Theodore Fields, MD, FACP
Gout is an ancient disease, clearly described in writings from the time of Hippocrates. The pace of research and new publications in gout was relatively slow until about four years ago, but since then the rate of gout publications has dramatically increased.
Many of the principles of gout management that will be discussed here are old, but several new options for the management of difficult gout cases have been developed in the last few years, and a number of gout agents are currently in development. Use of these new strategies and new agents for gout will improve treatment outcomes. However, even more important to ensuring effective treatment of this condition is the more precise use of both older and newer agents, along with patient education and motivation.
The best news about gout is that we can assure our patients that if they are compliant with their medications, the long-term prognosis is quite excellent. In a five-year, long-term extension study of gout in which the patients kept their uric acid below 6.0, by the end of the third year the percentage of patients experiencing gout attacks was approximately 2%, and at five years it was 0%.1 This is an important fact for patients to realize early on in their gout treatment. This knowledge can help them stay the course and deal with the early phase of gout management, when they may actually have increased numbers of attacks.
Causes and clinical characteristics of gout
Painful gouty attacks result from the accumulation of sodium urate crystals, which form in various tissues of the body as the blood level of uric acid rises. Sodium urate crystals in the joint cartilage and lining tissue of the joint get released into the joint fluid and stimulate an intense inflammatory reaction. The result is a joint, most commonly the first metatarsophalangeal joint of the foot, with the classic signs of inflammation, heat, erythema, and swelling, along with intense pain (see figure 1). In addition to the first toe, common sites for gout are the ankle, midfoot, knee, and elbow bursa. With time and gout progression, almost all joints can be subject to gout attacks.
Figure 1: Acute gout flare in ankle and first metatarso-phalangeal joint.
Gout is a strongly genetic disease.
Ninety percent of primary gout patients are underexcretors, meaning that the urate organic anion transporters in the proximal tubule of their kidney excessively reabsorb uric acid. Ten percent are overproducers, and produce too much uric acid related to overactivity of the purine metabolic cycle. There are also many patients with secondary gout, due to conditions or substances that increase urate production, such as malignancy, alcoholism, and sickle cell disease.
Gout can be set off by a variety of factors. Once a person has a critical mass of sodium urate crystals in a joint, an additional urate load can be enough to trigger an attack. Red meat, shellfish, and high-fructose corn syrup are among the types of food that have been shown to elevate blood uric acid levels. All types of alcohol inhibit uric acid excretion, and thus raise serum uric acid level. Beer is especially troublesome, as it not only inhibits uric acid excretion but also, due to its guanosine content, provides a purine load as the guanosine goes through the steps of purine degradation to the final point of the pathway (ie, uric acid).
Making the diagnosis of gout
Gout has a typical clinical pattern, which allows it in most cases to be diagnosed without the need for identification of sodium urate crystals in the joint fluid. The classic picture is a very rapidly accelerating joint inflammation, reaching a peak of intensity within 6-12 hours, with a tendency to recurrence. Most gout attacks will be self-limited within weeks even without treatment, but the pain and intensity is such that patients will almost always require treatment. When this picture is present in the first metatarsophalangeal joint in a patient with elevated serum uric acid and no clues to infection, the diagnosis is essentially secure. If there is any reason to suspect infection (eg, an immunosuppressed patient, or recent trauma or recent infection elsewhere in the body), then fluid aspiration and culture is necessary. If the only joint involved is the knee, aspiration is generally advised with analysis of the fluid for crystals, to separate gout from pseudogout, since the long-term management of those conditions is different. Although not every patient with gout needs crystal identification to make a confident diagnosis, any time fluid is obtained from a joint (eg, in the process of a joint injection) it is advised that it be sent for crystal analysis so that an absolute diagnosis can be made.2
In its advanced state, gout presents with frequent and often severe attacks, and can present with tophi in a variety of locations, especially over the first metatarsophalangeal joint and in the olecranon bursa. Joint damage can also be clearly visible on X-ray and characteristic gouty changes (as seen in figure 2) in the right clinical context are essentially diagnostic of gout.
Figure 2: Gouty changes (“punched out lesions”) with surrounding soft tissue Swelling representing a tophus (both arrows).
Gout and co-morbidities
It is rare (perhaps in less than 10% of cases) that a patient with gout presents with no comorbidities other than the gout itself. A wide variety of comorbidities have been associated with gout (see Table 1), and these have a significant impact on therapy for gout. Uric acid appears to be an independent risk factor for coronary disease and myocardial infarction, but to date we do not have adequate controlled data to be sure that lowering serum uric acid will reduce this risk.3
The presence of one, and often multiple, comorbidities in patients with gout makes gout more challenging for the primary care practitioner. The patient’s other comorbidities can dominate the visit, to the point that the patient doesn’t mention that their gout is uncontrolled. Focus groups with patients have shown that patients often don’t mention their gout attacks to their physician, especially if they are already on a medication for gout. In a busy primary care visit, it’s still very valuable for the patient if the physician asks about their gout, even if it’s the fourth or fifth item on their problem list.
Treating the acute attack of gout
Fortunately, we have a variety of options for managing gout. It is important that we have these, since the comorbidities so common in gout can make certain options more dangerous. See Table 2 for options in managing acute gout, with comments on how the best option can be chosen in a particular case. For example, if a patient has hypertension and diabetes mellitus, but a creatinine clearance > 30, colchicine might be a good option early in a gout attack. If used in the regimen described in Table 2, severe diarrhea did not occur, a welcome contrast to the severe diarrhea often seen with older colchicine regimens that involved hourly dosing.4 When all of the usual options for acute gout are either inappropriate for a particular patient or not effective, see “Treatments for Gout in Development” below for considerations. Such patients should probably be referred to a rheumatologist for evaluation.
When starting acute treatment for a painful gout attack, it is generally not advisable to start a urate-lowering therapy at the same time, since “mobilization flares” can occur as urate-lowering therapy begins. It is suggested that clinicians wait 2-3 weeks before initiating urate-lowering therapy.
Lowering uric acid level for long-term gout management
Not every patient with gout needs to be on urate-lowering therapy. Many rheumatologists confronted with a patient experiencing their first attack of gout will defer urate-lowering therapy, since it may be years until a second attack occurs. Once two attacks occur in a year, however, the progressive nature of gout suggests that urate-lowering therapy should be started. The presence of a tophus, or of X-ray or other imaging evidence of gouty bony damage, should also stimulate uratelowering therapy, regardless of the number of gout attacks that have occurred.
If the treating physician deems it appropriate to lower a patient’s uric acid, a large body of data supports a goal of < 6.0mg/dL.5 Getting to this level significantly reduces the risk of gouty flares, and can help shrink tophi and prevent future gouty joint/bone damage. In patients with tophi, the uric acid goal is often reduced to < 5.0, as data has clearly shown more rapid dissolution of tophi with lower levels of serum uric acid.
Once the decision to lower serum urate has been made, the physician must select the most appropriate drug for the individual patient. Currently, there are four FDA agents approved for urate lowering, and each has distinct characteristics. See Table 3 regarding options for long-term gout management, with comments regarding each.
Whichever prescription medication is chosen to manage uric acid, strong consideration should be given to the concurrent prescription of prophylaxis of gout attacks for the first six months of the urate-lowering therapy. The first six months is a time of “urate mobilization attacks” and prophylactic therapy can be a major benefit to the patient, and can help the patient stay on the urate-therapy long-term and achieve a long-term excellent outcome.
Patients often ask about cherry extract, and some early evidence suggests that it can help reduce serum uric acid, possibly via its Vitamin C content (research has shown that 500 mg/day of Vitamin C may help lower serum uric acid by about 0.5mg/dL). Probenecid can be used as a first-line agent to lower uric acid, but there are some caveats. It works by increasing uric acid excretion, so a patient who is an overproducer with high urinary urate may develop renal stones on this therapy. Therefore, a 24-hour urine is advised before starting probenecid, and if >600mg/24-hour uric acid is present, probenecid should not be used as first-line treatment. Probenecid is a twice-daily drug, is associated with a number of drug interactions, and is ineffective when serum creatinine is greater than ~ 2.0. For these reasons, most patients who need uric acid lowering start on allopurinol or febuxostat. Patients without comorbidities are generally started on allopurinol. Those with renal insufficiency with eGFR down to 30 ml/min (the level at which the agent has had its results published to date) may be given febuxostat as a first-line agent. If allopurinol is used as first-line treatment in those with Class 3 renal dysfunction (eGFR 30- 60ml/min) it should be started at a lower dose (eg, 100 mg once a day) and slowly increased, whereas with febuxostat the patient can start on 40 mg and can be increased if needed to 80 mg.
Patients need to be actively involved in the management of their gout. Studies have shown very poor compliance with long-term uric acid-lowering therapy. When contrasted with the high efficacy of long-term therapy, there is clearly a disconnect. For patients to remain on urate-lowering therapy even when their attacks have ceased, they need to understand that gout is a genetic disease and that stopping the medication will return them to their initial state of “uric acid overload.” Patients need to understand the importance of reaching the goal of uric acid less than 6.0 the same way they need to understand the importance of reaching blood pressure or HbA1c goals. They need to work at weight loss and dietary modification. They also need to be advised to let their treating practitioner know if they are having gout attacks. If they are on urate-lowering therapy and still have attacks over time, it is likely that their uric acid level is still > 6.0. Patients also need to understand that the six months following initiation of urate-lowering therapy can be a time of increased gout attacks. They should be given a prescription for the most appropriate acute gout treatment in their case and advised to take this within an hour of onset of a gout attack. They should understand that treating a gout attack quickly can lead to resolution within a day, whereas if started days into an attack it may take several days to get better. Patients should also understand the need to consider prophylactic therapy, colchicines, or low-dose NSAID, for the first six months of urate-lowering therapy.
Treatments for gout in development
Several agents are currently under study for gout. One medication which is presently FDA approved for daily self-injection in rheumatoid arthritis, anakinra (Kineret®) is an interleukin-1 receptor blocker. This is not an FDA-approved agent for gout, but two small uncontrolled trials showed excellent effectiveness of this agent in gout. This was not surprising from a pathophysiologic point of view, since interleukin-1β appears to be the key inflammatory cytokine in gout. Two other agents which block interleukin 1β, rilonacept and canakinumab, are also under study for gout, and have a longer half-life and therefore require fewer injections than anakinra. Lesinurad is a uricosuric agent under study that appears to have advantages over probenecid. It can be given once a day and appears to lack the drug interactions that are a problem with probenecid. BCX4208 is an investigational agent that blocks the production of uric acid by blocking the purine cycle at an earlier step than the xanthine oxidase step blocked by allopurinol and febuxostat. Both lesinurad and BCX4208 could be add-on agents in the future for patients who don’t achieve their uric acid goal with allopurinol or febuxostat.
Gout can have major impact on a patient’s quality of life, but fortunately our therapeutic arsenal is strong. Prevention of painful attacks is possible for the vast majority of gout patients. To properly manage gout, it is important to ask patients at each visit, even if the visit is for other problems, whether they are still experiencing gout attacks. Often patients will not bring up their recurrent attacks, thinking it is “their fault” because of what they ate, or because they incorrectly believe there is nothing the practitioner can do. It is likewise important to check gout patients’ uric acid periodically, because many patients will not be at their goal, due to inadequate dosing or non-compliance with treatment. Bringing the patient to a uric acid less than 6.0 is dramatically effective in the long-term eradication of gout attacks, so long as the medication is continued. Education of the gout patient is critical, since only the patient who understands their gout will stay with their medication long-term.