Essential Insights On Treating Lower Extremity Gout
Gout can cause patients significant pain in the lower extremity and chronic attacks of gout often follow acute incidents. With this in mind, these authors discuss essential diagnostic considerations as well as short-term and long-term treatment options.
Many patients seek medical advice when they experience prolonged joint pain, swelling or stiffness that does not resolve with time. As podiatric physicians, it is our responsibility to correctly diagnose and treat many different joint conditions including crystalline-induced arthropathy, also known as gout.
Gout has been affecting patients for eons and dates back to the fifth century as Hippocrates previously described gout as “the unwalkable disease” due to pain associated with joint involvement.1 Gout is a recurring inflammatory reaction to the overproduction of monosodium urate crystals that accumulate and deposit into joints. Gout is more common in men with an estimated 1 to 2 percent of the world’s population affected by gout.2 The first metatarsophalangeal joint (MPJ) is the joint most commonly affected by gout.
There are several theories on why the feet are often targeted by gout and a recent review by Stewart and colleagues presents several explanations including temperature, trauma and biomechanics.3 The authors’ temperature theory states that the joints in feet are cooler than the axial joints that allow urate crystals to precipitate more readily. The authors also explain that the foot is predisposed to daily trauma by activities such as walking or running, which may lead to repetitive microtrauma. This microtrauma ultimately may reduce the synovial fluid pH, causing a shift in calcium activity and favoring urate crystallization to occur. Their third theory relates to increased biomechanical loading during gait, leading to intra-articular debris acting as a scaffold for urate crystallization.
There are four recognized forms of gout. First, primary metabolic gout is due to an overproduction of uric acid, which is associated with a diet high in purines. Next, secondary metabolic gout is associated with myeloproliferative diseases as these are associated with high cellular turnover including increased production of uric acid. Thirdly, primary renal gout is associated with under-excreting uric acid due to renal impairment. Lastly, secondary renal gout is linked to under-excretion of uric acid secondary to renal disease other than a kidney lesion.4 For example, thiazide diuretics can increase serum uric acid.
Perspectives On The Etiology Of Gout
For centuries, people considered gout a disease of the wealthy and privileged as the disease has been associated with indulgent meals and alcohol consumption. Although many foods and alcohols have been linked to gout attacks, the etiological causes have been reexamined.
A recent article by Robinson transforms the definition of gout into an imbalance between the intake and excretion of uric acid, causing a buildup of uric acid crystals in tissues and joints.5 Robinson identifies three different etiologies for gout: genetics, environment and the transition of hyperuricemia to gout. According to Robinson, the majority of patients who experience gout attacks have “underexcretion” of uric acid, meaning their kidneys do not remove enough urate and the abundance accumulates within tissues, which precipitate a gout attack.
The most common proteins associated with gout are the solute carrier (SLC) family 2 and solute carrier family 22 that are encoded into genes that affect the tubular reabsorption rate of urate. Increasing the resorption rate of urate will cause hyperuricemia, leading to an increased risk of crystal deposition and gout attacks. In addition to genetics, the human environment plays a significant role in gout development. The majority of dietary urate comes from purines and other food-related items that metabolize into purines. Many foods are associated with purines, including alcohol, beer, sugar, organ meats and seafood, which metabolize into high amounts of purines contributing to hyperuricemia.
Finally, the transition from asymptomatic elevated uric acid to gout is not clearly understood. Many patients may have elevated uric acid and never experience a gout episode. Multiple studies have identified a link between elevated uric acid and gout. However, there is no one factor that triggers an attack. Therefore, it is difficult to say when and if a patient with elevated uric acid will have a gout episode.
Keys To The Diagnosis
A patient with an acute gout attack may present with a hot, red, swollen, painful joint. Remember, the great toe joint may be the most common location to have gout but gout can present in other foot joints. The diagnosis of gout is multifactorial but clinicians most commonly diagnose this condition via clinical findings including a comprehensive history and exam.
One can confirm gout by collecting a synovial fluid sample from the affected joint. Microscopic examination of the joint fluid reveals negative, birefringent, needle-shaped crystals. It is important to rule out other differential diagnoses including a septic joint or pseudo-gout, which on microscopic examination would reveal calcium pyrophosphate crystals that are rhomboid-shaped with weak positive birefringence on microscopic examination.6
The American College of Rheumatology identified criteria to diagnose gout.5 Their criteria include other findings in addition to synovial fluid analysis since it may not be practical or feasible to obtain joint fluid analysis or the sample of joint fluid may not be adequate. One may confirm the diagnosis if the patient meets six of the following criteria: radiographic evidence of an asymmetric swelling of the affected joint; abnormally increased uric acid level; joint tenderness; acute onset of inflammation affecting one joint; erythema over the affected joint; recurrence of inflammation to the same joint; subchondral cysts observed on radiographs; suspected tophaceous gout; and fluid analysis of the joint that was negative for bacterial organisms to rule out a septic joint.6
A Closer Look At Effective Treatment For Acute Gout Attacks
After diagnosing gout, it is important to determine which treatment is best for the patient. Treatment should include getting the patient through the acute period and then treating the gout in the long term with diet and medication to prevent future attacks.
One can treat an acute gout attack via several modalities including non-steroidal anti-inflammatories (NSAIDs), oral or injectable steroids, or colchicine. The most common NSAID clinicians use for an acute attack is indomethacin. However, the literature suggests most NSAIDs are effective.6 The dosing for indomethacin is 50 mg three times per day for four to 10 days. Use caution while prescribing NSAIDs in patients with renal disease, heart failure, gastric or peptic ulcer disease. Other common NSAIDs in use are naproxen and sulindac (Clinoril, Merck).6
Another effective first line of therapy for an acute gout attack is corticosteroids, which include oral, intramuscular and intra-articular treatments. Common oral steroid treatment includes prednisone, prescribed as a tapered dose. A typical dosing regimen for prednisone is 60/40/20/40/10/5 mg daily for three days each. Use steroids with caution in patients with diabetes as steroids can increase blood glucose levels and insulin demand. Patient education is extremely important with steroid use. One may utilize an intra-articular or periarticular injection of steroids in an acute gout attack.
Finally, colchicine may help treat an acute gout attack. The prescription for colchicine is two tablets (0.6 mg) by mouth followed by one tablet (0.6 mg) an hour later. Colchicine in theory interferes with many steps in the gout pathway although the mechanism is not well understood. The medicine reduces pain and inflammation by paralyzing white blood cells that are attempting to engulf the crystals (phagocytosis). Common side effects with colchicine involve gastrointestinal upset including nausea, vomiting and diarrhea. Use colchicine with caution when it comes to renal and hepatically impaired patients as there is an association with developing myelosuppression.6 It is important to educate patients on non-pharmacological means of symptom control which include ice, food modification and shoe wear modifications.
Managing Gout In The Long Term
After a patient gets through an acute gout attack, it is important to determine the cause of the hyperuricemia and initiate prophylaxis. You may have a team approach to manage gout, which may include input from internal medicine, endocrinology and/or rheumatology. Long-term treatment is based on several factors and requires some testing in order to identify the cause of the patient’s elevated uric acid. An estimated 60 percent of patients who experience a gout attack will have another episode in the following 12 months.6 One should start long-term gout treatment once the acute phase is complete as fluctuating uric acid levels can trigger another attack or prolong the inflammatory phase of the current attack.
Before initiating therapy, identify the mechanism of hyperuricemia via blood and/or urine tests. When serum uric acid is elevated greater than 7 mg/dL in men or 6 mg/dL in women, this is classified as hyperuricemia. Not all patients with hyperuricemia are symptomatic. Patients with elevated serum uric acid and symptoms may warrant urine testing such as 24-hour urine collection. The amount of uric acid excreted in 24 hours may determine if a patient is an under-excreter or overproducer of uric acid, and will dictate treatment. If 24-hour uric acid excretion is less than 700 mg, then the patient’s hyperuricemia results from being an under-excretor. If the 24-hour excretion of uric acid is greater than 700 mg, then the patient is an overproducer and the preferred medication is different than that for an under-excreter. It is important to know the etiology of hyperuricemia in order to select the best medication for each patient.
There are three classes of medications that are proven to reduce uric acid levels. These medications include uricosuric agents, xanthine oxidase inhibitors and uricase agents.
Uricosuric agents are thought to encourage uric acid excretion by interfering with urate absorption. Uricosuric medications are indicated in the group of gout patients considered under-excreters. Probenecid (Probalan) is the only uricosuric agent available in the United States. Initially, the dose of probenecid is 250 mg BID for one week followed by 500 mg BID thereafter. Probenecid is distributed intravascularly and is mainly bound to albumin. Probenecid is ineffective in patients with creatinine clearance less than 50 mL/min.7
Xanthine oxidase inhibitors are the most commonly used long-term gout medications and are indicated for overproducers of uric acid. Uric acid is the end product of purine metabolism, which is generated by the enzyme xanthine oxidase. Allopurinol is the most commonly used xanthine oxidase inhibitor. The starting dose of allopurinol is 100 mg oral daily. However, most patients will require a slow increase in dose until they reach their serum uric acid goal of <6 mg/dL. The maximum daily dose of allopurinol is 800 mg in a patient with normal renal function.
Finally, the last class of medication clinicians prescribe to treat long term-gout is the uricase agents. Humans do not have the uricase enzyme, which is responsible for oxidizing uric acid into a highly water soluble metabolite and ultimately reducing the level of uric acid in the body. The treatment of gout had not deviated from historical medications until 2010, when the Food and Drug Administration approved pegloticase (Krystexxa, Horizon Pharma) for the treatment of gout that did not respond to routine therapy. The recommended dosing of pegloticase is 8 mg every two weeks given intravenous over two hours. Since the uricase enzyme is not native to humans, it is recommended to administer pegloticase with an antihistamine or steroid to reduce allergic reaction.
Many providers may be unfamiliar with this new medication and its associated indications. It is important to understand the difference between pegloticase and traditional gout medications as pegloticase contributes to the resolution of chronic tophaceous gout. Once one has administered pegloticase intravenously, the medication remains for two weeks in systemic circulation. During that time, pegloticase works to degrade uric acid to allantoin, which creates a uric acid concentration gradient that draws extravascular urate into systemic circulation, which is ultimately degraded and broken down by these enzymes.7
Guttmann and colleagues conducted a study to evaluate refractory gout and target serum uric acid levels.7 This double-blinded randomized placebo trial enrolled 212 patients with refractory gout unresponsive to standard treatment. The participants were divided into three groups including those treated with IV infusion of 8 mg of pegloticase every two weeks, those treated with 8 mg of pegloticase infusion every four weeks and a placebo group, all for six months in duration.
This study found that 42 percent of the biweekly infusion group achieved a target serum urate level of <6 mg/dL, 35 percent of the monthly infusion group achieved the target serum urate level and none of the placebo group achieved the target serum urate level. Not only did these authors evaluate target serum urate levels, they also evaluated the physical tophaceous gout burden, which was reduced in both treatment groups in comparison to the placebo group. The study authors concluded that pegloticase is effective at reducing the amount of uric acid in patients with chronic refractory gout and improving their quality of life.
In Conclusion
Gout is a crystal-induced arthropathy that has been burdening patients for ages and continues to affect patients throughout the world. It is important to know how to diagnose and treat gout, and continue to educate patients on this life-altering disease.
Sixty percent of patients who experience a gout attack will have a second attack within one year.6 This is important information to communicate with your patients as the acute period resolves.
It is important to determine the cause of the hyperuricemia and gout attack by obtaining blood and urine tests that will contribute to the proper medication regimen for each individual patient. Remember, patients with elevated serum uric acid levels who do not have symptoms may not require medication at all and may be monitored instead.
Dr. Jensen is a third-year resident at Maricopa Medical Center in Phoenix.
Dr. Fishco is a faculty member of the Podiatry Institute and is in private practice in Phoenix. He is a Fellow of the American College of Foot and Ankle Surgeons.
References
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3. Stewart S, Dalbeth N, Rome K. The impact of gout on the foot: a review. Gout Hyperuricemia. 2016; 3(1):1-8.
4. Brook R, Forsythe A, Smeeding J. Chronic gout: epidemiology, disease progression treatment and disease. Curr Med Res Opin. 2010; 26(12):2813–21.
5. Robinson PC. Gout- an update of aetiology, genetics, co-morbidities and management. Maturitas. 2018; 118:67-73
6. Punzi L, Scanu A, Ramonda R, Oliviero F. Gout as autoinflamatory disease: new mechanisms for more appropriated treatment targets. Autoimmunity Reviews. 2012; 12(1):66-71.
7. Guttmann A, Kransnokutsky S, Pillinger MH, Berhanu A. Pegloticase in gout treatment- safety issues, latest evidence and clinical considerations. Ther Adv Drug Saf. 2017; 8(12):379-388.
8. Nielson SM, Zobbe K, Kristensen LE, Christensen R. Nutritional recommendations for gout: an update on clinical epidemiology. Autoimmunity Reviews. 2018; 17(11):1090-1096.
