Prakash Pispati, M.D., FRSM (Lon)
Director of Rheumatology,
Jaslok Hospital, Mumbai
Senior Consultant Rheumatologist,
Saifee Hospital, Mumbai
Hon. Member & Past President – APLAR
Past President – Indian Rheumatology
Is gout an ancient disease of the rich and famous? Historically, yes. Monarchs and noblemen, artists and authors, poets and celebrities often are ‘proud patients’ of gout. Why, even the father of modern medicine, Hippocrates, who described gout with such fine clinical acumen, was a victim of gout. In our country, it is commonly believed that gout is a privilege of non-vegetarians and alcoholics, but this fact is not necessarily true. Vegetarians and teetotalers are equally afflicted as illustrated in the following case:
The chairman of a prominent bank phoned me to say that he had unbearable pain in his right knee and it was getting swollen by the minute. He had self-made a diagnosis of gout for which he had been taking a tablet of allopurinol daily. He was the strictest vegetarian and a teetotaler. “Why this punishment for me?”was the question he posed. The first concern in my mind was to rule out pyogenic infection and then to begin to control his agony from the acute attack of gout. Once treatment was initiated, the rest was history. In 24 hours, there was significant improvement and within the next day he could resume work.
Why then are there some patients who suffer episodically with agonizing pain over many years? Why do some patients have unsightly, embarrassing tophi, at times oozing caseous discharge ?
The first barrier to adopting progressive therapies is to overcome the following myths (Figure 1):
It is indeed unnecessary and repetitive to discuss acute gout, inter-critical gout, chronic gout, tophaceous gout, and hyperuricemia with or without symptoms of gout, be they acute or chronic. A dramatic onset of acute gout is far too well known to merit description here, but a patient’s agonies following the typical red-hot joint presentation, however, needs to be differentiated from septic arthritis. Manifestations of chronic gout can be subtle and deceptive and elude a precise diagnosis. A few examples of musculoskeletal manifestations of gout are given in Table 1.
Who is a candidate for gout?
Recent studies have clearly shown that a patient with certain predisposing risk factors is likely to develop gout. These are best described as the Six H’s (Figure 2).
Gout is commonly thought to be a localized joint disease. It is however a systemic metabolic disorder with serious extra-articular consequences. Gout can accelerate atherosclerosis and can precipitate cardiovascular events, such as myocardial infarction, and longevity can be decreased.
This is critical because what may look like straightforward, monoarticular acute gout may instead be dangerous, pyogenic septic arthritis. What may look like polyarticular systemic rheumatoid arthritis (RA) may be chronic gout mimicking RA, and what may be thought of as gout may be other crystal-induced arthritic entities.
Laboratory investigations are essential. Six vital steps are to be taken:
- Blood tests (inflammatory markers): CBC, ESR, CRP
- Serum uric acid (repeated as necessary).
- Imaging: X-rays of the joints, chest, KUB, ultrasound, Computed Tomography(CT) scan, as required.
- Blood sugar, lipid profile, renal profile to detect comorbidities.
- Synovial fluid: Appearance, microscopy (cells, crystals), polarizing microscopy to countercheck.
- Urinalysis: Cells, urate crystals, 24-hour uric acid.
Laboratory parameters are not without misgivings. Hyperuricemia is a persistent elevation of serum urate over 7 mg/dL, as a broad value. Earlier, the therapeutic gold standard was to maintain it around this figure. Today, the conservative objective is to ensure that it will not exceed 6 mg/dL. This is when allopurinol often falls short in efficacy and when novel therapy febuxostat, comes in as a supplement or even as a substitute. Even more recent is the advancement made by uricases.
In laboratory work up, the focus is always on serum uric acid levels subject to the caveat that a gouty patient will not necessarily always have an elevated serum urate; gout can be precipitated despite a normal serum uric acid level. After all, gout manifestations happen due to the deposition of monosodium urate (MSU) crystals at the joints, muscles, tendons and other target sites. When the uric acid level is above 6.8 mg/dL, crystallization of the uric acid as sodium urate can occur in a joint. This property is best explained by understanding that when solute dissolves in a solvent it becomes a solution. If this solution is supersaturated with higher concentrations of solute, the solute will precipitate out of the solution. Other determinants may be minute changes in the pH in the blood, oxygen tension, microcirculation, concentration and penetration in the target joint and its responsiveness. Thus, MSU crystals get deposited in the joints, inciting inflammation causing a painful, red-hot joint or else, triggering a low-grade, chronically gouty, joint arthritis. High concentrations of more than acceptable serum uric acid levels may happen due to the underexcretion of urate by the
kidneys or overproduction by the liver. In the plasma, subtle changes in the pH, oxygen tension, pattern of migratory cells such as white blood cells (WBCs), influence of drugs and trauma to a target joint, predispose to deposition of MSU crystals (Figure 3) thereby inciting acute or chronic gout.
The key is inhibition of xanthine oxidase (XO). Febuxostat inhibits both the isomers unlike allopurinol and hence, is more effective. Patients not responsive to allopurinol can respond to febuxostat. It has been shown that febuxostat at a daily dose of 80 mg or 120 mg was more effective than allopurinol at the commonly used fixed dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus areas occurred in all treatment groups.
This has been used for over four decades and merits a review.
- Allopurinol is a pro-drug for oxypurinol.
- Oxypurinol does not effectively inhibit the oxidized form of xanthine oxidase.
- Renal elimination of oxypurinol complicates dosing with renal insufficiency.
- Allopurinol non-selectively affects purine and pyrimidine metabolism.
- Drug interactions may occur (e.g. with azathioprine or ampicillins).
- Hepatotoxicity and minor gastrointestinal and central nervous system side effects reported.
- Rash occurs in about 2% of treated patients.
- Major allopurinol hypersensitivity syndrome is rare, but has a mortality rate of approximately 20%.
- Many patients do not achieve serum urate level less than 6 mg/dL on standard doses,and optimal dosing is controversial, particularly with renal insufficiency.
- Tophus reduction is typically slow.
- Patient compliance is only about 50%.
How does febuxostat address the limitations of allopurinol? What is the mechanism of action (Table 2) and dosage required?
- 40 mg once daily regardless of food
- If serum uric acid is >6 mg/dL, after 2 – 4 weeks of starting treatment, then febuxostat increased to 80 mg or 120 mg once daily maybe considered.
WHAT IS DIFFICULT GOUT ?
Haven’t we come across patients who are depressed because of repeated or continuous symptoms of gout? This spectrum is described as difficult gout.
The key features are:
- Destructive tophi
- Polyarticular gout or frequent flares of monoarticular or oligo articular gout.
- Renal insufficiency, with creatinine clearance more than 60 ml/min.
- History of urolithiasis or documented uric acid overproduction.
- Cardiovascular, diabetic, hepatic or upper gastrointestinal tract comorbidities.
- Intolerance or refractory state to non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, ACTH, and/or glucocorticosteroids.
- Major organ transplantation or cyclosporine use.
- Polypharmacy and drug interactions (e.g. statins, macrolide antibiotics or anticoagulants).
- Age of 70 years or older also, failure to satisfactorily lower serum urate.
- Allopurinol hypersensitivity or intolerance.
WHAT ABOUT DIET?
Nearly every patient inquires about the recommended diet. They are all mostly advised on the Don’ts. Clearly, there is a need for lowering protein-rich intake, but with the objective of helping our patients lead normal lives. Hence diet recommendations should be humanized as much as possible. This will ensure that patients are compliant to the recommended treatment. Or else, they will shy away from both dietary and drug advice.
In today’s world, gout is regarded by many physicians as not so exciting to learn about afresh. It is common thinking that ‘I know how to treat it, so I don’t need to know more.’ Likewise, many patients may not think it necessary to consult a rheumatologist, with the belief that a tablet a day of allopurinol is good enough! Nearly four decades have elapsed. Now,
there is an awakening at last. Firstly, there is a prudent realization that gout and hyperuricemia are not only destructive to the joints, but also to the cardiovascular system, inciting and hastening atherosclerosis and resulting in cardiovascular events and often reducing life expectancy.
The American College of Rheumatology guidelines for the management of gout emphasizes on early diagnosis of gout,
keeping serum uric acid under 6mg/dL and initiating the treatment of an acute attack of gout within 24 hours (which are among some of the recommendations).
Second, there is the recognition that at all costs the serum uric acid level must never exceed 6 mg/dL and that allopurinol by itself is often not good enough to achieve this level. With better insight into purine metabolism, we now have the novel drug, febuxostat. After many long decades of allopurinol monotherapy, febuxostat fills in the gap, hitherto unknown in the comprehensive management of gout. Further, newer options include uricases and even the biological “Infliximab” for resistant tophi.
Gout is a disease with perceptible results when treated appropriately, and a physician can earn the gratitude of an ailing patient, as the results are almost immediate. Also, a rheumatology referral is well merited for better treatment outcomes.
1. Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo A, et al. Febuxostat compared to allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353:2450-2461.
2. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for the management of Gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.Arthritis Care and Research. 2012;