Rheumatology: Gout Flashcards
Pathophysiology of Gout
Gout is caused biochemically by extracellular urate supersaturation (uric acid becomes suprasaturated)
This can lead to:
Repeat attacks of acute inflammatory arthritis
Build up of urate crystals causing tophaceous/tophi (gritty) deposits
Uric acid nephrolithiasis
Nephropathy
Synthesis of Urate
End product of purine synthesis, interconversion, and degradation of DNA, RNA, Ribose-5-P, and Mg-ATP
Xanthine is converted to urate via xanthine oxidase
Movement of uric acid in and out of cells occurs on the proximal tubule via many types of transporters
2 Main Causes of Gout
15% of all patients with hyperuricemia develop gout- therefore, you can have high UA but not develop gout
Hyperuricemia is defined as serum uric acid concentrations >7 mg/dl in men and >6 mg/dl in women.
Gout has 2 main causes:
Over production
Under excretion
Causes of Overproduction
Ethanol HGPRT or G6PD deficiency Lesch-Nyhan PRPP synthetase overactivity Myeloproliferative disorders Cytotoxic chemotherapy Sickle-cell anemia Obesity Diet – high in purines B12 Deficiency Fructose Nicotinic Acid Cytotoxic Drugs Warfarin Psoriasis
Foods to Limit
Meat items that are particularly high in purines: beef, pork, lamb, and “organ meats” (such as liver, kidney, and brain).
Reduce or eliminate alcohol consumption, especially beer.
Reduce oatmeal, dried beans, peas, lentils, spinach, asparagus, cauliflower, and mushrooms.
Specific types of seafood found to be associated with higher levels of uric acid include: anchovies, sardines, roe (fish eggs), herring, mussels, codfish, scallops, trout, and haddock
Causes of Under-Excretion
ACBG abnormality URAT 1 abnormality Medullary Cystic Kidney Drugs Age and Gender Renal Insufficiency Renal insufficiency Lead nephropathy (saturnine gout) Diabetic ketoacidosis Lactic acidosis Preeclampsia Obesity Hyperparathyroidism Hypothyroidism Sarcoidosis
Drugs and Toxins that cause Under-Excretion
Diuretics (thiazides and loop diuretics) Ethanol Cyclosporine A Pyrazinamide Low-dose aspirin Levodopa Laxative abuse Salt Restriction
Test: Under-Excretion or Overproduction
Most of the time the case in under excretion
How to differentiate: 24 hour urine for uric acid and creatinine levels; if over 800 or more over producer, but under 800 patient is under excretion
Four Stages of Gouty Arthritis
- Asymptomatic hyperuricemia- gout crystals form at serum uric acid (sUA) level of 6.8
- Acute gouty arthritis
- Intercritical gout
- Chronic Tophaceous gout
Path to a Gout Flare
- Asymptomatic hyperuricemia
- Supersaturation
- Crystal Formation
- Microcrystal release
- Inflammatory Cascade
- Gout Flare!
Manifestation of Gout
Early attacks are usually monoarticular, beginning early am or during the night when body temperature is lower
The joint is red, warm, swollen and extremely painful.
Acute gout can occur in non-articular sites: bursa, Achilles tendon etc.
Early attacks spontaneously resolve in 3-10 days.
Subsequent attacks can become polyarticular and last longer
The 1st MTP of the great toe (podagra) is involved >50% in first attacks and >90% overall and is called podagra.
Gout can affect the instep, heels, knees, wrists, fingers and elbows; DIP joints in hands
From the 1st attack to the appearance of tophi can take on average 10years
Synovial Fluid Aspiration Findings
Inflammatory with 20,000-100,000 leukocytes/mm3
Uric acid crystals
Negatively birefringent; needle-shaped crystals under polarized light
Crystals appear yellow when parallel to axis of red compensator of polarized light, and blue when perpendicular
Lab Testing: UA Levels
Uric acid can be normal in up to @50% of acute attacks.
This is why it is important to check uric acid levels @2weeks after the flare during the intercritical period.
Most important: The fluid has to be looked at within the 1st hour from the tap as crystals dissolve at room temperature
X-Ray Findings: Gout
Soft tissue swelling
Tophi which can appear calcified
Bony erosions that appear “punched out” with sclerotic margins and overhanging edges – “rat bite erosions”.
Joint space early in gout is preserved and there is no osteopenia
UA Levels and Risk for Recurring Flare
UA of 10mg/dL = 90% UA of 9.0mg/dL = 65% UA of 8.0mg/dL = 65% UA of 7.0mg/dL = 20% UA of 6.0mg/dL = 10%
Treating Acute Gout
Steroids or NSAIDs
Colchicine: 0.6mg – give two or 1.2mg once then 1hr later 0.6mg again.
ACTH can be used but very costly and not first line recommendation.
During an acute attack allopurinol, febuxostat should not be started.
After the acute attack focus on looking at modifying risk factors and diet
Appropriate first-line therapy for acute gout includes NSAIDs, corticosteroids, or oral colchicine.
For severe or refractory attacks, certain combinations of these drugs may be used
Colchicine
Has no effect on serum urate conc or metabolism. ½ life is 4 hours
It is an anti-inflammatory drug by inhibiting neutrophil chemotaxis and phagocytosis and inhibits phospholipase A2.
Toxicities: GI, bone marrow suppression, neuromyopathy, alopecia, CNS dysfxn
Indications for Chronic Treatment
>2 or 3 attacks within 1-2 years Renal stones Tophaceous gout Chronic gouty arthritis with erosions Asymptomatic hyperurecemia >12mg/dl
Chronic Treatment/Therapy
Start prophylaxis with either a NSAID or colchicine 0.6mg bid.
Then start ULT (urate lowering therapy) appropriate for the patient @2weeks after the acute flare while on the prophylaxis and continue the prophylaxis for 6mo.
ULT Drugs
Urate lowering therapy
Allopurinol and Febuxostat
Hypoxanthine analogues (xanthine oxidase inhibitors) that inhibit uric acid synthesis.
Lower serum and urine conc. uric acid.
Metabolized by xanthine oxidase to oxipurinol
ULT Interactions with 6-Mercaptopurine and Imuran
Say treating lupus, kidney transplant, leukemia, lymphoma, crohn’s, ulcerative colitis, meds for these interact with allopurinol and have toxic effects; must cut the dose for 6-mercaptopurine or stop the gout treatment meds (allopurinol)
Allopurinol
Dose: 100mg-800mg/day. Over 300mg/day give in divided doses.
With CRI need to lower the dose:
Crcl 40-60: 200mg/day
Crcl 20-40: 100mg/day
Crcl 10-20: 100mg/2 days
Crcl 0-10: 100mg/3 days
Toxicities: acute gout flare, rash (3%), GI, LFT abnl, HA, cataracts,
Rare: TEN, allopurinol hypersensitivity syndrome (5-10%)
TEN = toxic epidermal necrolysis, which is a rash that needs immediate ER attention because it is fatal
Febuxostat
Brand name: Uloric
Dose 40 or 80mg daily - always start with 40 no matter what the UA level is
Primarily excreted by the liver and is safer in patients with kidney disease.
Insufficient data on use in patients with Crcl
Uricosuric Drug
Probenacid
Used in relative renal underexcretion of uric acid (ie, normal values for uric acid excretion in the presence of hyperuricemia).
Uricosuric agents should be avoided in patients with nephrolithiasis, cystinuria, renal insufficiency or where uric acid nephropathy might occur
Not widely used (allopurinol and febuxostat is more common)
Probenacid: Interactions and Side Effects
The major side effects of Probenacid are rash, precipitation of acute gouty arthritis, GI intolerance, uric acid stone formation, increases urinary calcium excretion
Urinary excretion of penicillin and ampicillin are decreased by probenecid, prolonging of the ½ lives.
The uricosuric effect may be reduced by relatively large doses of salicylates
Pegloticase
First biologic IV infusion for gout.
PEGylated uricase enzyme- breaks down uric acid to almost nothing within 24 hours
Dose 8mg IV q2/wk for up to 6mo.
Adverse reactions: gout flares, infusion reactions (27%), nausea, anaphylaxis (5%),chest pain
Very high reaction rate – not really used in primary care settings; tumor lysis syndrome at the hospital mostly uses this
Maintenance of Gout
Target serum urate level should be lower than 6 mg/dL, and often lower than 5 mg/dL, to maintain improvements in gout signs and symptoms.
The starting dosage of allopurinol should not exceed 100 mg/day. This should be gradually titrated upward.
Even in patients with CKD (chronic kidney disease), the maintenance dose of allopurinol can exceed 300 mg daily
Genetic Screening & Allopurinol
Prior to initiation of allopurinol, rapid PCR for HLA–B*5801 screening should be considered in subpopulations where it is linked to causing high risk for severe allopurinol hypersensitivity.
e.g., Koreans with stage 3 or worse CKD and all those of Han Chinese and Thai descent; also Jewish population
Changing Dosing and Medications for Patients with Lack of Response
When appropriate dosing of an XOI does not achieve the serum urate target, combination oral ULT with 1 XOI agent (allopurinol or febuxostat) and 1 uricosuric agent (probenacid) is recommended.
For patients with severe gout disease burden and lack of response to or intolerance of appropriately dosed oral ULT, pegloticase may be used
Anti-Inflammatory Prophylaxis & ULT
All patients with gout who are starting to receive ULT should receive pharmacologic anti-inflammatory prophylaxis.
This should be continued if there is any clinical evidence of continuing gout disease activity and/or the serum urate target has not yet been reached
Over Production and Under Excretion Therapy
Under Excretors: Probenacid is best
Over Producers: Allopurinol and Febuxostat
*achieve serum urate level of 6mg/dL or under
