Key Considerations in Treating Uncontrolled Gout

Gout is the most common inflammatory arthropathy in the United States, affecting over 9 million adults (3.9% of the population).¹ Gout commonly affects the first metatarsophalangeal joint (MTPJ); thus foot and ankle specialists should be well-versed on the manifestations and treatment strategies.

Gout results from the deposition of monosodium urate (MSU) crystals within joints, resulting in an inflammatory reaction noted by increased warmth, redness, swelling, and pain within the foot (Figure 1). Nodular formations can be noted around periarticular regions within the foot, as well as extrusion of gouty tophi in tophaceous gout (Figure 2). Similar nodules may be noted in other joints throughout the body (Figure 3). MSU crystals begin to develop when the serum uric acid levels rise above the normal physiologic threshold. Pathological levels of hyperuricemia are noted at 6.8 mg/dL.²

What Are the Risk Factors for Uncontrolled Gout?

Aside from hyperuricemia, multiple other risk factors have been identified for the development of gout and exacerbation of gouty flares. Comorbidities such as hypertension and chronic renal disease with concomitant use of thiazide and loop diuretics can result in a higher risk for gouty flares.³

Diet can play a significant role in gout. Alcohol consumption can precipitate gouty flares.⁴ Food sources such as sugar-sweetened drinks, fructose, red meat, and seafood have been shown to increase the risk for gout.⁵ Additionally, gout is more common in males,⁶ individuals > 60 years old,⁷ and patients with a higher body mass index (BMI).⁸ We always include patient education on risk factors for exacerbation of gouty flares, and potential lifestyle modifications, within our treatment protocol.

Pearls on Making a Diagnosis

For classic presentations of gout, the diagnosis can be made from a clinical perspective. Patients will often note an acute onset of severe pain and swelling. The pain is most often experienced at night and in the early morning when cortisol levels are low.9 In our experience, patients will often describe that they are “unable to tolerate bed sheets.”

The “gold standard” route of diagnosis is through identification of MSU crystals via arthrocentesis. One will be able to visualize a yellow-colored synovial fluid sample, with needle-shaped and negatively birefringent crystals.¹⁰ Synovial fluid analysis is also beneficial in ruling out other potential diagnoses, such as septic arthritis.

Laboratory studies can assist in making a clinical diagnosis of gout. Elevations in the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein can be seen during acute flares.¹¹ However, these laboratory values are non-specific and do not confirm the diagnosis of gout. Hyperuricemia (values > 6.8 mg/dL as mentioned above) can support a diagnosis of gout in symptomatic patients, but it should be noted that hyperuricemia alone does not definitively confirm the diagnosis. Serum urate levels can be altered during an acute flare. The best timeframe to assess serum urate levels to establish a baseline is 2 or more weeks after an acute flare subsides.¹²

Imaging modalities can assist in the diagnosis of gout. Plain films are less helpful in the early stages of gout, and may not show radiographic changes initially, but may prove more helpful for chronic tophaceous gout. Implementation of ultrasound can assist in diagnosing and monitoring the progression of gout. Ultrasound can identify changes in synovial fluid, bony erosions, tophi, and an articular cartilage defect known as the “double contour sign,” which is highly specific for gout.¹³ A relatively newer imaging modality, dual-energy CT (DECT) has also been described for diagnosing gout. Although it does show promise in identifying urate deposition, its availability limits its usage in everyday practice.¹⁴

In our hospital system we tend to use a combination of arthrocentesis (when feasible), laboratory studies, and plain films or CT scans when indicated (Figure 4a-c).

How to Treat Gout

The American College of Rheumatology (ACR) has released guidelines for the management of gout.¹⁵ The most recent ACR guidelines made the following “strong” recommendations:

• Initiation of urate-lowing therapy (ULT) in patients with tophaceous gout, radiographic damage secondary to gout, or frequent gout flares
• Allopurinol should be the first-line ULT, even in patients with chronic kidney disease
• Beginning with a low starting dose of allopurinol (<100 mg/day, and lower in CKD) or febuxostat (<40 mg/day)
• Treat-to-target management strategy with ULT titration guided by serial serum urate values, with a serum urate target <6mg/dL
• Utilization of concomitant anti-inflammatory prophylaxis for at least 3–6 months when initiating ULT
• Recommended anti-inflammatory options for acute flares, including colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids

Diving Deeper Into Conservative Management for an Acute Gout Flare

The primary goal of therapy during acute gout flares is to decrease the inflammation and increase pain relief. Ideally, treatment should be initiated within the first 24 hours of onset to reduce the severity and duration of symptoms.¹⁶ The duration of treatment should be continued for at least 7–10 days to reduce the risk of rebound flare-ups.¹⁷

Colchicine, NSAIDs, and glucocorticoids are all first-line treatments, and the choice of agent should be based on patient factors and preferences.¹⁵

Colchicine. Colchicine should be initiated within 12 hours of flare onset if possible. Patients should initially be given a loading dose of 1mg followed 1 hour later by a dose of 0.5mg on day 1.¹⁸ The maximum dose for day 1 should not exceed 1.8mg, although some recommend dosing of 0.6mg and a max dose of 1.2mg. Colchicine should then be taken once or twice daily until symptoms resolve. Of note, the AGREE trial found that when colchicine is taken within 12 hours of flare onset, low-dose colchicine (1.8mg) was just as effective as high-dose (4.8mg) and thus the recommendation is to utilize lower doses.¹⁹ Contraindications for the use of colchicine include patients with severe renal impairment (GFR <30 mL/min), or patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors.¹⁸

NSAIDs. Therapy should be initiated within 48 hours to be most effective. Therapy should last at least 5–7 days. No literature supports the use of one NSAID over another. Options include indomethacin (50mg, 3 times daily), naproxen (500mg twice daily), meloxicam (15mg daily), ibuprofen (800mg, 3 times daily), diclofenac (50mg twice or 3 times daily), or celecoxib (200mg twice daily). Contraindications include active gastric ulceration, cardiovascular disease, or CKD (with a CrCl of <60 mL/minute).

Glucocorticoids. Oral steroids are considered for patients with contraindications to NSAIDs or colchicine. Intra-articular injections of corticosteroids is considered safe and a viable option in patients with monoarticular gout. Steroids are the drug of choice for patients with renal insufficiency. Recommended dosing of prednisolone 30–35 mg/dL for 5 days is effective.¹⁸ This dosing regimen has been found to have equivalent effects to naproxen 500mg twice daily²⁰ while having analgesic effectiveness equivalent to indomethacin.²¹ Extended tapers of 2–3 weeks can be considered. Some adverse effects include hyperglycemia, fluid retention, and hypertension. These agents should be used with caution in patients with diabetes, infections, and in postoperative states as there are not only hyperglycemic changes but also can result in impaired wound healing capabilities.

Interleukin-1 (IL-1) inhibitors. These agents are recommended as an alternative if there are contraindications to taking colchicine, NSAIDs, or glucocorticoids.¹⁸ Anakinra (Kineret, Sobi) 100mg/day subcutaneous for 3 days or canakinumab 150mg subcutaneous are effective in refractory cases. There is an increased risk of sepsis in patients taking IL-1 blockers, and thus infection is a contraindication.¹⁸

Prophylaxis for acute gout flares. The most recent EULAR guidelines recommend a “pill in pocket” approach to treating flares in patients that have been well-educated on their condition.¹⁸ Additionally, prophylaxis should be considered when initiating urate-lowering drug therapy. Low-dose colchicine is the first choice, dosed at 0.5–1.0 mg/day.¹⁸ One study found that low-dose naproxen at 250mg twice daily is effective as well. The prophylactic regimen should be continued for a 6-month duration.²² The same contraindications as mentioned above should be considered prior to initiation of a prophylactic regimen.

Conservative Management of Chronic Gout

As previously mentioned, the 2020 guidelines released by the American College of Rheumatology recommend targeting serum urate to <6mg/dL treated with titrated dosing of ULT.¹⁵ Further recommendations for chronic gout management include:

• When uricosurics, XOI, and other medications are failing, recommend switching to pegloticase—unless they have infrequent gout flares and no tophi present.
• Lifestyle management
• Hypertensive and other medication adjustment

Xanthine oxidase inhibitors (XOI). XOIs ultimately inhibit the production of urate in those who have increased serum urate secondary to metabolic overproduction and in those with gastrointestinal or renal under-secretion.²³ These medications require prolonged use and are not appropriate for initial treatment of acute gouty flares, as they produce a transient hyperuricemia, which may exacerbate symptoms. It is commonly started with acute flare management medications including NSAIDs, corticosteroids, or colchicine. Furthermore, they do not treat the pain associated with an acute gouty flare. Allopurinol and febuxostat (Uloric) are the two most commonly used XOIs on the market.²³

Allopurinol is the most commonly used XOI and the primary choice for most physicians.²³ Its primary metabolite is oxypurinol, which is the more active metabolite. It is a purine analogue that competitively inhibits xanthine oxidase, which plays an integral role in the purine synthesis pathway where uric acid is a product. They are metabolized by the liver and excreted by the kidneys. It is renal protective and beneficial for those with chronic kidney disease (CKD), a common underlying condition causing gout. The starting dose is 100mg daily, increased 100mg every 2–5 weeks until the serum urate goal is reached, with a maximum daily dose of 800mg.²⁴ In those with CKD, starting with 50mg and escalating 50mg every 2–5 weeks is more appropriate.²⁵ Allopurinol and oxypurinol are both able to be dialyzed and therefore safe in those with end-stage renal disease (ESRD) on hemodialysis or peritoneal dialysis. Allopurinol does have a classic hypersensitivity reaction to be aware of, which is rare but can be fatal.

Febuxostat is a non-purine, non-competitive inhibitor of xanthine oxidase, unlike allopurinol. It is appropriate for those who have normal renal function. Similar to those taking allopurinol, there is a tapered dosing strategy to an appropriate serum urate target. The CARES trial shows concern for increased risk of morbidity and mortality for those taking febuxostat with concomitant cardiovascular disease,²⁶ though multiple design flaws in the original study and subsequent studies have not been able to confirm this suspicion.²⁷ With this in mind, using allopurinol as the first line for chronic gout is the most common choice.

Uricosurics. Uricosurics are inhibitors of URAT-1, a uric acid transporter in the proximal tubule of the kidney, which ultimately increases the urine concentration of uric acid subsequently decreasing serum concentrations.²⁸ The most commonly used uricosuric medication is probenecid. It is typically a second line agent for chronic gout treatment after refractory gout after XOI attempts. Since probenecid increases the concentration of uric acid in the kidneys, there is an increased risk of kidney stones, and the medication must be taken with aggressive hydration. Probenecid relies on properly functioning kidneys to work and is contraindicated in renal disease. Like other chronic gout medications, it is not used for acute flares and may worsen symptoms initially.

Uricases. Pegloticase (Krystexxa, Horizon) is saved for those who have chronic, refractory gout who have failed XOI and uricosuric therapy. There is an enzyme called uricase present in other mammals, but not humans, which degrades uric acid. Pegloticase is a pegylated recombinant mammalian uricase which acts as a “replacement enzyme” for uricase.²⁹ PEGylation helps increase the medications half-life as well as decrease its immunogenicity.³⁰ Studies show there are significant improvements in clinical symptoms, and reduced serum urate without significant detriment to kidney function.³¹ There are downsides, however, including immunogenicity creating a drop in efficacy and an infusion reaction.³⁰ It is also an intravenous infusion administered over 2 hours every 2 weeks, which can be difficult on patients as far as scheduling.

The Effect of Exercise, Diet, and Lifestyle Changes on Gout

Gout is often a consequence of metabolic disease as previously discussed. Attempting to control these underlying conditions is of utmost importance.

Reducing high-purine foods is thought to reduce the risk of gout, so avoiding high intake of various foods and drinks, including alcohol, red/organ meat, seafood, and potatoes (though the list is long) is believed to help reduce serum urate. There is controversial evidence on this discussion, though, as just weight loss without the low purine diet helps reduce uric acid levels, and not all high-purine foods like spinach and asparagus are linked with an increase in gout attacks.³²

Staying hydrated, exercising, decreasing saturated fats, and increasing protein and complex carbohydrates are all recommendations for gout management.³² A Mediterranean diet has been shown to reduce cardiovascular disease and decrease uric acid.³³ Diets should be geared toward controlling the underlying cardiometabolic disease processes in the patient.

Other Meds to Consider Switching or Using

The ACR guidelines for gout management recommend changing hypertensive medications like hydrochlorothiazide to something else, preferentially losartan.¹⁵ The guidelines also recommend not stopping low-dose aspirin especially when used to treat other comorbidities, even though aspirin can cause hyperuricemia by reducing uric acid excretion.^15,34 

What You Should Know About Surgical Management

Surgical management of gout is mostly an ancient remedy dating back to Hippocrates. With the advent of ULTs, surgical treatment for gout has mostly gone to the wayside.

However, there are some specific scenarios when surgical management is indicated in tophaceous gout. Surgical management should be limited to patients who have failed or have contraindications to ULTs, have concomitant infection, entrapment neuropathy, or are at risk for permanent joint destruction.³⁵ Treatment options range from incision with aspiration for soft tophi, curettage/sharp debridement (tophectomy) for softer lesions within joints or tendons, and arthroplasty/arthrodesis for joints with destructive changes and/or large voids.

Wang et al³⁶ reported a case series on 28 patients, 15 of whom underwent arthroscopic debridement of tophi at the first MTPJ. Both the surgical and conservatively managed groups continued ULTs. Both groups had significant improvement in the number of acute gouty attacks and AOFAS scores. Kim et al³⁷ reported on 15 patients, comparing tophectomy alone (8 patients) to tophectomy with first MTPJ fusion (7 patients). They found that patient satisfaction, Visual Analogue Scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) scores were all improved more in the arthrodesis group. Overall, surgical management can be beneficial for refractory cases of tophaceous gout but should be limited to the above-mentioned indications.

In Conclusion

Treatment for uncontrolled gout has evolved over the years and is mostly managed with medicinal measures. The ACR guidelines provide great recommendations for managing these patients. Colchicine, NSAIDs, and glucocorticoids are all first-line treatments for acute gouty flares. Goals for long term treatment include a serum urate <6mg/dL. Long-term management includes utilizing ULTs such as xanthine oxidase inhibitors, uricosurics, or uricases. Exercise, diet, and lifestyle changes should be included when counseling and educating patients. Surgical management should be reserved as a last resort option for refractory cases that are causing a severe burden to the patient.

Dr. Barron is a board certified foot and reconstructive rearfoot/ankle surgeon. He practices at Gentle Foot Care—A Division of Ohio Foot & Ankle Specialists. He is the Podiatry Division Chief at Doctors Hospital in Columbus, OH, and is the Assistant Director of Research to the Grant Medical Center Foot and Ankle Residency Program.

Dr. Brown is a second-year resident in the Grant Medical Center Foot and Ankle Residency Program.

Dr. Bykowski is a first-year resident in the Grant Medical Center Foot and Ankle Residency Program.

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