Severe Gout Refractory to Conventional Therapy

S: A 56-year-old man presents for management of podagra.

O: Imaging of the right foot shows radiolucency of the metaphysis of the first metatarsal, suggestive of gout.

A: The patient is started on allopurinol. Over the course of 3 visits in 6 months, his serum urate levels partially decrease, but his symptoms progress to the point where he experiences weekly flares.

P: Treatment is reviewed with the patient, and he is switched to pegloticase with methotrexate. He is cautioned to refrain from alcohol and triggering foods. He is scheduled to return in 1 month for monitoring.


Many factors may contribute to hyperuricemia, which is often associated with the presence of conditions such as hypertension, congestive heart failure, diabetes, kidney disease, and obesity, as well as a family history of gout. Treatments for these conditions (eg, thiazide diuretics, often prescribed for mild hypertension) are also associated with increases in serum urate levels, which can cause gout. These cases of gout may be particularly resistant to conventional therapies and require strategies designed to lower serum urate levels, such as uricase agents.1,2

Case Scenario

Tom is a 56-year-old White man who works as a supervisor in a tool-making factory. He spends much of his day on his feet and frequently goes out after work for drinks with his peers. His wife works as a hospital nurse, often on a later shift, which leaves him alone in the evenings. He and his wife have no children at home.

Tom is overweight, and he eats at diners and sports bars 3 to 4 times per week. He usually orders cheeseburgers or fried seafood with fries. He has 2 to 3 beers with dinner, followed by a few more drinks at home. Outside of work, he leads a sedentary lifestyle, generally sitting in front of the television until he falls asleep.


Tom is referred to you by his primary care physician for a history of podagra, although he is in no acute distress at the time of your examination.

Personal and Family History

Tom reveals a history of hypertension, chronic kidney disease stage 2, coronary artery disease (status: post-stent placement), and metabolic syndrome.

Tom describes recurring episodes, which occur several times per year, of pain and swelling in his great toe; the frequency of these episodes has recently increased from every few years to every few months. Both he and his wife have noticed that these episodes are associated with eating shellfish and commonly occur during football season, when he typically consumes more alcohol.

His family history is notable for the presence of obesity in both parents and 2 siblings. He also has an uncle with gout.

Prior Medications

Tom has been treated for 20 years for hypertension. He is currently taking a thiazide diuretic, an angiotensin-converting enzyme (ACE) inhibitor, and a beta blocker. He also takes low-dose aspirin.

Clinical Examination

On examination, Tom appears to be in no acute distress. General examination is largely unremarkable except for the presence of generalized obesity and mild hypertension.

Examination of his joints and extremities reveals bilateral hallux valgus with slight fluctuance of the first metatarsal phalangeal joint of the right foot, without warmth or redness.

Imaging Studies

Imaging obtained of Tom’s feet shows radiolucency of the metaphysis of the first metatarsal on the right foot, suggestive of gouty erosions and slight soft tissue haziness.

Laboratory Findings

Tom’s serum urate level is 9.5 mg/dL, his glomerular filtration rate is 45 mL/min, and his creatinine level is 1.6 mg/dL. His laboratory findings are otherwise normal.


Tom is diagnosed with gouty arthritis and hyperuricemia.


Tom is started on 100 mg allopurinol, with plans to increase his dosage by 100 mg each month in an effort to achieve a target serum urate level of 6 mg/dL or lower. Tom is concurrently started on colchicine 6 mg every other day.

Follow-Up Visit: 4 Months Later

Tom reports intermittent adherence to allopurinol 200 mg/day. He has experienced recurrent episodes of gout, which initially worsened when he began taking allopurinol. Clinical examination reveals fullness in the right knee, along with limited effusion and a bulge sign; it also shows warmth over the left midfoot. Laboratory assessment reveals a serum urate level of 8 mg/dL.

You instruct Tom to increase his allopurinol dosage to 300 mg/day, maintain colchicine at 6 mg every other day, and return for a follow-up visit in 3 months.

Acute Relapse: 1 Month Later

You receive a call from Tom, who reports now-weekly occurring flares of gout. He has also noticed the development of 2 new nodules: near his elbow and on the dorsum of his right foot, near his great toe. He reports that he has continued to use allopurinol, typically 200 to 300 mg/day.

Follow-Up Visit: 1 Week Later

You see Tom in the clinic 1 week later, and laboratory assessment indicates that his serum urate level has increased to 8.5 mg/dL. He has several swollen joints, as well as nodules over his foot with characteristic skin translucency and an underlying whitish discoloration, suggestive of gouty tophi.

You discuss various therapeutic options with him, including a change in his xanthine oxidase inhibitor treatment or the addition of a uricosuric agent. You mutually elect to initiate pegloticase in combination with methotrexate to prevent immunogenicity.

You caution him about the need to abstain from alcohol, and you plan to initiate the pegloticase regimen when you have confirmed that his glucose-6-phosphate dehydrogenase (G6PD) level is normal. You recommend that he return for another follow-up visit in 1 month.

Discussion of Uricase Treatment

Many agents have been approved for the treatment of gout, which is achieved through a combination approach. Early flares of gout should be treated with any monotherapy or combination of colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and oral or intra-articular steroids to reduce inflammation and pain around the joints. An interleukin (IL)-1 blocker should be considered for patients with repeated flares, as well as patients in whom side effects or comorbid conditions contraindicate first-line therapies.3

Because gout is a chronic condition, the treatment of repeated flares includes the addition of urate-lowering therapies (ULTs) such as allopurinol, the preferred first-line therapy, to alleviate acute symptoms and prevent future attacks via reduced production of serum urate.3,4 Febuxostat is a second-line ULT because of concerns regarding its potential greater cardiovascular toxicity. Patients are also counseled to avoid foods that are high in purine (eg, seafood, red meat, and organ meats), which contribute to serum urate accumulation; they are also counseled to substantially reduce their consumption of beer and hard alcohol.4

Despite lifestyle modifications and the use of conventional ULTs, nearly 2% of patients with gout continue to experience flares and their serum urate levels remain elevated.5 Desired serum urate levels are <6 mg/dL (360 µmol/L) for all patients and <5 mg/dL (300 µmol/L) for patients with visible tophi.3 For patients with severe refractory gout (particularly patients with tophaceous disease), pegloticase is an alternative therapy.3,5

Pegloticase has shown efficacy in the rapid resolution of tophi and can significantly reduce serum urate levels; compared with other types of ULTs, pegloticase functions through a unique mechanism that involves the enzymatic degradation of serum urate.5 Common drug-related immunogenicity and anti-pegloticase antibody challenges can be managed by coadministration of medications such as methotrexate or mycophenolate mofetil, thereby extending the duration of pegloticase efficacy.6,7


Kenneth G. Saag, MD, MSc, is the division director of Clinical Immunology and Rheumatology and director of the Comprehensive Arthritis, Musculoskeletal, Bone, and Autoimmunity Center at the University of Alabama at Birmingham. Dr Saag is also the founding director of the UAB Center of Research Translation in Gout and Hyperuricemia.


1. Kuwabara M. Hyperuricemia, cardiovascular disease, and hypertension. Pulse (Basel). 2016;3(3-4):242-252. doi:10.1159/000443769

2. McAdams DeMarco MA, Maynard JW, Baer AN, et al. Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012;64(1):121-129. doi:10.1002/art.33315

3. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. doi:10.1136/annrheumdis-2016-209707.

4. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180

5. Schlesinger N, Lipsky PE. Pegloticase treatment of chronic refractory gout: update on efficacy and safety. Semin Arthritis Rheum. 2020;50(3S):S31-S38. doi:10.1016/j.semarthrit.2020.04.011

6. Botson JK, Saag K, Peterson J, et al. A randomized, placebo-controlled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: primary efficacy and safety findings. Arthritis Rheumatol. 2023;75(2):293-304. doi:10.1002/art.42335

7. Khanna PP, Khanna D, Cutter G, et al. Reducing immunogenicity of pegloticase with concomitant use of mycophenolate mofetil in patients with refractory gout: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2021;73(8):1523-1532. doi:10.1002/art.41731

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Reviewed March 2023