With recently published guidelines and emerging medications, this author offers a closer look at key principles in diagnosing and treating chronic gout.
When patients are diagnosed with gout, they often have many questions. One of the most frequently asked questions pertains to whether this gouty attack is a one-time event or whether it is chronic gout that needs prophylactic treatment. Thankfully, due to the new 2012 American College of Rheumatology guidelines and other research, the treatment of chronic gout has recently become clearer.
Not so long ago my management of gout patients left a lot to be desired. I thought gout was easy. We have all treated the extraordinarily painful, red hot, swollen, acute gout foot with success. We give an injection or write a prescription and shortly thereafter, the patient thinks you are a hero. You have a grateful patient. Case closed and you can move on to the next patient. This treatment plan may sound familiar to some of you.
Here is the problem with that line of thinking. Just because the patient is in an intercritical and asymptomatic period does not mean our job has ended. Treating all podagra patients symptomatically without regard to their total body uric acid is a recipe to create chronic gout.
Gout is a progressive disorder with acute attacks followed by intercritical periods. If the serum uric acid is above the level of solubility, the total body urate pool is increasing as urate precipitates out in tissues. As the total body urate pool increases, the acute gouty attacks become more and more frequent. These attacks also become more aggressive and longer lasting. Elevated total body urate is also associated with tophi formation as well as polyarticular disease. The understanding that gout is a progressive disorder is critical if we are going to treat acute or chronic gout appropriately.
There is significant evidence that debulking the total body urate pool leads to fewer gout attacks. There have been multiple studies that support this idea but Li-Yu and colleagues performed one of the most compelling studies in 2001.1 This study revealed that patients with a serum uric acid of greater than 6 mg/dL experienced a mean of six acute gouty attacks per year while patients who had a serum uric acid below 6 mg/dL for 12 months had a mean of one attack per year. Half of those patients had no attacks at all. Perez-Ruiz and colleagues performed a similar study, revealing that after two years of controlling the serum uric acid below 6 mg/dL, acute gouty attacks had been completely eradicated.2
Imagine a cold glass of iced tea on a hot summer day. As you add sweetener to the glass, it dissolves into the iced tea until you reach the solubility limit. Any sweetener one adds over the solubility limit will be visible as precipitate at the bottom of the glass. This analogy is similar to what happens physiologically with hyperuricemia. Uric acid above the solubility limit precipitates out in the soft tissue, increasing the total body urate pool. By decreasing the serum uric acid to below the solubility limit, monosodium urate crystals can dissolve, most often leading to resolution of the symptoms associated with gout.
The solubility of uric acid at physiologic temperature and pH is 6.8 mg/dL.3,4 With this knowledge, it makes sense that the therapeutic target for serum uric acid is below 6 mg/dL. The European League against Rheumatism Task Force for Gout and the American College of Rheumatology guidelines have both set the therapeutic target for serum uric acid at <6 mg/dL.5,6 The British Society of Rheumatology, however, has published more stringent guidelines, setting the target for serum uric acid at <5 mg/dL.7
As the serum uric acid falls into the therapeutic range, the total body urate can start to decrease but this process is slow unless the gradient is high according to Le Chatelier’s principle. Perez-Ruiz and coworkers confirmed this in 2002.8 They noted that the speed of tophi resolution was inversely proportional to the serum uric acid level. Therefore, the lower serum uric acid is, the quicker the debulking of the total body urate will occur.
After making the diagnosis of gout and getting the acute flare under control, our job is not complete. The American College of Rheumatology guidelines recommend a multipronged nonpharmacological approach for all patients who have been diagnosed with gout.6 Among these are patient education, consideration of secondary causes of hyperuricemia and elimination of nonessential prescription medications.
Patient education about the disease as well as dietary and lifestyle modifications have been partially efficacious. Studies have shown a 10 to 18 percent reduction in serum uric acid with exercise and dietary modification alone. However, in patients with serum uric acid above 7 mg/dL, this is often not adequate to decrease the serum uric acid to under the target of <6 mg/dL.6,9 The reason for this is fairly simple. Ninety percent of uric acid in the body is from endogenous sources while only 10 percent is from exogenous sources. In other words, only 10 percent of the uric acid is from dietary purines and 90 percent is from tissue purine synthesis. That is why controlling gout by diet alone often fails, necessitating urate lowering therapy.
It is also important that we consider secondary causes of hyperuricemia and seek to modify these when possible. Some of the most common secondary causes of hyperuricemia include obesity, diabetes mellitus, hypertension, hyperlipidemia, excessive alcohol intake, chronic renal disease and lead intoxication.9,10 Clearly, coordination of the patient’s care with the entire healthcare team is critical to the success in addressing the secondary causes of gout. Often, specialists are maligning these secondary causes of gout and despite optimal treatment, the serum uric acid continues to be uncontrolled.
Several medications are associated with hyperuricemia. In a 2005 study, there was a 77 percent increase in relative risk for gout in men who were taking thiazide diuretics.11 This was true even after controlling for other risk factors associated with gout. Other urate elevating prescriptions include loop diuretics, niacin and pyrazinamide. In some situations, treating hyperuricemia may be as easy as discontinuing the offending medication. In consultation with the prescribing provider, consider elimination of any nonessential urate elevating prescription medications.
The American College of Rheumatology guidelines have identified four situations in which one should initiate urate lowering therapy.6 The first situation is having tophus or tophi present upon examination or imaging studies. The second is frequent gouty attacks defined as more than one acute attack per year. The third indication for urate lowering therapy is chronic kidney disease of stage II or worse. Lastly, patients with past urolithiasis should start on urate lowering therapy. Many of the patients presenting to my office with an acute gouty attack qualify for the initiation of urate lowering therapy. It is incumbent upon us either to treat the patient’s hyperuricemia or refer the patient to a primary care provider or rheumatologist who will manage the patient’s chronic gout appropriately.
First-line therapies for hyperuricemia include allopurinol or febuxostat (Uloric, Takeda Pharmaceuticals), which are both xanthine oxidase inhibitors. If the patient can tolerate neither of these medications or if these medications are contraindicated, probenecid could be a first-line alternative. As I discussed previously, one should use urate lowering medications to obtain a serum uric acid below 6 mg/dL. Targeting a serum uric acid level below 5 mg/dL is preferable so one can debulk the total body urate pool more quickly.8
Allopurinol is the most widely prescribed urate lowering medication. Allopurinol use should start at no greater than 100 mg per day and no more than 50 mg per day for patients who have stage IV or higher chronic kidney disease. Monitor serum uric acid levels and titrate the allopurinol dosing up every three to five weeks until the patient has met therapeutic goals or the maximum dosage of 800 mg. It is important to note that multiple studies have revealed that allopurinol given at 300 mg per day often fails to attain the target serum uric acid of less than 6 mg/dL.10,12 Also keep in mind that one can utilize allopurinol in patients with chronic kidney disease provided there is adequate monitoring and patient education.
The newest xanthine oxidase inhibitor on the market is febuxostat, which one can start at 40 or 80 mg per day. In the clinical trials for febuxostat, the percentage of patients who obtain a serum uric acid below 6 mg/dL was much higher for patients utilizing the 80 mg per day dose in comparison to those who had the 40 mg per day dosing regimen.12 The 40 mg per day dosing reduced the serum uric acid level to less than 6 mg/dL in 45 percent of patients while the 80 mg per day dose reduced the serum uric acid level to less than 6 mg/dL in 70 percent of patients.
If patients cannot tolerate allopurinol or febuxostat, or if the drugs are contraindicated or ineffective, probenecid becomes the first-line alternative medication. The dosing for probenecid starts at 250 mg PO b.i.d. times seven days. After a week, the dose increases to 500 mg PO b.i.d. One may also need to titrate up probenecid to obtain serum uric acid in a therapeutic range.
Probenecid is contraindicated in patients with urate nephropathy and renal stones. Do not use probenecid in patients with a creatinine clearance of less than 50 mL per minute. Obtain a urinary uric acid level prior to initiating probenecid. An elevated urinary uric acid level is indicative of uric acid overproduction and one should not use probenecid in these patients. Clinicians should also continue to monitor urinary uric acid levels while the patient is on probenecid.
It is important to educate patients that paradoxically, the initiation of urate lowering therapy can trigger acute gouty attacks. This is thought to be secondary to the rapid decrease in the serum uric acid that causes a large change in the concentration gradient. This concentration gradient causes mobilization of the urate, which is thought to increase so-called “mobilization flares.”
Therefore, one must utilize concomitant use of nonsteroidal anti-inflammatory medications when initiating urate lowering therapy. It is important to note colchicine (Colcrys, Takeda), given at 0.6 mg PO q.d. or b.i.d., is the only FDA approved medication for gout prophylaxis.
Refractory chronic gout occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are not adequately controlled with xanthine oxidase inhibitors. Patients with chronic refractory gout often present to our offices with large tophi with or without ulceration. Historically, these patients have had surgical excision of the tophi. However, patients with refractory chronic gout most often present with a high comorbidity burden, adding significant risk to any planned surgical intervention. There are also the significant complications that can occur after the tophi excision itself.
What if one could resolve tophi without surgery? A new medication, pegloticase (Krystexxa, Savient Pharmaceuticals), now offers hope for these patients with refractory chronic gout. Pegloticase catalyzes the breakdown of uric acid into allantoin, which the kidneys easily excrete. Pegloticase has the power to decrease serum uric acid to near undetectable levels.13 As I discussed above, this creates a strong gradient that acts as a powerful debulking agent. Therefore, pegloticase can significantly and quickly reduce the total body urate pool.
Pegloticase is exciting for its potential to resolve tophi. In clinical trials, there was 100 percent resolution of at least one tophi in 45 percent of patients.13 These results can be quite rapid and dramatic. Although no medication is without risk, surgery in this patient population is not exactly risk-free either. Pegloticase offers the prospect of preventing surgery and resolving tophi pharmacologically, which is an option we have not had in our armamentarium until relatively recently.
Everyone is going to have a different level of comfort when treating chronic gout. Some podiatrists may choose only to manage acute gouty flares while others may choose to manage the patient’s urate lowering therapy. Either choice is reasonable as long as someone on the patient’s medical team initiates urate lowering therapy in a timely manner. At the very least, it is the job of every podiatrist to obtain the proper care and consults to help prevent the next acute gouty attacks.
No matter what your level of expertise is, having a good working relationship with a local rheumatologist will become necessary at some point. When should you consider calling on the expertise of a rheumatologist? Here are some clinical scenarios that may warrant a possible consult:
• if there is an unclear etiology of hyperuricemia;
• if there are refractory signs and symptoms of gout;
• if there is difficulty in reaching the target serum urate levels; and/or
• if there have been multiple and/or serious adverse events from urate lowering therapy.
Dr. Neville is a Fellow of the American College of Foot and Ankle Surgeons. He is in private practice in Indianapolis.
The author gives special thanks to Herbert Baraf, MD, for the tophi pictures in this article.
1. Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol. 2001; 28(3):577-80.
2. Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized actively controlled study. J Clin Rheumatol. 1999; 5(2):49-55.
3. Neogi T. Clinical practice: gout. New England J Med. 2011; 364(5):443-52.
4. Terkeltaub R. Update on gout: new therapeutic strategies and options. Nature Reviews Rheumatology 2010; 6(1):30-8.
5. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65(10):1312-24.
6. Khanna, Dinesh et al. American College of Rheumatology guidelines for management of gout, part 1 & 2. Arthritis Care Research. 2012; 64(10): 1431-1461.
7. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology. 2007; 46(8):1372-4.
8. Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002; 47(4):356-60.
9. Singh JA, Reddy SG, Kundudkulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. 2011; 23(2):192-202.
10. Zhang Y, Woods R, Chaisson CE, Neogi T, Niu J, McAlindon TE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med 2006; 119(9):800.e13-8.
11. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the healthcare professionals follow-up study. Arch Int Med. 2005; 165(7):742-8.
12. Becker MA, Schumacher HR, Espinoza LR, Wells AF, McDonals P, Loyd E, et al. The urate lowering efficacy and safety of febuxostat in the treatment of hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010; 12(2):R63.
13. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional therapy. JAMA. 2011; 306(7):711-720.
For further reading, see “Recognizing And Treating Lower Extremity Gout” in the February 2012 issue of Podiatry Today.