Gout and Tumor Lysis Syndrome
Gout
Gout is an intermittent inflammatory arthritis caused by the formation of uric acid crystals in joint fluid. Uric acid is an end product of purine nucleotide metabolism; in almost all other animals, the enzyme uricase breaks down uric acid into the highly soluble allantoin. In humans and a few other primate species, the uricase gene is knocked out by a pair of nonsense mutations. Uric acid has not been shown to have any function in humans (though an antioxidant role has been hypothesized as urate can remove singlet oxygen and radicals as effectively as vitamin C). However, at serum levels above 7 mg/dL, uric acid crystallizes – and these crystals can lead to intensely painful joint inflammation and can be deposited with associated inflammatory cells in joints and soft tissue, forming masses called tophi. Chronic elevation of serum urate can also lead to the development of renal calculi composed of uric acid crystals. While there is not a rigid correlation between uric acid levels and the frequency of gout flares in individual patients or between patients, on an aggregate basis, those with uric acid levels between 7 mg/dL and 9 mg/dL are five times as likely as those with normal uric acid levels to have gout, and at 10 mg/dL seven times as likely. The shaky correlation between serum uric acid levels and flares is probably a function of the multiple local factors that play a role in the solubility of uric acid in joint fluid, including temperature, pH, ionic strength of the joint fluid, level of intra-articular hydration, and the presence of potential nucleating agents within the joint.
Patients with elevated uric acid may remain asymptomatic, though many of them will go on to experience one or more attacks of acute gout. An acute gout flare may last for several days and is managed mainly by treating pain and inflammation – non-steroidals are the front-line therapy of choice, followed by colchicine and then corticosteroids. For patients with tophaceous gout or with more than three attacks per year, chronic therapy with uric acid lowering drugs is warranted. Changes in diet can have a meaningful impact on uric acid levels, but diet alone rarely represents an effective solution. The majority of patients needing chronic therapy end up on allopurinol, a drug that inhibits the synthesis of uric acid, even though only 10%-20% of gout patients are hyperuricemic because of uric acid overproduction (the majority have reduced uric acid excretion from the kidneys). While probenecid and sulfinpyrazone increase renal urate excretion, they are far less commonly used than allopurinol, which is conveniently dosed once daily and lowers serum urate regardless of the etiology. While many patients benefit tremendously from allopurinol, approximately 2% develop hypersensitivity to it. Since allopurinol hypersensitivity can lead to very serious complications and even death, these patients do not generally continue on allopurinol. Other patients simply do not experience a potent enough response to allopurinol and so continue to have acute flares, and/or continue to experience destructive joint damage and tophus formation. Such patients have few therapeutic options.
Gout Demographics and Subpopulations
Gout is a common disease with increasing incidence, driven mainly by an aging population (the likelihood of having elevated levels of uric acid increases sharply with age over 65 or so) with some contribution from the increasing prevalence of obesity and the use of diuretics. Allopurinol total monthly prescriptions have been growing at 6-9% for the past two years (IMS data). According to the NHANES (National Ambulatory Care survey of the CDC), over 5 million adults report having been diagnosed with gout. While it is often stated that the prevalence is about 1%-2% in the United States, this number comes from self-reporting of the diagnosis on surveys – self-reporting often inflates true disease prevalence by up to 50% compared with smaller, more detailed studies. The true prevalence is probably around 0.7%, or about 2 million patients in the United States. Substantial variability in the prevalence of gout exists among various populations, ranging from 0.2% to 6% (in the Maori population of New Zealand). Hyperuricemia and gout are also associated with solid organ transplantation, particularly in the setting of cyclosporine use.
Resistant and Refractory Gout
According to one review, only 10% of patients progress to chronic gouty arthritis without intervention, and those failing or intolerant to chronic therapy seem to be about 5-10% of this group. By these numbers, the resistant/refractory gout population may be around 10,000-20,000 patients in the United States. One paper placed the number of patients with "uncontrolled gout" at 6,000 in the United States, but this number clearly does not reflect the entire resistant/refractory population. Based on our proprietary market research, we believe the percentage of resistant/refractory patients currently under a physician’s care for gout may be around 10% or higher, depending on how one defines “refractory.”
Tumor Lysis Syndrome
Tumor lysis syndrome is an oncologic emergency characterized by severe electrolyte abnormalities, high uric acid levels, and commonly results in acute renal failure. It typically occurs in patients with acute lymphoproliferative malignancies after the initiation of chemotherapy. The cytotoxic drugs cause massive tumor cell lysis, which in turn releases large amounts of potassium, phosphate, and uric acid. Deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure; preexisting renal insufficiency can exacerbate these metabolic derangements.
Although tumor lysis syndrome is most commonly observed in patients with high-grade lymphoproliferative malignancies, including acute lymphocytic leukemia and Burkitt's lymphoma, it has also been reported in many solid tumors, including lung and breast cancer. Risk factors for the development of tumor lysis syndrome include large tumor burdens, lactate dehydrogenase levels above 1500 IU, extensive bone marrow involvement, and high tumor sensitivity to chemotherapeutic agents. Chemotherapeutics associated with the syndrome include cisplatin, etoposide, fludarabine, intrathecal methotrexate, and paclitaxel. It is relatively uncommon in adult patients (approximately 2% of those with leukemias and lymphomas)
The hyperuricemia associated with tumor lysis syndrome tends to develop around two to three days after the initiation of chemotherapy, although some patients with very high tumor loads can present with elevated uric acid and signs of renal failure. The basic pathyphysiology is driven by the massive release of purine nucleotides (present in particularly high levels in rapidly dividing tumor cells), which are metabolized into uric acid. Treatment consists of both inhibition of uric acid synthesis and promotion of uric acid clearance. As noted above in the discussion of urate nephrolithiasis, urinary alkalinization increases the solubility of uric acid, so this is one part of the treatment regimen. Allopurinol is used at a dose of up to 800 mg daily.