A 57-Year-Old Man With a History of Podagra, Hyperuricemia, and Mild Renal Insufficiency
Robert H. Shmerling, MD, Discussant
ABSTRACT
Gout is an ancient disease. Despite significant advances in the understanding of its risk factors, etiology, pathogenesis, prevention, and treatment, millions of people with gout experience repeated attacks of acute arthritis and other complications. The incidence of gout is increasing, most likely reflecting increasing rates of obesity and other lifestyle factors, including diet. Comorbid conditions that often accompany gout, including chronic kidney disease and diabetes mellitus, present challenges for the management of gout. Using the case of Mr R, a 57-year-old man with a history of podagra, hyperuricemia, and mild renal insufficiency, the diagnosis and treatment of gout are discussed. For those with moderate to severe gout, urate-lowering treatment can eliminate acute attacks of arthritis and prevent complications. In the near future, it is likely that new risk factors for gout will be identified and new ways of preventing and managing this common disease will become available.
DR DELBANCO: Mr R is a 57-year old man with a history of podagra (acute first metatarsal-phalangeal joint pain and swelling), hyperuricemia, and mild chronic kidney disease. An immigrant from Eastern Europe, Mr R worked as an engineer and is now retired. He lives with his wife and has several children. For many years, he has been a patient at a hospital-based primary care practice. He has a 60-pack-year history of smoking but does not abuse alcohol or other drugs. He has no family history of gout, but his grandfather and father had renal disease of uncertain etiology.
In 1993, Mr R experienced his first episode of podagra and was treated with indomethacin and an "injection into my toe." Five years later, his first measurement of uric acid was 7.7 mg/dL. Over the next 10 years, recurrent episodes of podagra were accompanied by uric acid levels as high as 9 mg/dL. Treatment with colchicine caused diarrhea without pain relief. He has adamantly refused further colchicine treatment. A consulting rheumatologist recommended that he use ibuprofen as his principal medication during acute episodes. In 2006, his serum creatinine level was first elevated to 1.3 mg/dL (with an estimated glomerular filtration rate of 57 mL/min/1.73 m2); it later increased to 1.5 mg/dL but stabilized more recently at 1.3 mg/dL. He has had microalbuminuria, most recently with an albumin-creatinine ratio of 442 mg/g (normal range,
At the time of the elevation in creatinine, Mr R started therapy with allopurinol, 100 mg/d, which he continues. His uric acid levels range between 6 and 7 mg/dL. He has never had physical stigmata of gout other than intermittent swelling, redness, and pain in his great toe. He has not had recurrent symptoms since initiating allopurinol.
Mr R has long-standing obesity. His height is 68 in (173 cm); weight, 258 lb (116 kg); and body mass index (calculated as weight in kilograms divided by height in meters squared), 39.2. His blood pressure has been mildly elevated. He has a long history of hyperlipidemia. Currently, his low-density lipoprotein cholesterol level is 172 mg/dL (ideal range,
At the time of the conference, physical examination was unremarkable except for obesity. Mr R had no joint abnormalities and there were no visible tophi. In addition to the medications to manage gout and hyperlipidemia, he was taking aspirin, amlodipine, and ramipril.
MR R: HIS VIEW
I heard of gout through my friends; actually, the name was podagra. It was taken lightly at that point years ago. First time I received the attack on my toe was probably 20 years ago. When I went to the hospital, they said once you have it you always will have it, and I had a very hard time accepting that I will have some sickness or illness in my body that I will not be able to get rid of. My friends told me about podagra as being a rich man's sickness. If you live well and eat well, podagra will be unavoidable; it identifies with well-lived men, but I don't think that there is any truth to that. It's a legend, I guess, or that's how they explained it. It was a sharp pain, as in needles sticking into the joints on my toe to the point that at first you may ignore it, but half an hour later it started to test my tolerance. So the attack was so severe, pain-wise, that I had to go to the hospital for a remedy.
If I saw an expert and had a chance to ask him a question regarding gout, the first thing that would come to my mind is, is there any remedy or medicine or injection that will relieve the pain immediately or in a short time frame? That pain is very severe and it's almost not tolerable. So I think for people who have gout, immediate relief is extremely important. And then I would ask the expert, is there a permanent solution for keeping uric acid in balance in your body, whether it's by food intake or through nature, instead of medicine?
AT THE CROSSROADS: QUESTIONS FOR DR SHMERLING
Does Mr R have gout? How should acute attacks of gout be treated? How should attacks of gout be prevented? Which urate-lowering therapy is best, and how should it be prescribed? How should gout be monitored? When should the patient with gout be referred to a specialist? What do you recommend for Mr R?
DR SHMERLING: Gout is an old disease. The first description of what was almost certainly gout dates back to the Egyptians in 2600 BC.1 Hippocrates called it "the unwalkable disease," and for good reason. The prototypic acute inflammation of the first metatarsal-phalangeal joint (podagra) can make walking—and almost every other activity—unthinkable.
Although much about its pathophysiology is well understood, much about gout remains mysterious. For example, even though a number of risk factors for the development of gout are well established, it is unclear why it afflicts some people and spares others, even when the unaffected share risk factors. It is also not clear why acute gout attacks are self-limited or why gout attacks can be triggered by a decreasing level of serum uric acid.
Gout is caused by monosodium urate crystals precipitating and depositing in the joints and other tissues. Hyperuricemia is a key pathophysiologic predisposition, although most people with hyperuricemia never develop gout. A complex interplay of genetics, diet, medications, comorbidities, and inflammatory response clearly contributes to the risk of developing gout and to its course.
A recent study of twins found that genetic factors play a major role in the risk of developing hyperuricemia, while the risk of gouty arthritis was largely driven by environmental influence.2 Recent genome association studies have identified genetic variants, including the ABCG2 gene, that encode for variants in urate exporters that regulate renal urate excretion and an increased risk of hyperuricemia and gout.3
Impaired renal excretion of uric acid (perhaps related to defective urate transporters across membranes of the proximal tubules4), overproduction of uric acid, consumption of dietary purines (that are metabolized to uric acid), or a combination of these underlie an individual's hyperuricemia. Though a number of genetic mutations predispose to hyperuricemia, the usefulness of genetic testing in the management of gout is unknown and is not standard practice.
Gout is common, affecting nearly 4% of US adults (8.3 million people). Its prevalence is increasing,5 probably owing to lengthening life span, increasing rates of comorbidities (eg, chronic kidney disease, obesity, and type 2 diabetes), diuretic use, dietary choices, and use of certain medications, such as cyclosporine.6- 8
Mr R has a number of risk factors and comorbidities typical of individuals with gout.9 He is male, older than 30 years, and obese and has chronic kidney disease, hypertension, diabetes mellitus, cardiovascular disease, and hyperuricemia. His presentation (recurrent podagra) is typical for gout, as is his intermittent adherence to urate-lowering therapy.10 Motivation to take daily medications during asymptomatic periods (intercritical gout) often wanes with time.
DIAGNOSIS OF GOUT
Ideally, the diagnosis of gouty arthritis is established through analysis of joint fluid or a tophaceous deposit. The identification of negatively birefringent, needle-shaped crystals, typical of monosodium urate crystals, by polarized microscopy is diagnostic. However, criteria and guidelines also acknowledge that a diagnosis of gout can be made solely based on clinical presentation without synovial fluid examination (Table 1).11- 15 Dual-energy computed tomography16 or ultrasound17 may be useful to suggest a diagnosis of gout, but further study is needed before these tests are routinely used.
For patients with suspected acute gouty arthritis, the most important alternative considerations are infectious arthritis, calcium pyrophosphate deposition disease (pseudogout), and spondyloarthropathy (Box). Their joint manifestations may be identical, so joint aspiration may be as important to rule out another condition as it is to confirm gout.
Box. Distinguishing Features of Gout Mimics
Patients with gout usually have hyperuricemia, but a normal uric acid level does not exclude the possibility of gout. In one study, about one-third of patients with gout at initial presentation had a serum uric acid level less than 8.0 mg/dL and 14% had a level less than 6.0 mg/dL.18 (To convert uric acid to micromoles per liter, multiply by 59.485.) Coupled with the observation that most patients with hyperuricemia never develop gout,19 uric acid measurement as a diagnostic test is neither sensitive nor specific.
TREATMENT OF GOUT ATTACKS
The treatment of acute gouty arthritis has long relied on 3 options20: nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids.
A reasonable first choice is an NSAID with a rapid onset of action. Indomethacin and ketorolac are common choices in urgent care settings. Many patients with gout have absolute or relative contraindications to NSAIDs (eg, hypertension, chronic kidney disease, gastropathy), but most patients with gout tolerate these drugs well.
Colchicine may be effective, though less so if symptoms have been present for more than 24 to 36 hours. Diarrhea is a common adverse effect; after his poor experience, Mr R refused to consider even low doses of the drug. A recent randomized, double-blind trial21 comparing high-dose and low-dose colchicine (4.8 mg over 6 hours vs 1.8 mg over 1 hour) found that the low-dose regimen was as effective and caused less toxicity. However, the response rate at 24 hours was relatively low in both groups (about 38% in the low-dose group and 33% in the high-dose group).
Of note, generic colchicine was removed from the US market recently as part of the US Food and Drug Administration's (FDA's) program to take unapproved drugs through its approval process. Brand-name colchicine is currently $5.82 per pill, while generic colchicine was only $0.56 per pill before it was withdrawn from the market. The resumption of sales of generic colchicine is eagerly anticipated.
Effective corticosteroid treatment can include a short course of low- to medium-dose prednisone (eg, 30-40 mg/d, discontinued over 5-10 days) or intra-articular or parenteral corticosteroid injection (such as intramuscular triamcinolone). Although adverse effects of corticosteroids are always a concern, the self-limited nature of acute gout attacks requires only short-term use and, as a result, a generally acceptable rate of toxicity. A Cochrane review published in 200822 concluded that corticosteroids and NSAIDs appear to have similar efficacy for patients with acute gout, though the studies were of limited quality. When monotherapy is ineffective, short-term combination therapy (eg, colchicine and an NSAID) can provide relief.
A novel treatment approach currently under investigation for acute gouty arthropathy is interleukin 1 inhibition. This follows advancing insights into the interactions between monosodium urate crystals and the cryopyrin (NLRP3) inflammasome23 (Figure). Although limited studies suggest that these drugs (including anakinra, canakinumab, and rilonacept) might be effective to prevent or treat acute gout, they are not yet approved for this purpose, must be given by injection, and are quite expensive. The future role of interleukin 1 inhibitors for acute gouty arthritis is unclear.
A limited number of controlled trials have compared treatments for acute gout (eTable 1).21,24- 31 Most document improvement with corticosteroids and NSAIDs and find little difference among them.
I believe NSAIDs should be considered the drug of first choice for acute gout, but comorbidities, concomitant medication use, cost, and patient preference weigh heavily on individual patient choice.
