Gout

Definition: monosodium urate (MSU) crystal deposition disease.

Risk Factors

• Peak age in fifth decade but can present in any age. Family history in 20%.
• Male > female. Urate levels rise after menopause with parallel increase in incidence. Hyperuricemia defined as serum uric acid concentration > 7-8 mg/dl in males and > 6-7 mg/dl in females.
• Any acute increase or decrease in uric acid levels can precipitate gout flare.
  • Common culprits include: aspirin, diuretics (both loop and thiazide), dietary factors (meat, seafood), EtOH, initiation of allopurinol/probenecid, minor trauma, surgery or acute illness.

Etiology

Under-excretors (90%):

• Primary: idiopathic.
• Secondary: renal insufficiency, inhibition of tubular urate secretion (ketoacidosis and lactic acidosis), enhanced tubular reabsorption (diuretics and dehydration), drugs (cyclosporine, pyrazinamide, ethambutol, low dose aspirin), lead, EtOH.

Over-producers (10%): defined as > 800 mg uric acid/day on normal diet.

• Primary: purine pathway (idiopathic, HGPRT deficiency, increased PRPP synthetase activity).
• Secondary: increased cell turnover (hematologic malignancies, psoriasis, Paget’s disease, chemotherapy), increased purine intake (EtOH), accelerated ATP degradation (ETOH, muscle over-exertion, rhabdomyolysis).
• Both mechanisms: EtOH, G6PD deficiency, fructose-1-phosphorylase deficiency.
• Uric acid levels: only 10-25% of hyperuricemic patients will develop gout. However, risk increases with increasing serum uric acid levels. Duration and magnitude of hyperuricemia directly correlates with likelihood of gouty arthritis and age of onset.

Evaluation / Differential Diagnosis

• Acute flare: acute, monoarticular arthritis that can be exquisitely painful; involved joint is usually markedly erythematous and swollen. May have fever, leukocytosis, and elevated ESR. Often confused with cellulitis, especially when involving the dorsal hand or foot. Recurrent attacks can be polyarticular. Ddx: septic joint, CPPD, spondyloarthropathy, RA.
• May progress to tophaceous gout after many years of undertreatment.
• Synovial fluid findings: MSU crystals are needle-shaped and negatively birefringent.
• Cell count, gram stain and culture: the presence of crystals does not exclude a concomitant septic arthritis. WBC usually 15,000-20,000 WBC/mm3 (can be as high as 80,000!).
• Other labs: serum uric acid (30% of patients have normal levels during an attack), BUN and Cr, and CBC to evaluate for infection (though mild leukocytosis is common during gout flare).
• Radiographic: punched out erosions (“rat-bite”) seen in chronic gout; findings in acute flare may be normal. Radiographs of hands and feet are recommended at time of diagnosis to stage disease (erosive versus non-erosive).

Management

• Acute therapy:
  • NSAIDs (such as naprosyn 500mg PO bid) are rapidly effective. Start with maximal dose of your preferred NSAID (do not use aspirin given paradoxical effects of salicylates on serum urate). Treat at max dose for 3-5 days then taper at ½ dose for 3-5 days. Caution in patients with renal insufficiency, cardiovascular disease, or risk for GI bleed.
  • Intra-articular steroid injection are helpful in patients with contraindications to NSAIDs with monoarticular gouty arthritis (after septic joint has been ruled out)
  • Systemic steroids (given in prednisone equivalents): example regimen = 0.5mg/kg/day x 2-5 days followed by 7-10 day taper.
  • Colchicine is most effective if started within first 12-36 hours of attack. 1.2 mg at onset, then 0.6 mg 1 hour later, followed by prophylactic dosing (0.6 mg BID) 12 hours later until gout flare resolves. Dose reduction is required in patients with hepatic or renal impairment and the elderly. The most common side effect is GI symptoms (abdominal cramping and diarrhea).
  • Consider anakinra (IL-1 antagonist) in refractory cases in conjunction with rheumatology consult.
• Anti-hyperuricemic therapy: indicated in patients with recurrent flares (≥ 2 /year), tophi, CKD, or nephrolithiasis. Consider initiating during a flare.  Must continue flare prophylaxis medications while initiating uric acid lowering therapy.
  • Allopurinol: first line prophylaxis. 100 mg PO daily to start, then uptitrate based on uric acid goal over weeks. Start at 50 mg in patients with renal insufficiency or advanced age. Can cause severe hypersensitivity syndrome. Risk significantly increased in patients who are HLAB5801 positive (more common in those of Han Chinese, Korean, and Thai descent). Genotyping is recommended in the above ethnic groups and use of allopurinol should be avoided in those who are HLAB5801 positive. Not nephrotoxic – can be used in patients with CKD but dose-reduction required.
  • Probenecid: use in under-excretors with normal GFR, and no history of nephrolithiasis. Start 250 mg PO BID then titrate. Inhibits excretion of multiple drugs (penicillin, indomethacin, dapsone, etc.). Encourage hydration to prevent stone formation. Contraindicated in renal insufficiency, tophaceous gout, history of nephrolithiasis and rapid cell turnover state.
  • Febuxostat: newer (more expensive) xanthine oxidase inhibitor. Metabolized by liver rather than kidney. For use in patients who are unable to tolerate allopurinol. Initiate at 40 mg daily, max dose 120 mg daily. May cause LFT abnormalities (tolerate 2-3 ULN), nausea, rash or arthralgias. FDA black box warning for possible risk of increased CV events.
  • Pegloticase: recombinant uricase. Used in chronic refractory gout or more commonly in tumor lysis syndrome. Highly immunogenic, associated with infusion reactions. Expensive!
  • Prophylaxis: necessary when initiating or titrating dose of anti-hyperuricemic to prevent acute flares. Colchicine (0.6mg/day) is first line in this context; adjust for renal insufficiency. NSAIDs or low dose prednisone can be used as an alternative prophylactic agent if colchicine is contraindicated.

Key Points

• MSU crystals are needle-shaped, negatively birefringent.
• Presence of crystals does not exclude a concomitant septic arthritis.
• Uric acid values cannot diagnose or exclude gout - may be falsely normal during flare.
• Treatment of acute flares is with NSAIDs, steroids (intra-articular or systemic depending on number of joints involved), or colchicine.
• Don’t stop uric acid lowering therapy abruptly on admission - may cause flare!
• Consider starting uric acid lowering therapy during flare.
• When initiating uric acid lowering therapy, start prophylaxis with colchicine.

Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016 Oct 22;388(10055):2039-2052.

Sundy JS. Progress in the pharmacotherapy of gout. Curr Opin. Rheumatol. 2010; 22; 2: 188-93.

Eggebeen AT. Gout: an update. Am Fam Physician 2007;76:801-808.

Keith MP, Gilliland WR. Updates in the management of gout. Am J Med 2007;120:221-224.

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.

CPPD

Definition: Arthritis that is caused by calcium pyrophosphate dihydrate (CPPD) deposition in joints. Commonly known as pseudogout.

Etiology / Risk Factors

• Up to 4% adult population, increased prevalence with increased age.
• Pathogenesis: deposition of calcium-containing crystals in articular cartilage, menisci, synovium and nearby tendons or ligaments.
• Idiopathic: most common. Onset over age 55-60.
• Hereditary: usually autosomal dominant mutation in pyrophosphate transporter.
• Metabolic associations: hemochromatosis, hyperparathyroidism, hypophosphatemia, hypomagnesemia, hypothyroidism.
• Precipitating factors: trauma, surgery, post-parathyroidectomy and severe illness.

Evaluation

• Synovial fluid analysis: weakly positively birefringent, rhomboid-shaped CPPD crystals by polarized light microscopy (can be difficult to detect and are often missed). Fluid WBCs 15-30,000 WBC/mm3 (can be as high as 50,000).
• Radiographic: chondrocalcinosis (linear or stippled calcification of articular cartilage) is the classic radiographic finding. Other findings of chronic CPP can include severe articular destruction, calcification of tendons/fascia, and squared-off bone ends with hook-like osteophytes in the MCP joints (particularly the 2^nd and 3^rd MCPs).
• Labs: rule out secondary causes of CPPD with serum calcium, phosphorous, magnesium, alkaline phosphatase, ferritin, iron, and transferrin.

Management

• NSAIDs are first line followed by intra-articular or systemic corticosteroids.
• Consider colchicine 0.6mg daily or BID (renally dosed).
• Treat underlying associated metabolic diseases.
• There are no proven disease modifying therapies for chronic CPP crystal-related inflammatory arthritis but hydroxychloroquine or methotrexate may confer benefit for refractory cases.

Key points

• CPPD crystals are weakly positively birefringent and rhomboid shaped.
• As with gout - presence of crystals does not exclude concomitant septic arthritis.
• Acute therapy is typically NSAIDs, steroids, or colchicine.

References

Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl JMed. 2016 Jun 30;374(26):2575-84.

Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology. 2009; 48; 7: 711-5.

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

Rosenthal AK. Calcium crystal deposition and osteoarthritis. Rheum Dis Clin North Am. 2006; 32; 2: 401-12