Gouty Arthritis

Aka: Gouty Arthritis, Gout, Podagra

1. See Also
   1. Joint Pain
   2. Monoarticular Arthritis
   3. Polyarticular Arthritis
   4. Purine Containing Food
2. Definitions
   1. Joint and tissue deposition of monosodium urate crystals
3. Epidemiology
   1. Men and post-menopausal women more commonly affected
      1. Estrogen is protective pre-Menopause by increasing Uric Acid excretion
   2. Age
      1. Gout is rare under age 20 years old
   3. Prevalence
      1. Men: 3-6%
      2. Women 1-3%
      3. Increasing Prevalence in United States related to Obesity and aging population
      4. Affects 8 million in United States (most common inflammatory Arthropathy)
      5. Prevalence increases with age (affects 12% of those over age 80 years old)
      6. Black patients have a higher Prevalence
   4. Incidence of gout attacks
      1. Uric Acid 7 to 8.9 mg/dl: 0.5% annual Incidence
      2. Uric Acid >9 mg/dl: 4.5% annual Incidence
4. Pathophysiology
   1. See Uric Acid
   2. See Hyperuricemia
   3. Isolated and asymptomatic Hyperuricemia is common and requires no treatment
      1. Elevated levels are common, and most Hyperuricemia will not result in gout or other adverse effects
   4. Gout occurs when Uric Acid levels exceed solubility limits
      1. Monosodium urate crystals deposit in joints, Kidney, and soft tissues
      2. Crystal deposition triggers a inflammatory response from Cytokines and Neutrophils
      3. Joint space is irreversibly injured with ongoing attacks
5. Risk Factors
   1. Most common
      1. Obesity
      2. Alcohol use (especially beer)
      3. Diet high in Purine Containing Food (red meats, turkey and wild game, organ meats, seafood)
      4. Drinks sweetened with high fructose corn syrup
      5. Diuretic therapy including Thiazide Diuretics and Loop Diuretics
      6. Hyperuricemia
   2. Other risks
      1. Diabetes Mellitus
      2. Hyperlipidemia
      3. Hypertriglyceridemia
      4. Hypertension
      5. Atherosclerosis
      6. Renal Insufficiency
      7. Myeloproliferative disease
      8. Tacrolimus (Prograf)
      9. Ethnicity (indigenous Tiawan, Pacific Islanders, Maori of New Zealand)
6. Causes: Triggers for acute gout attacks
   1. See Hyperuricemia
   2. See Risk Factors above
   3. Recent increase in Alcohol or Purine intake
   4. Medication use (Allopurinol stopped or started, Diuretic or Chemotherapy started)
   5. Acute infection
   6. Intravenous Contrast dye exposure
7. Presentations
   1. Monoarthritis (most common)
   2. Acute Bursitis
   3. Tenosynovitis
   4. Acute Polyarticular gout
8. Symptoms
   1. Associated Symptoms
      1. Chills
      2. Fever as high as 104 F (40 C)
   2. Severity: Very severe pain
      1. Unable to bear weight
      2. Too painful to put on socks
      3. Intollerant to light touch from blankets
   3. Distribution: Lower extremities
      1. First Metatarsophalangeal joint of great toe (56-78% of cases, most common)
         1. Known as Podagra
         2. Affected in 50% of first gout attacks
      2. Mid-tarsal joints (25-50% of cases)
      3. Ankle Joints (18-60% of cases)
      4. Knee Joints
   4. Distribution: Upper extremities
      1. Finger interphalangeal Joints (6-25% of cases)
      2. Wrists
      3. Elbows
   5. Characteristics: Joint Pain
      1. Excruciating, crushing type pain
   6. Timing: Joint Pain
      1. Acute onset of lower extremity Joint Pain, typically peaking in the first 24 hours
      2. Wakens patient from sleep
9. Signs
   1. Acute
      1. Joint Inflammation
         1. Erythema, tenderness and swelling at affected joint
         2. Pain extends well beyond joint
            1. Entire foot involved in some cases
         3. Asymmetric joint involvement
            1. May only involve one side with the first attack
      2. Skin over joint is tense and shiny
   2. Chronic
      1. Gouty Tophi (develop after 10 years)
         1. Subcutaneous Nodules of monosodium urate crystals and lipids, Proteins and mucopolysaccharides
         2. May drain chalk-like material
         3. Common sites include ear, olecranon bursa, fingertips
      2. Chronic Arthritis
         1. Chronic deposition occurs with recurrent attacks
10. Labs
    1. Complete Blood Count
       1. Leukocytosis (may be as high as 40,000 wbc/mm3)
    2. Serum Uric Acid increased
       1. Hyperuricemia (typically defined as serum Uric Acid >6.8 mg/dl)
       2. Normal Uric Acid does not exclude gout
          1. Uric Acid levels are often suppressed to normal levels during a gout flare
          2. Schlesinger (2009) J Rheumatol 36(6): 1287-9 [PubMed]
    3. Synovial Fluid Exam (critical if Septic Arthritis is considered)
       1. Polarizing Light Microscopy
          1. Negatively birefringent
          2. Needle shaped Uric Acid crystals
       2. Gram Stain and Culture
          1. Rule out Septic Arthritis
    4. Urine Uric Acid (24 hour collection)
       1. Not typically recommended
11. Imaging
    1. See XRay Changes in Rheumatic Conditions
    2. Xray Findings
       1. Nonspecific and asymmetric swelling is often the only XRay finding
       2. Subcortical cysts without bony erosions
    3. Joint Ultrasound findings (any of three findings are consistent with Gouty Arthritis)
       1. Double contour sign
       2. Tophus
       3. Snowstorm appearance
       4. Ogdie (2017) Arthritis Rheumatol 69(2): 429-38 [PubMed]
    4. CT Joint
       1. Conventional CT identifies Gouty Tophi and bony erosions
       2. Dual-Energy CT detects monosodium urate deposits
       3. Bongartz (2015) Ann Rheum Dis 74(6): 1072-7 [PubMed]
12. Diagnosis: Requires one of the following
    1. Monosodium urate crystals in Synovial Fluid OR
       1. Test Sensitivity: 84%
       2. Test Specificity: 100%
    2. Gouty Tophi with urate crystals identified on Nodule aspirate OR
       1. Test Sensitivity: 30%
       2. Test Specificity: 99%
    3. Minimum of 6 criteria present from the following list
       1. Plain radiograph demonstrates subcortical cysts without erosions
       2. Plain radiograph demonstrates asymmetric swelling within a joint
          1. Test Sensitivity: 42%
          2. Test Specificity: 90%
       3. First metatarsophalangeal joint tender or swollen
          1. Test Sensitivity: 96%
          2. Test Specificity: 97%
       4. Hyperuricemia
          1. Test Sensitivity: 92%
          2. Test Specificity: 91%
       5. Unilateral first metatarsophalangeal joint Arthritis
       6. Unilateral tarsal joint Arthritis
       7. Inflammation peaked within one day
       8. Monoarthritis episode
       9. More than one acute Arthritis attack
       10. Effected joints with overlying redness
       11. Gouty Tophi suspected (but not yet confirmed by aspirate)
       12. Synovial Fluid culture negative for organisms during an Acute Monoarthritis attack
    4. References
       1. Wallace (1977) Arthritis Rheum 20(3): 895-900 [PubMed]
13. Differential Diagnosis
    1. Septic Arthritis
       1. Critical to distinguish (especially in large joints: Shoulder, elbow, hip and knee)!
       2. Concurrent infection with gout history may occur (esp. knee, and to lesser extent in ankle, Shoulder, wrist)
       3. A red, warm, edematous joint is only proven not septic by Joint Aspiration (do not assume gout)
    2. Pseudogout (Calcium pyrophosphate deposition disease)
       1. Differentiate from gout based on Joint Fluid analysis
    3. Trauma
       1. Trauma may also precipitate a gout flare
    4. Other conditions
       1. Bacterial Cellulitis
       2. Reactive Arthritis
       3. Rheumatoid Arthritis
       4. Osteoarthritis
       5. Sarcoidosis
       6. Neuropathic Arthritis (e.g. Charcot Joint)
14. Management: Acute attack
    1. NSAIDs (any are effective if adequately dosed)
       1. Avoid in elderly, renal or liver disease, Heart Failure, or Peptic Ulcer Disease
          1. In these cases, use Corticosteroids instead
       2. Indomethacin (historically has been preferred NSAID in gout)
          1. Start: 50 mg orally three times daily for 2-3 days
          2. Then: 25 mg orally three times daily for 4-10 days
       3. Naproxen 500 mg orally twice daily for 4-10 days
       4. Sulindac 200 mg orally twice daily for 4-10 days
    2. Colchicine (Colcrys)
       1. Less viable option (too expensive) now that generic preparations were removed from the market
          1. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227796.htm
       2. Other disadvantages
          1. Gastrointestinal adverse effects (Nausea, Vomiting, Diarrhea) at treatment doses
          2. Avoid in severe liver or Kidney disease
          3. Requires adjusted dosing in renal disease
          4. No intrinsic Analgesic effect
       3. Dosing
          1. Single bolus at onset (2 dose one hour apart)
             1. Colchicine 1.2 mg now, then additional 0.6 mg orally in one hour
             2. Take at onset of symptoms
             3. As effective as high dose protocols
             4. Terkeltaub (2010) Arthritis Rheum 62(4): 1060-8 [PubMed]
          2. May consider 0.6 orally daily to twice daily taken as adjunct to NSAID (see above)
             1. Most beneficial if started within first 24 hours of attack
             2. May be ineffective if started >3-4 days after symptom onset
    3. Corticosteroids
       1. Precautions
          1. Rule-out Septic Arthritis first!
          2. Use with caution in Diabetes Mellitus
          3. Effective alternative to NSAIDs (less risk of peptic ulcer)
       2. Efficacy
          1. Prednisolone 35 mg daily is equivalent to Naprosyn 500 mg twice daily
          2. Janssens (2008) Lancet 371(9627):1854-60 [PubMed]
       3. Systemic agents
          1. Intravenous
             1. Methylprednisolone 40 mg (consider if NPO in hospital)
          2. Intramuscular
             1. Depo-Medrol 80 to 120 mg single dose IM
          3. Oral
             1. Start: Prednisone 40 mg orally daily for 5 days
             2. If persistent symptoms, continue as taper (not needed in many cases)
                1. Next: Prednisone 20 mg orally daily for 5 days
                2. Next: Prednisone 10 mg orally daily for 5 days
       4. Intra-articular Corticosteroid
          1. Large single joints and refractory cases to other treatment
          2. However, no evidence to support their use in acute Gouty Arthritis
          3. Wechalekar (2013) Cochrane Database Syst Rev (4): CD009920 +PMID:23633379 [PubMed]
    4. Interleukin-1 Receptor Antagonist (e.g. Anakinra)
       1. May be considered in gout flares in which all other antiinflammatories are ineffective or contraindicated
    5. Other non-medication palliative measures
       1. Ice Therapy
    6. Avoid exacerbating or unhelpful measures
       1. See Prevention below (including Purine avoidance)
       2. Aspirin in small doses aggravates disorder
       3. Acetaminophen not helpful
       4. Phenylbutazone risks outweigh any benefits
          1. Bone Marrow suppression
          2. Aplastic Anemia
15. Prevention: Prophylactic Medications
    1. Typically start concurrently with NSAIDs, Corticosteroids or Colchicine (see below)
    2. Contraindications
       1. Do not use in acute attack (however, see Allopurinol for caveats)
       2. Avoid prophylaxis after only first gout attack or in asymptomatic Hyperuricemia
          1. Exception: Uric Acid > 9 mg/dl, Urolithiasis or Chronic Kidney Disease stage >=3
    3. Indications
       1. Recurrent Gout
          1. Two gout attacks per year or
          2. Consider if 1 gout attack per year if other factors present (e.g. Chronic Kidney Disease)
       2. Tophaceous gout
       3. Nephrolithiasis
       4. Radiographic damage attributable to gout
    4. Therapy goal
       1. Serum Uric Acid <5-6 mg/dl
       2. Some protocols recheck Uric Acid every 2-4 weeks and increase medication doses if not at target
    5. Xanthine Oxidase Inhibitors
       1. First-line agents for prevention
          1. Originally targeted at Uric Acid over-producers based on 24 hour Uric Acid
          2. Now used for under-excreters and over-producers
       2. Allopurinol (preferred)
          1. See Allopurinol for dosing guidelines, contraindications
          2. Standard Dosing (GFR>30 ml/min)
             1. Start 100 mg orally daily and advance to 300 mg daily
             2. In severe Uric Acid elevation, may be titrated every few weeks up to a max of 800 mg/day
             3. Doses higher than 300 mg/day should be divided and taken after meals
             4. May also add probenacid or Lesinurad to reach adequate Uric Acid control
          3. Renal Dosing (GFR <30 ml/min)
             1. Start 50 mg/day (reduces Hypersensitivity Reaction riskl)
             2. Titrate to maximum of 300 mg/day
          4. Genetic Testing (HLA B5801)
             1. Obtain prior to use if risk of severe Hypersensitivity skin reaction
             2. Risks include southeast asian (esp. Hans Chinese, Thai, Korean) and African American
          5. See Allopurinol for initiation protocol (start with antiinflammatory agent to prevent triggering gout attack)
          6. Stop medication and seek medical attention for signs of Hypersensitivity Reaction (e.g. rash, Pruritus)
       3. Febuxostat (Uloric)
          1. Dose: 40 mg daily (up to 80 mg/day if Uric Acid still >6 mg/dl after 2 weeks of therapy)
          2. Contraindicated with Azathioprine (Imuran) or mercaptopurine
          3. Much more expensive than Allopurinol
          4. Increased risk of cardiovascular related death in known CV disease (NNH 91)
             1. White (2018) N Engl J Med 378:1200-10 [PubMed]
    6. Other preventive agents
       1. Colchicine
          1. Dose: 0.6 mg orally daily to twice daily
       2. Pegloticase (Krystexxa)
          1. Intravenous, pegylated recombinant uric-oxidase enzyme (uricase)
             1. Converts Uric Acid to inactive water soluble form
             2. Mechanism related to Uric Acid metabolism to allantoin
          2. Dose: 8 mg IV every 2 weeks
          3. Indicated in severe, gout refractory to maximized Uricosurics and lifestyle change
             1. Serum Uric Acid not at target AND continued gout flares >=2/year or tophi
          4. Very expensive (costs $5000 per dose)
       3. Probenacid
          1. Dose: 250 mg orally twice daily, gradually increased to up to 2 grams daily
          2. Originally targeted at Uric Acid under-excreted (based on 24-hour Urine Uric Acid)
             1. Now rarely used (replaced by Allopurinol used in over-production and under-excretion)
             2. May be used as adjunct to Allopurinol or febuxostat in refractory Hyperuricemia
          3. Significantly increased risk of Nephrolithiasis
             1. Maintain hydration and use Potassium citrate to prevent Nephrolithiasis
          4. Avoid in combination with Methotrexate or Ketorolac
       4. Lesinurad (Zurampic)
          1. Released in 2015 and no longer available in United States due to low demand as of 2019
          2. Dose: 200 mg/day
          3. Indicated as adjunct to Allopurinol or febuxostat, for added Uric Acid control
          4. Contraindicated as mono-therapy to lower Uric Acid (Renal Failure risk)
          5. Similar to Probenacid, inhibits renal Uric Acid transporters (preventing Uric Acid reabsorption)
          6. Must be used in combination with Allopurinol or febuxostat (due to risk of renal stones, Renal Failure)
          7. Very expensive ($12/tablet) and offers little benefit over probenacid (which is one sixth of the cost)
          8. (2016) Presc Lett 23(10)
    7. Concurrently start Uric Acid lowering agents with prophylaxis, low dose for 3-6 months
       1. NSAIDS (avoid in Chronic Kidney Disease, heart disease or liver disease)
          1. Aleve 220 mg (OTC) orally twice daily or
          2. Naprosyn 250 mg orally twice daily or
          3. Indomethacin 25 mg orally twice daily (avoid extended use due to adverse effects)
       2. Prednisone (if NSAIDs contraindicated)
          1. Maintenance: 10 mg orally daily, then 5 mg orally daily for 3-6 months
          2. Acute Exacerbation (start at first symptoms of gout recurrence): 40 mg orally for 1-3 days
             1. Have available as emergency prescription
       3. Colchicine
          1. Colchicine was a first line agent until generic preparations removed from market (now too expensive)
          2. Colchicine 0.6 mg orally daily to twice daily
16. Prevention: General
    1. Avoid provocative factors (See Hyperuricemia)
       1. Avoid Purine-rich foods (See Purine Content in Foods)
          1. Especially avoid red meats (beef, lamb, pork), wild game, organ meats and shellfish
          2. Vegetable/grain high Purine foods do not increase risk (nuts, oatmeal, asparagus, legumes, mushrooms)
       2. Avoid Alcoholic beverages (especially beer)
       3. Avoid fruit juice and drinks sweetened with high-fructose corn syrup
          1. Increases Uric Acid as a byproduct of ATP catabolism
       4. Avoid Thiazide Diuretics
          1. Consider Losartan instead (see below)
          2. Thiazides result in only small Uric Acid increases
          3. Hueskes (2012) Semin Arthritis Rheum 41(6): 879-89 [PubMed]
       5. Avoid weight gain
          1. Weight loss (if Overweight) lowers the gout risk
    2. Avoid unhelpful or harmful measures
       1. Vitamin C: 500 mg/day does not appear effective in Gouty Arthritis
          1. Initially found to lower Uric Acid 0.5 mg/dl, but clinically insignificant benefit
          2. Huang (2005) Arthritis Rheumatism 52(6):1843-7 [PubMed]
          3. Stamp (2013) Arthritis Rheum 65(6): 1636-42 [PubMed]
    3. Adjunctive agents to consider
       1. DASH Diet (including vegetable sources of Protein, soybean)
          1. Rai (2017) BMJ 357 +PMID:28487277 [PubMed]
       2. Dairy products (skim milk, low fat yogurt) may be protective
          1. Choi (2004) N Engl J Med 350:1093-1103 [PubMed]
       3. Eating cherries lowers serum Uric Acid
          1. Jacob (2003) J Nutr 133(6): 1826-9 [PubMed]
       4. Coffee lowers gout attack risk
          1. However significant decrease only at >3 cups/day
          2. Choi (2007) Arthritis Rheumatism 56(6): 2049-55 [PubMed]
    4. Adjunctive Uricosuric medications
       1. Losartan (Cozaar)
          1. Not seen with other Angiotensin Receptor Blockers
       2. Fenofibrate (Tricor)
17. Associated Conditions: Other Uric Acid Conditions
    1. Asymptomatic Hyperuricemia
    2. Uric Acid Nephrolithiasis
       1. Occurs in 10-25% of gout patients
       2. Even higher risk with increasing Uric Acid levels (e.g. 50% Prevalence in those with Uric Acid >13 mg/dl)
18. Course
    1. Gout attack episodes last 5-7 days with or without treatment
19. Resources
    1. Gout risk calculator
       1. http://www.gp-training.net/rheum/gout_calc.htm
    2. ACR/Eular Gout Classification Tool
       1. https://www.mdcalc.com/acr-eular-gout-classification-criteria
20. References
    1. (2020) Presc Lett 27(7): 39
    2. Klippel (1997) Primer Rheumatic Diseases, p. 230-4
    3. Papp and Mann (2016) Crit Dec Emerg Med 30(8): 17-23
    4. Buckley (1996) Am Fam Physician 54(4): 1232-8 [PubMed]
    5. Clebak (2020) Am Fam Physician 102(9): 533-8 [PubMed]
    6. Eggebeen (2007) Am Fam Physician 76:801-12 [PubMed]
    7. Fitzgerald (2020) Arthritis Rheumatol 72(6): 879-95 +PMID: 32390306 [PubMed]
    8. Hainer (2014) Am Fam Physician 90(12): 831-6 [PubMed]
    9. Harris (1999) Am Fam Physician 59(4): 925-34 [PubMed]
    10. McDonald (1998) Postgrad Med 104(6): 117-27 [PubMed]
    11. Pittman (1999) Am Fam Physician 59(7):1799-1806 [PubMed]
    12. Terkeltaub (2003) N Engl J Med 1647-55 [PubMed]