Resident Editor: Joseph Cartwright, MD, MEd

Faculty Editor: Maria Wamsley, MD

BOTTOM LINE ✔ Typical presentation is acute, painful monoarticular arthritis; joint is usually red and swollen. ✔ If in doubt, rule out septic joint. ✔ First-line treatment for acute gout is either NSAIDS, colchicine, steroid injection, or oral prednisone. ✔ Urate-lowering therapies (e.g. allopurinol) should be continued during flares, and may be initiated during flares with prophylactic colchicine (and careful uptitration).

GOUT

Background

• Inflammatory arthritis due tdeposition of monosodium urate crystals (MSU)
• Affects approx. 4% of the U.S. population
  • increases with age (>80yo: 9% men, 6% women)
  • Predominates in men (4:1) overall
• Patients with hyperuricemia (21% of the U.S. population) are most susceptible tgout.
  • Additional risk factors: male sex, Filipinancestry, obesity, DM, HTN, HLD.
• >90% of patients are treated in primary care settings.

Causes of Increased Urate Levels

Underexcretion (> 90%)	Overproduction (< 10%)	Both mechanisms
Primary causes Idiopathic   Secondary causes Renal insufficiency Impaired tubular secretion (ketoacidosis, lactic acidosis, IV contrast) Increased tubular reabsorption (diuretics, dehydration) Medications (cyclosporine, tacrolimus, low-dose ASA, beta-blockers, insulin, niacin, ethambutol, pyrazinamide) Lead Hypertension Hyper/hypo-PTH	Primary causes Idiopathic HGPRT deficiency PPRP synthetase overactivity   Secondary causes Increased cell turnover (hematologic malignancy, hemolysis, psoriasis, Paget’s disease, chemotherapy) Increased purine intake (meat, seafood, soft drinks, fructose) Increased ATP degradation (rhabdomyolysis, sustained exercise, glycogen storage disease)	Alcohol G6PD deficiency Fructose-1-phosphorylase deficiency

Precipitants

• Any acute increase or decrease in uric acid levels can precipitate a gout flare
• Common culprits include aspirin, diuretics, heavy meals and excessive meat and seafood intake, alcohol (especially beer and spirits), sugar-sweetened drinks, initiation of allopurinol/probenecid, minor trauma, surgery, and acute illness
• Flares often occur at sites of prior joint damage, i.e. DJD/trauma.

Clinical Presentation

• Typical presentation: Acute, monoarticular arthritis that can be exquisitely painful; involved joint is usually markedly erythematous and swollen.
  • Often confused with cellulitis, especially when involving the dorsal hand or foot
• Joints commonly affected: 1st MTP joint (podagra) most common. Other common joints- midfoot, ankles, heels and knees. Less commonly wrists, fingers and elbows.
• Possible accompanying signs: Fever (>38), leukocytosis, and elevated ESR
• Atypical presentations:
  • Polyarticular gouty arthritis rarely an initial manifestation of gout (< 20%). More common in late disease; polyarticular initial presentation raises concern for underlying myeloproliferative or lymphoproliferative disorder
  • Early-onset gout: 3-6% have onset before 25 y/o. These cases have strong genetic components and require more aggressive therapy. Associated with frequent nephrolithiasis. (ex- Lesch-Nyhan syndrome, glycogen storage dz, sickle cell)
• 50% of untreated patients will experience second attack within 1 year, 80% within 2 years

Evaluation

• Historically, arthrocentesis was emphasized as required for the diagnosis of gout.
• Practically, gout is often diagnosed clinically, and the following diagnostic rule was validated for diagnosis of gout in primary care settings (among patients with monoarthritis):
  • Criteria:
    • Male sex=2 pts
    • Previous arthritis attack=2 pts
    • Onset within 1 day=0.5 pts
    • Joint erythema=1 pt
    • First MTP joint involved=2.5 pts
    • HTN or 1+ CVD variable=1.5 pts
    • Serum uric acid >5.88 mg/dL=3.5 pts
  • Interpretation:
    • LOW SCORE (<5 pts): 95% negative predictive value
    • INTERMEDIATE SCORE (5-7 pts): consider arthrocentesis and/or careful follow-up.
    • HIGH SCORE (8+ pts): 85% positive predictive value.
• If the presence of synovial fluid crystals cannot be confirmed, musculoskeletal ultrasound or Dual Energy CT of an involved joint sometimes can provide additional data supporting the diagnosis of gout (Sensitivity 92%, Specific 89%).
• If there is concern for infection (alone or in combination with gout), it is critical tperform arthrocentesis with synovial fluid analysis (see next). Imaging (ultrasound or DECT), closer patient follow-up, and/or referral trheumatology or orthopedic surgery, may be warranted. Up t5% of patients with acute monoarticular arthritis and crystals encountered on arthrocentesis will have concomitant infection. Serum CRP <100 and synovial WBC <10,000 favor gout, while synovial WBC>50,000 or involvement of atypical joints (for gout) favor septic arthritis.
• Arthrocentesis: the gold standard diagnostic test for gout. Diagnosis is confirmed by the presence of MSU crystals in synovial aspirate (negatively birefringent needle-shaped crystals, classically intracellular); WBC count may be as high as 80,000/mm³ (average 15,000-20,000).
• Initial Labs: Serum uric acid (30% of patients have normal levels during an attack), BUN and Cr, and CBC tevaluate for infection (mild leukocytosis can be expected)
• Subsequent labs: Can evaluate if patient over-producer or under-secretor with 24 hr urine uric acid. Clinically, however, commonly choose ttreat with allopurinol as first line. Trend uric acid levels tdetermine if treatment is reaching goal (<6 mg/dL).
• Imaging
  • Xray: See erosions with overhanging edges (“rat bites”) in long-standing chronic gout.
  • Ultrasound: Limited studies. May be useful in early detection of gout (double-contour sign seen on ultrasound); wide range of sensitivity/specificity
  • DECT: Limited studies. Quantifies tophaceous and non-tophaceous soft tissue deposition; sensitivity 85-100% and specificity 83-92% for predicting gout
• HLA*5801 Testing: If considering allopurinol use among Han Chinese, Thai, or Korean patients, test for human leukocyte antigen-B*5801, as a positive result indicates a significantly higher risk of allopurinol hypersensitivity syndrome. In these cases, allopurinol should not be used.

 

Treatment

Acute Flare

• General principle: treat as soon as possible; counsel patients tself-medicate.First line medications include NSAIDs, colchicine, and corticosteroids (either intraarticular or oral). IL-1 receptor antagonists (e.g. anakinra) can be used if the other agents are contraindicated or the patients has had rebound flares despite appropriate therapy.

 

FIRST-LINE MEDICATIONS (for TREATMENT of ACUTE FLARES)
MED	DOSE	CONSIDERATIONS in CKD	SIDE EFFECTS	CONTRA- INDICATIONS
NSAIDS             *dnot use aspirin (it has paradoxical effects on serum urate)	indomethacin 50mg TID naproxen 500mg BID ibuprofen 800mg TID celecoxib 200mg BID   (+ PPI if appropriate)   Use max dose for 3-5d (until improvement), then half dose and taper off over 3-5d.	CrCl<60: AVOID	GI upset, bleeding	Child-Pugh C liver disease (decrease dose 50% in Child-Pugh “B”), age>60, cardiovascular disease (CAD, CHF), anticoagulant treatment.
colchicine	1.2mg x1 then 0.6mg 1h later x 1   followed by daily prophylactic dosing 0.6mg BID   Can be used in combwith NSAIDs.	CrCl<30: dnot redose x2 wk. Decrease prophylactic dose t0.3-0.6mg daily   HD: max 0.6mg/attack; dnot redose x2wk	Abdominal cramping, diarrhea, neuromyopathy, myelosuppresion, rhabdomyolsis.	Avoid if strong CYP3A4 or P-glycoprotein inhibitors
intraarticular steroid injections	triamcinolone 10-40mg - 10mg (large e.g. toe) - 30mg (medium e.g. elbow, ankle) - 40mg (large e.g. knee)		injection site reaction	Joint infection
oral steroids (prednisone)	prednisone 30-40mg daily until resolution, then taper over 7-10 days		mood changes, hyperglycemia, HTN, fluid retention	perioperative, active infection, brittle diabetes, CHF, frequent attacks (i.e. potential for high cumulative steroid burden)
IL-1 receptor antagonists   *consider if contraindications tabove or if hx of “rebound” flares	anakinra 100mg SC q24h x3d   also: rilonacept, canakinumab	CrCl<30: give q48   HD: not defined	infusion reactions, sepsis	active infection

 

Prevention of Recurrent Attacks

• Indications for treatment with uric acid lowering therapy (ULT):
  • Age <40 at diagnosis
  • Serum uric acid > 8 mg/dl (higher risk of recurrent attacks)
  • Greater than 2 attacks per year
  • Tophaceous gout
  • Urolithiasis
  • CKD
  • HTN
  • CHF
  • Ischemic Heart Disease
• General considerations:
• Goal of therapy is serum uric acid level < 6, or < 5 if tophaceous gout.
• Recent guidelines support initiation of ULT during a flare.
• Flare prophylaxis with colchicine 0.6mg BID should be prescribed for the first 6 months of ULT.
• Discontinue medications contributing thyperuricemia, if possible, including thiazides and loop diuretics.
• Identify and treat risk factors including diet, HTN, hyperlipidemia, obesity, EtOH.
• Allopurinol
• 1^st line agent. Xanthine oxidase inhibitor. Effective prophylaxis for both overproducers and underexcretors
• Start at 100 mg daily (lower in patients with stage 4 CKD) and titrate upwards every 2-5 weeks until target uric acid levels are met. Rarely used in doses >600 mg daily
• Common side effects: pruritis/dermatitis, mild LFT abnormalities
• Serious side effects include hypersensitivity syndrome that can include Stevens-Johnson syndrome/TEN (should stop allopurinol with ANY rash), leukopenia.
  • Serious hypersensitivity rxn associated with: renal insufficiency, concomitant diuretic use and Han Chinese heritage (HLAB5801). Those at risk should be tested prior tinitiating allopurinol (Korean descent with stage 3 CKD or Han Chinese/Thai regardless of kidney function.)
• Probenecid
• Increases renal excretion of urate; effective for underexcretors only
• First-line agent in patients under age 60 whexcrete < 800 mg of uric acid daily.
• Contraindicated in renal insufficiency, tophaceous gout, history of nephrolithiasis, rapid cell-turnover state
• Start at 250 mg BID and increase t1 g BID as needed
• Encourage hydration tmaintain good urine output and prevent stone formation
• Febuxostat
• Newer xanthine oxidase inhibitor with efficacy similar tthat of allopurinol.
• Metabolized by liver rather than kidneys scan be used in CKD
• Start at 40 mg daily, increase dose of 80-120mg/day tachieve goal uric acid level.
• Side effects include LFT abnormalities (tolerate 2-3x upper limit of normal), nausea, rash, arthralgias; hypersensitivity risk as seen with allopurinol has not been associated with febuxostat tdate; possible increased risk of cardiovascular thrombotic events
• Newer and emerging therapies:
• IL-1 antagonists: Anakinra, rilonacept, canakinumab
• Pegloticase (recombinant uricase): Approved 2010 for chronic refractory gout, highly immunogenic with infusion reactions common. Used mostly for tumor lysis syndrome.

Pseudogout (AKA calcium pyrophosphate deposition disease, or CPPD)

Background

• Caused by deposition of calcium-containing crystals primarily in articular cartilage, menisci, synovium, and nearby tendons or ligaments
• May present similar tgout attack with acute onset of pain, erythema, swelling of a joint +/- fevers and chills. Alsmay look like septic arthritis.
• Etiology
• Usually idiopathic, though risk increases with age
• Provoking factors: trauma, surgery, post-parathyroidectomy, severe illness
• Hereditary form caused by autosomal dominant mutation in pyrophosphate transporter.
• Associated with hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatemia, hypothyroidism

Signs and Symptoms

• Osteoarthritis-like (50%): Chronic, with bilateral involvement
• Gout-like (25%): Acute monoarticular arthritis
• “CPPD” (20%): Asymptomatic, with chondrocalcinosis noted on X-ray.
• Pseudorheumatoid (5%): Severe destructive arthritis or chronic synovial inflammation
• Joints commonly affected: Classically affects knees but can alsbe seen in wrists, ankles, elbows, toes, shoulders and hips

Evaluation

• Arthrocentesis: Diagnosis confirmed by rhomboid, weakly positively birefringent crystals (blue); WBC count can be as high as 50,000/mm³ (usually 15-15,000)
• Labs: Rule out secondary causes of CPPD with serum calcium, phosphorus, magnesium, alkaline phosphatase, TSH, ferritin and uric acid
• Imaging: X-rays can be suggestive of diagnosis if they show linear or stippled calcification in articular cartilage or menisci (chondrocalcinosis)

Treatment

• As with gout, NSAIDs, colchicine, and intraarticular or oral corticosteroids are first-line for acute flares.
• Prophylaxis with colchine (0.6mg BID) is alseffective, and should be considered for patients with three or more attacks annually.
• There are ndrugs that deplete the CPPD crystals or prevent new ones from forming; search for underlying cause and treat it if possible (although this does not remove the existing CPPD crystals from the synovium).

References

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Imboden JB et al. Current Rheumatology Diagnosis and Treatment. 2nd ed. New York: McGraw-Hill, 2007.

Janssens HJ et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med 2010;170(1):1120-1126.

Klippel JH et al. Primer on the Rheumatic Diseases. 13th ed. New York: Springer, 2008.

Neogi T. Clinical practice: Gout. New Engl J Med. 2011 Feb 3;364(5):443–52.

Papanicolas LE et al. Concomitant septic arthritis in crystal monoarthritis. J Rheumatol. 2012 Jan;39(1):157–60.

Richette P et al. 2016 updated EULAR recommendations for the management of gout. Ann Rheum Dis 2017;76:29-42.

Rosenthal AK et al. Calcium pyrophosphate crystal deposition disease, pseudogout, and articular chondrocalcinosis. In: Arthritis and Allied Conditions. 15th ed. Philadelphia: Lippincott, 2005.

Shekelle, Newberry et al. Management of Gout: A systematic review in support of an American College of Physicians Clinical Practice Guideline. Annals of Int Med. 2017;166(1):37-51.

Zhang W et al. 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. 2006 Oct;65(1):1312–24.