The Pathophysiology and Pharmaceutical Treatment of Gout

It should be noted that most of the research conducted on the prevalence of gout was based upon clinicalassessments, self-reports and medical record or database reviews. However, these are not as sensitive oras specific as microscopic identification of monosodium urate crystals within inflamed joints which isconsidered the “gold standard” for gout diagnosis. 9 Identification of intracellular urate crystals in thesynovial fluid or tophus substantiates the diagnosis of gout, but it does not exclude other causes of jointinflammation such as acute pseudogout, active rheumatoid arthritis, or in rare cases, septic arthritis. 10Crystal-induced arthritis can mimic septic arthritis in terms of severe pain, fever, high synovial whiteblood cell count and other constitutional symptoms. Septic arthritis should be suspected in patients withworsening synovitis despite treatment of suspected acute gout. Synovial fluid gram stain and culture arecritical in aiding with the diagnosis in such patients.Several studies have also examined the incidence of gouty arthritis. For example, the Framingham HeartStudy, which followed over 5,000 people for almost three decades, discovered that the incidence of goutper 1,000 people was 1.4 women and 4.0 men, indicating that gout is almost three-times more common inmen. 11 In other studies, gout incidence was also higher in men than in women and the rates increased withadvancing age.Risk FactorsSeveral risk factors have been identified for the development of gout including hyperuricemia.Hyperuricemia, or high levels of uric acid in the blood serum, is considered the most essential factor inthe pathogenesis of gout. In a Taiwanese study, the prevalence of gout was over four times higher in menwho had been previously diagnosed with asymptomatic hyperuricemia. 12 Uric acid precipitates out ofsolution and forms urate crystals when it reaches a saturation threshold that is partially dependent on pHlevels and other biochemical factors.Genetic factors are also fairly evident in gout, but gene expression is quite variable, which accounts forthe differences in an individual’s genotype and phenotype. Because the kidneys excrete the majority ofuric acid from the body, families with genetic conditions limiting kidney clearance often have a higherincidence of gout. 13 For example, a certain gene codes for human “urate transporter-1,” which isimportant for controlling reabsorption of uric acid from the proximal tubules of the kidneys. As such,urate transporter-1 is targeted by many drugs that influence serum uric acid levels in efforts to reduce theprevalence of gout.A direct link between gout and diet has been recognized for centuries, which is why gout has been labeledthe “rich man’s arthritis” for many years. In general, diets high in purines, which are found in abundancein organ meats, cured meats, seafood, some vegetables, aged cheese, and red wine and beer, significantlyincrease the risk of gout because the purines are metabolized into uric acid within the body. In scientificstudies, dietary consumption of meats and seafood was found to be associated with the highest risks ofgout, whereas consumption of certain dairy products such as milk appeared to offer protection. 14 Otheridentified risk factors include consumption of sugar-sweetened soft drinks, candy, and sugarycarbohydrates such as donuts, whereas other protective factors include consumption of caffeinated coffeeand high doses (greater than 1,500 mg daily) of vitamin C. 15 Excessive alcohol consumption (seven ormore drinks within 48 hours) is a well-established trigger of acute gout attacks. 16Specific purine-rich foods to avoid or minimize in order to reduce the risk of acute gout attacks includebeef, liver, kidney, game meats, goose, pork, sweetbreads, anchovies, herring, sardines, mackerel,mussels, crab, shrimp, lobster, caviar, mussels, mushrooms, yeast, asparagus, spinach, cauliflower, peas,beans, lentils, most nuts and seeds, wheat, rye and essentially any form of alcohol. 17Dufton – Pathophysiology and Treatment for Gout Page 2

consumption of antioxidant-rich foods or strong antioxidant supplements such as vitamins C and E inefforts to minimize joint tissue damage, eating sour cherries and cranberries or drinking their juices inattempts to dissolve the urate crystals, avoiding purine-rich foods, reducing alcohol consumption, andincreasing purified water consumption to dilute the crystals and help flush them out of the body. Tocombat pain and inflammation, non-pharmacological compounds commonly used includemethylsulfonylmethane (MSM), Harpagophytum procumbens (Devil’s claw), Uncaria tomentosa (Cat'sclaw), Ananus comosus (bromelain) and Curcuma longa (turmeric). 21 Acupuncture and homeopathictinctures are also utilized for pain and inflammation control, although no scientific studies have examinedtheir effectiveness for acute gout attacks. Alternating hot and cold compresses is a simple inflammationcontrol method that is backed by some research in regards to acute gouty arthritis. 22In conclusion, gout is the most common form of inflammatory arthritis and its prevalence and incidencehave risen in recent decades. Numerous risk factors for the development of gout in both men and womenhave been established and include hyperuricemia, genetic factors, age, purine-rich diet, alcoholconsumption, sluggish metabolism, obesity, diuretic use, renal disease, hypertension and possiblyosteoarthritis. Gout can mimic other types of arthritis and joint injuries, so urate crystals from joint fluidmust be identified for accurate diagnosis. Alternative therapies have been used to combat gout forcenturies, although pharmaceutical treatment is the best researched and most utilized by modernmedicine. Untreated, gout can cause significant short-term and long-term disability.The Pharmaceutical Treatment of GoutThe majority of patients who experience gout are cared for by their family physicians. Although both thephysician and patient may easily recognize that they are dealing with an acute gout attack, errors inselecting the most appropriate medication and proper dose are common. The clinical stages of gout aredivided into the asymptomatic hyperuricemia stage, the intermittent acute flare-up stage and the chronictophi-forming stage. 23,24 Treatment of gout usually commences after the first acute attack, especially ifpodagra is involved. The aims of treatment are threefold: to alleviate the pain and inflammationassociated with acute attacks, to prevent future attacks and to decrease uric acid levels in the serum. Assuch, anti-inflammatories, analgesics and urate-lowering drugs are typically deployed in combination tocombat gout.The critical issues when starting drug therapy for acute gout are rapid initiation of the therapy, adequatedrug dosing and appropriate duration of therapy. The options available for the treatment of gout arenonsteroidal anti-inflammatory drugs (NSAIDs), systemic and intra-articular corticosteroids, colchicineand xanthine oxidase inhibitors.1) NSAIDs for the Treatment of GoutIn a patient without complications, NSAIDs are the preferred therapy for the treatment of acute goutattacks. Combination therapy with NSAIDs and colchicine is used by 50-64 percent of rheumatologistswhen treating acute gout attacks. 25 NSAIDs reduce joint pain and improve joint function through antiinflammatoryand analgesic properties, but they do not prevent the progression of disease. NSAIDsmainly inhibit prostaglandins that are present in many cell types and responsible for the inflammationresponse. Common over-the-counter NSAIDs include ibuprofen (Advil, Motrin, Midol), naproxen (Aleve,Naprosyn) and aspirin. More powerful prescription NSAIDs include celecoxib (Celebrex), diclofenac(Voltaren) and indomethacin (Indocin). Due to low-cost and convenience, ibuprofen is the mostcommonly used NSAID for the symptoms of gout. 26Dufton – Pathophysiology and Treatment for Gout Page 4

at dosages of 0.6 mg every 1-2 hours for acute gout attacks until the patient is pain-free or diarrheaensues. The FDA-approved dose of oral colchicine (Colcrys) for the treatment of acute gout is a single 1.2mg dose followed by a 0.6 mg dose (for a total of 1.8 mg) within 12 hours from the onset of symptoms. 35Research suggests that low-dose colchicine is effective for acute gout if started within 12 hours ofsymptoms, although there is a need to avoid colchicine or adjust the dose in patients with renal or hepaticimpairment and/or those who are taking drugs that interact with colchicine. 36Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents ofmicrotubules. Availability of tubulin is essential to mitosis, thus colchicine essentially acts as a “mitoticpoison.” In addition to inhibiting mitosis, colchicine also inhibits neutrophil motility and activity, leadingto a net anti-inflammatory effect. Colchicine is primarily eliminated by the hepatobiliary tract, althoughrenal excretion accounts for 10-20 percent of colchicine elimination in patients with normal kidneyfunction. 35Colchicine is often recommended when a patient is unable to take NSAIDs such as ibuprofen. However,the drug’s effectiveness is usually offset by intolerable side effects. Common side effects of colchicineusage include gastrointestinal upset, nausea, vomiting, diarrhea and neutropenia, although high doses canalso damage bone marrow and lead to anemia, which is related to the hyper-inhibition of mitosis. Primaryside effects associated with all mitotic inhibitors are muscle damage and peripheral neuropathy, ornumbness and tingling in the hands and feet due to peripheral nerve damage.Symptoms of colchicine poisoning start within 2-5 hours after the toxic dose has been ingested andinclude burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure.Onset of multiple-system organ failure may occur within 24-72 hours. There is no specific antidote forcolchicine, although various treatments do exist and recovery may begin within 6-8 days. 374) Xanthine Oxidase Inhibitors for GoutIt is important to note that resolution of the acute attack by controlling inflammation and pain is not a curefor gout. As such, employing urate-lowering therapy in efforts to reduce serum urate levels below thethreshold of super-saturation is essential in allowing the dissolution of existing urate crystals in the jointsand to stop the deposition of new crystals. Medication that blocks uric acid production is classified asxanthine oxidase inhibitors, which include allopurinol (Zyloprim, Aloprim) and febuxostat (Uloric).Xanthine oxidase inhibitors work by non-competitively blocking the molybdenum pterin center which isthe active site on xanthine oxidase. Xanthine oxidase is needed to oxidize both hypoxanthine and xanthineto uric acid in the body. As such, allopurinol and febuxostat inhibit xanthine oxidase, which reducesproduction of uric acid.There is evidence to suggest that if serum uric acid levels are maintained at or below 6.0 mg/dL, then goutattacks can be reduced, crystals can be depleted from joints, tophi deposits can be reduced and theirrecurrence prevented. 38,39,40 Urate-lowering therapy is most effective when initiated about 2-4 weeks afterresolution of the first acute gouty attack and should be continued long-term if not lifelong. Urate-loweringtherapy should not be initiated during acute gout attacks, although it should be continued if administeredfor previous attacks. It is important to emphasize that urate-lowering therapy should not be stopped onceinitiated because intermittent usage can lead to recurrent gout attacks. 41Dufton – Pathophysiology and Treatment for Gout Page 7

When starting urate-lowering therapy, or even prior to, it is important to also initiate anti-inflammatoryagents such as low-dose oral colchicine, glucocorticoids or NSAIDs such as ibuprofen because xanthineoxidase inhibitors do not make a significant impact on inflammation, pain or fever.The most commonly used urate-lowering drug is allopurinol, which was approved by the FDA in 1966and normally used in a preventative capacity for the chronic tophi-forming stage of gout. Allopurinol isapproved at daily doses of 100-800 mg daily, although the standard dose of allopurinol that achievesserum urate levels below 6.0 mg/dL is at least 300 mg daily. In the United States, 95 percent of dosing is≤ 300 mg daily, which achieves the target urate level in less than half of cases. 42The main limitation for the use of allopurinol is the concern of increased toxicity in patients with renalfailure. 43 Clinicians are also concerned about the more common severe side effects of allopurinol use,such as rash formation with eosinophilia, low blood counts, systemic symptoms and Stevens–Johnsonsyndrome. 44Febuxostat is a fairly new xanthine oxidase inhibitor that was approved by the FDA in February of 2009,and it is quickly becoming a leading choice in the treatment of chronic gout and hyperuricemia.Febuxostat is especially valuable in patients with allopurinol hypersensitivity and in patients with kidneydisease. Unlike allopurinol, febuxostat inhibits oxidized as well as reduced forms of xanthine oxidasebecause it cannot be easily displaced from the molybdenum pterin site. Further, febuxostat is metabolizedmainly by the liver with little intact drug excreted through the kidneys. As such, febuxostat is muchfriendlier on the kidneys compared to allopurinol.The CONFIRMS trial presented at the 73rd Annual Scientific Meeting of the American College ofRheumatology showed that febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol 300/200mg at achieving a serum urate level < 6.0 mg/dL. 45 Febuxostat 40 mg and allopurinol 300/200 mg werecomparable in patients with normal renal function, but in patients with mild/moderate renal impairment,both febuxostat doses were more efficacious than allopurinol and equally safe.The reported side effects of febuxostat considered relatively common included rash, nausea, diarrhea,headache, joint achiness and reduced liver function as measured by hepatic serum enzyme levels. 46In conclusion, the primary aims of the treatment of gout are threefold: to alleviate the pain andinflammation associated with acute attacks, to prevent future attacks and to decrease uric acid levels inthe blood serum. The mainstays of acute gout management are NSAIDs, colchicine and systemic or intraarticularcorticosteroids. NSAIDs are preferable to colchicine because they cause fewer side effects.Successful treatment occurs with the prompt initiation of high-dose, short-term NSAIDs such asibuprofen. Since many gout patients have conditions that preclude the use of NSAIDs or colchicine,systemic glucocorticoids are commonly used to treat acute gout attacks. Intra-articular injections ofglucocorticoids are appropriate with mono- or oligoarticular involvement. Urate-lowering therapy withthe use of xanthine oxidase inhibitors helps reduce serum urate levels and lower the risk of recurrentflare-ups and tophi formation.Dufton – Pathophysiology and Treatment for Gout Page 8

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