 days (30 mg for two days, 20 mg for two days, 10 mg for two days) and colchicine 0.6 mg/day.[9] An advantage of this regimen is the reduced toxicity from the low dose of colchicine and that the colchicine helps prevent flares if allopurinol is later started. Colchicine has been combined with NSAIDs[10] that are not metabolized by the CYP3A4 isoenzyme of cytochrome P-450 (naproxen is not metabolized by CYP3A4). Combining glucocorticoids with NSAIDs increased the risk for gastrointestinal drug toxicity[11]

Local ice

Ice packs, applied for 30 minutes 4 times per day, can help according to a randomized controlled trial without allocation concealment.[9] In this trial, ice reduced the visual pain analog score by an additional 33 mm beyond the reduction provided by a combination of glucocorticoids and colchicine.

Non-steroidal anti-inflammatory agents

Non-steroidal anti-inflammatory agents (NSAIDs) are better than placebo according to a randomized controlled trial of 30 total patients.[12] According to a summary of this trial, "the knee was affected in 14 cases and the great toe in only two cases. After 24 h, 67% of tenoxicam group had ≥50% reduction in pain compared with 26% of placebo group (P<0.05). However, at the end of the treatment (4 days), there was no significant difference between the groups."[13]

Glucocorticoids

Comparison of NSAID and steroids for acute gout
  Patients Interventions Results
Steroid NSAID
Janssens et al 2008[14] 120 total patients with uric acid crystals on arthrocentesis Prednisolone 35 mg once daily for 5 days Naproxen 500 mg twice daily for 5 days NSAID trended better (88% versus 80% response; p=0.3)
No differences in rates of drug toxicity.
Man et al 2007[15] 90 total patients with clinical diagnosis of gout† Initially prednisolone 30 mg
Followed by prednisolone 30 mg daily for 5 days and as needed acetaminophen
Initially diclofenac 75 mg with indomethacin 50 mg
Followed by indomethacin 50 mg every 8 hrs for 2 days then 25 mg every 8 hrs for 3 days and as needed acetaminophen.
Steroids faster reduction in pain.
Steroids used more acetaminophen.
More adverse effects from indomethacin.

Indomethacin trended to more relapses at 2 weeks (11% vs 17%).

Notes:

† Clinical diagnosis of gout was "pain and warmth in a joint, and presented within 3 days of the onset of pain and also had 1 or more of the following: metatarsal-phalangeal joint involvement; knee or ankle joint involvement and aspirate containing crystals; or typical gouty arthritis, with either gouty tophi present or previous joint aspiration confirming the diagnosis of gout." Seven patients allowed arthrocentesis and all were positive for gout.

Randomized controlled trials find similar benefit from non-steroidal anti-inflammatory agents and oral glucocorticoids. In the first trial the reduction in visual analog scale after 5 days was 44.7 with prednisolone and 46.0 with naproxen.[15] Less adverse drug reactions occurred in the glucocorticoids group; however, the NSAID group received a high dose (50 mg every 8 hours for 2 days, followed by 25 mg every 8 hours for 3 days)[16].

In the second randomized controlled trial statistically equal effect resulted from prednisolone 35 mg orally per day or naproxen 500 mg orally twice per day; however there was an insignificant 8% improvement in the NSAID group.[14] There were no significant differences in drug toxicity.

Colchicine

Colchicine is better than placebo according to a systematic review by the Cochrane Collaboration[17] that found a single randomized controlled trial of 43 patients[18]. In this study, colchicine 1 mg orally, followed by 0.5 mg every two hours led to a 50% reduction in pain in about 70% of patients compared to about 35% of patients who received placebo. However, all patients had drug toxicity from colchicine and in 90% of the patients toxicity occurred before 50% reduction in pain.

Regarding the best dose, 1.2 mg followed by 0.6 mg in 1 hour may be as effective as higher dose.[19]

To avoid drug toxicity, lower doses of colchicine (0.6 per day) have been used in combination with glucocorticoids.[9] The UK National Library for Health recommends 0.5 mg two to four times a day.[20]

Anti-cytokines

The monoclonal antibody against interleukin-1 beta, canakinumab, may help according to a randomized controlled trial.[21]

Prognosis

Acute flares

Without treatment, one third of flares improve within 2 days.[18]

Prevention

Diet

Avoiding products with high fructose such as sugary soft drinks (sweetened with high fructose corn syrup), and other high-fructose products, such as fruit juice, apples, and oranges may help.[22]

Medications

Xanthine oxidase inhibitors

Allopurinol can reduce frequency of attacks.:

  • According to a small randomized controlled trial, allopurinol can be initiated at the time acute therapy is initiated for a flare without increasing complications among patients also started on indomethacin 50 mg 3 times per day for 10 days and colchicine 0.6 mg twice per day.[23] Previously, allopurinol was delayed till resolution of the acute attack.
  • Colchicine 0.6 mg twice daily should also be used to prevent a flare. In a randomized controlled trial, co-treatment with colchicine 0.6 mg twice daily while allopurinol was tapered up from 100 mg/day until 3 months after the serum urate concentration < 6.5 mg/dl, reduced flares of gout from 77% in the placebo broup to 33% with colchicine prophylaxis. Most of these patients had tophi.[10] One third of the patients had diarrhea and many reduced the medication to once per day.
  • Colchicine, or a non-steroidal anti-inflammatory agent, may be needed for six months.[24]

Allopurinol should be increased as possible to achieve a goal serum urate of <6 mg/dl (360 micromoles/liter).[25]

Febuxostat, a non-purine inhibitor, is equally effective as allopurinol when compared in a randomized controlled trial.[26][27]

Uricosuric agents

Famous persons with gout

Holy Roman Emperor Charles V had gout[28] and Theodore Roosevelt may have had gout.[29]

References

  1. Anonymous (2015), Gout (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Choi HK, Soriano LC, Zhang Y, Rodríguez LA (2012). "Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.". BMJ 344: d8190. DOI:10.1136/bmj.d8190. PMID 22240117. PMC PMC3257215. Research Blogging.
  3. 3.0 3.1 Malik A, Schumacher HR, Dinnella JE, Clayburne GM (2009). "Clinical diagnostic criteria for gout: comparison with the gold standard of synovial fluid crystal analysis.". J Clin Rheumatol 15 (1): 22-4. DOI:10.1097/RHU.0b013e3181945b79. PMID 19125136. Research Blogging.
  4. 4.0 4.1 4.2 Janssens HJ, Fransen J, van de Lisdonk EH, van Riel PL, van Weel C, Janssen M (2010). "A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis.". Arch Intern Med 170 (13): 1120-6. DOI:10.1001/archinternmed.2010.196. PMID 20625017. Research Blogging.
  5. 5.0 5.1 5.2 Schlesinger N, Norquist JM, Watson DJ (June 2009). "Serum urate during acute gout". J. Rheumatol. 36 (6): 1287–9. DOI:10.3899/jrheum.080938. PMID 19369457. Research Blogging.
  6. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T et al. (2012). "2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.". Arthritis Care Res (Hoboken) 64 (10): 1447-61. DOI:10.1002/acr.21773. PMID 23024029. Research Blogging.
  7. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T et al. (2012). "2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.". Arthritis Care Res (Hoboken) 64 (10): 1431-46. DOI:10.1002/acr.21772. PMID 23024028. Research Blogging.
  8. Zhang W, Doherty M, Bardin T, et al (October 2006). "EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)". Ann. Rheum. Dis. 65 (10): 1312–24. DOI:10.1136/ard.2006.055269. PMID 16707532. Research Blogging.
  9. 9.0 9.1 9.2 Schlesinger N, Detry MA, Holland BK, et al (2002). "Local ice therapy during bouts of acute gouty arthritis". J. Rheumatol. 29 (2): 331–4. PMID 11838852[e]
  10. 10.0 10.1 Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA (December 2004). "Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis". J. Rheumatol. 31 (12): 2429–32. PMID 15570646[e]
  11. Fries JF, Williams CA, Bloch DA, Michel BA (September 1991). "Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models". Am. J. Med. 91 (3): 213–22. PMID 1892140[e]
  12. García de la Torre, Ignacio. (1987) Estudio doble-ciego paralelo, comparativo con tenoxicam vs placebo en artritis gotosa aguda (A comparative, double-blind, parallel study with tenoxicam vs placebo in acute gouty arthritis). Invet Med Int '14:'92–7 [Abstract in Spanish]
  13. Sutaria S, Katbamna R, Underwood M (November 2006). "Effectiveness of interventions for the treatment of acute and prevention of recurrent gout--a systematic review". Rheumatology (Oxford) 45 (11): 1422–31. DOI:10.1093/rheumatology/kel071. PMID 16632483. Research Blogging.
  14. 14.0 14.1 Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C (May 2008). "Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial". Lancet 371 (9627): 1854–60. DOI:10.1016/S0140-6736(08)60799-0. PMID 18514729. Research Blogging.
  15. 15.0 15.1 Man CY, Cheung IT, Cameron PA, Rainer TH (2007). "Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial". Annals of emergency medicine 49 (5): 670–7. DOI:10.1016/j.annemergmed.2006.11.014. PMID 17276548. Research Blogging.
  16. Henry D, Lim LL, Garcia Rodriguez LA, et al (June 1996). "Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis". BMJ 312 (7046): 1563–6. PMID 8664664. PMC 2351326[e]
  17. Schlesinger N, Schumacher R, Catton M, Maxwell L (2006). "Colchicine for acute gout". Cochrane Database Syst Rev (4): CD006190. DOI:10.1002/14651858.CD006190. PMID 17054279. Research Blogging.
  18. 18.0 18.1 Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M (June 1987). "Does colchicine work? The results of the first controlled study in acute gout". Aust N Z J Med 17 (3): 301–4. DOI:10.1111/j.1445-5994.1987.tb01232.x. PMID 3314832. Research Blogging. Summary at Bandolier
  19. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (2010). "High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.". Arthritis Rheum 62 (4): 1060-8. DOI:10.1002/art.27327. PMID 20131255. Research Blogging.
  20. CKS (2007) Gout - Management (Topic Review). Clinical Knowledge Summaries. http://cks.library.nhs.uk/gout/management [Accessed: Date]
  21. So A, De Meulemeester M, Pikhlak A, Yücel AE, Richard D, Murphy V et al. (2010). "Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.". Arthritis Rheum 62 (10): 3064-76. DOI:10.1002/art.27600. PMID 20533546. Research Blogging.
  22. Hyon K Choi and Gary Curhan, “Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study,” BMJ (January 31, 2008): bmj.39449.819271.BE.
  23. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA (2012). "Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial.". Am J Med 125 (11): 1126-1134.e7. DOI:10.1016/j.amjmed.2012.05.025. PMID 23098865. Research Blogging.
  24. Wortmann RL, Macdonald PA, Hunt B, Jackson RL (2010). "Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials.". Clin Ther 32 (14): 2386-97. DOI:10.1016/j.clinthera.2011.01.008. PMID 21353107. Research Blogging.
  25. Perez-Ruiz F, Lioté F (2007). "Lowering serum uric acid levels: What is the optimal target for improving clinical outcomes in gout?". Arthritis Rheum. 57 (7): 1324–8. DOI:10.1002/art.23007. PMID 17907217. Research Blogging.
  26. Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA et al. (2005). "Febuxostat compared with allopurinol in patients with hyperuricemia and gout.". N Engl J Med 353 (23): 2450-61. DOI:10.1056/NEJMoa050373. PMID 16339094. Research Blogging.
  27. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E et al. (2010). "The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.". Arthritis Res Ther 12 (2): R63. DOI:10.1186/ar2978. PMID 20370912. PMC PMC2888216. Research Blogging.
  28. Ordi J, Alonso PL, de Zulueta J, et al (August 2006). "The severe gout of Holy Roman Emperor Charles V". N. Engl. J. Med. 355 (5): 516–20. DOI:10.1056/NEJMon060780. PMID 16885558. Research Blogging.
  29. Pinals RS (February 2008). "Theodore Roosevelt's inflammatory rheumatism". J Clin Rheumatol 14 (1): 41–4. DOI:10.1097/RHU.0b013e3181639ad0. PMID 18431099. Research Blogging.