Gout and Crystal Deposition Disease

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Gout and Crystal Deposition Disease Brian F. Mandell CASE STUDY 1  Acute Gout

A 66-year-old man is seen in consultation for acute foot pain 3 days following partial colectomy with reanastomosis for diverticulitis. There had been no surgical complications. He recalled no similar episodes of foot pain. A year earlier, he had experienced knee pain and swelling, for which he took over-the-counter ibuprofen following dancing at his daughter’s wedding. The patient’s past medical history included a myocardial infarction several years ago without adverse sequelae, hyperlipidemia, hypertension, type 2 diabetes, and a nephrectomy for renal cell carcinoma 10 years earlier. Medications at home included aspirin, atorvastatin, glyburide, hydrochlorthiazide, and enalapril. All of these medications except enalapril are still being held since his diet is being advanced to full liquids following surgery. He is receiving unfractionated heparin 5000 U every 8 hours. His oral temperature is 100.8° F; other vitals include a heart rate of 86 and blood pressure of 146/92. His examination is remarkable for a clean surgical wound and nontender abdomen. Lungs are clear and there is a soft systolic ejection quality murmur (also noted on admission). There is trace pitting edema of both pretibial areas. The left foot is warmer than the right, with tenderness of the midfoot when it is squeezed, and there is marked swelling and warmth around the medial malleolus with extreme pain to any motion of the ankle. There are normal pulses and no embolic lesions. Laboratory studies, obtained before the consultation are notable for a white blood cell count of 10,200, with 84% neutrophils, glucose of 174, normal electrolytes, creatinine 1.8, serum urate of 6.8, and an ESR of 54. Discussion of Differential Diagnosis The patient has acute arthritis of the ankle and probably midfoot in the perioperative setting. On a statistical basis, this is most likely a result of crystalinduced inflammation, probably due to monosodium urate (gout). Because the rates of morbidity and mortality (11%) associated with bacterial infectious arthritis are high, infection should be directly excluded as a cause of the arthritis, particularly in the postoperative patient who has several potential portals of infection. In several retrospective studies, delay in diagnosis and

appropriate treatment of infectious arthritis has been shown to be associated with an increased likelihood of permanent joint dysfunction. Among 100 consecutive patients with acute monoarticular arthritis in the hospital and emergency room setting, 80% was due to microcrystalline disease (Mandell BF, unpublished information). Other potential etiologies, such as psoriasis, enteropathic, and spondylitis, are relatively uncommon and generally occur in patients with known underlying disease (e.g., psoriasis, inflammatory bowel disease, and ankylosing spondylitis). The immediate distinction in this patient must be made between crystal-induced and infectious arthritis. This distinction cannot be reliably made on clinical grounds. The presence or absence of fever, elevated peripheral white blood cell count, or elevated acute phase reactants will not distinguish crystal-induced from septic arthritis. This has been shown in several published studies,1 and in the postoperative setting, there are additional reasons for the vital signs and laboratory studies to be abnormal. Radiographs are of little assistance in determining the etiology of acute peripheral joint arthritis, and obtaining these studies often delays the appropriate evaluation. The serum urate level is generally higher than the saturation point of 6.7 mg/dL at the time of an acute attack of gout, but this is not always the case. Also, patients with infectious arthritis or acute arthritis of other etiologies may also have hyperuricemia because it is so common in the general population. Additionally, an acute decrease in the serum urate level due to the initiation of a hypouricemic drug2 or acute intravenous hydration is a well recognized and frequent initiator of acute gouty arthritis. Thus, measurement of the serum urate level is not a sensitive or specific test to determine the etiology of acute arthritis and should not be relied on to distinguish between crystal-induced and infectious arthritis. The test of choice in determining the etiology for acute monoarticular arthritis is synovial fluid analysis, with culture being the gold standard to diagnose bacterial infection3 and polarized microscopy the test of choice for crystal-induced arthritis. Anticoagulation, in this case heparin, should not be a deterrent to synovial fluid aspiration. Gram staining 293

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of the fluid to demonstrate the presence of bacteria is notoriously insensitive4 and fraught with the additional problem of false-positive results due to misinterpretation. Higher synovial white blood cell counts (>50,000 cells per mm3) are more frequently associated with infection than with crystals, but there is too much overlap to use the total white blood cell count or percentage of neutrophils to make this distinction with confidence.5 The patient with inflammatory fluid and the absence of observed crystals should generally be treated as if he or she has septic arthritis until the cultures return clearly negative. The finding of crystals in the fluid confirms the diagnosis of gout (monosodium urate) or pseudogout (calcium pyrophosphate) but does not exclude the relatively uncommon6 coexistence of infection and crystal disease. Thus, it is reasonable to send fluid for culture even if crystals have been observed in the fluid, especially if the suspicion for infection is particularly high (i.e., in the setting of recently documented or suspected bacterial infection elsewhere in the patient or if intra-articular corticosteroid therapy is planned). The role of polymerase chain reaction and other molecular tests to confirm the diagnosis of septic arthritis has yet to be fully defined. Synovial fluid glucose or lactate levels are not routinely useful. Crystals, although present, may occasionally not be observed on the initial evaluation; thus, subsequent aspirated fluid samples should be re-examined for the presence

of crystals. The fluid can be centrifuged in a conical test tube, and the pellet evaluated for the presence of crystals. This may increase the sensitivity of the crystal analysis. Alizarin stain may be used to facilitate the recognition of calcium-containing crystals. However, this stain is not universally available, and should be filtered before use because it tends to precipitate. If necessary, synovial fluids can be stored in the absence of anticoagulant and examined at a later point in time when a more experienced observer is available. In the described patient, monosodium urate crystals were observed in the fluid aspirated from his ankle. The midfoot tenderness also had suggested gout as the likely diagnosis, because this is one of very few anatomic areas affected by gout but generally not by infection in the acute setting. Culture of the fluid was negative. He was treated with 1.0 mg of intravenous colchicine (a therapy no longer available in many regions due to safety concerns). He had a rapid response over 24 hours, with normalization of his temperature and relief of most of his pain, avoiding the less specific antipyretic and the gastric and renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and the hyperglycemic and (theoretical) wound healing effects of corticosteroids. Appropriately dosed intravenous colchicine does not cause nausea or diarrhea. It is worth noting the multiple risk factors for coronary artery disease (CAD) that this patient exhibited. This is not unusual in patients with gout.

CASE STUDY 2  Polyarticular Gout A 59-year-old woman was seen in the office for evaluation and treatment of chronic polyarticular arthritis. The arthritis has been present for several years, and her daily function has deteriorated since going on hemodialysis for chronic kidney disease (CKD) due to biopsy-documented damage from hypertension and diabetes. The arthritis affected her peripheral interphalangeal (PIP) joints more than the metacarpophalangeal (MCP) joints of both hands, both wrists, ankles, and knees. She had chronic olecranon bursitis. She had a positive antinuclear antibody (ANA) test (homogenous), antimicrosomal antibodies, and rheumatoid factor in the past. She had no detectable hepatitis B or C antibodies before receiving the hepatitis B vaccine last year. She had experienced minimal response to methotrexate a few years previously, with reduced swelling and stiffness of the hands, but still had experienced arthritis flares requiring steroid therapy with “dose packs.” The methotrexate was stopped as the renal function worsened. Over the past year, there had been fewer flares, but increased pain and stiffness of the involved joints. Medications included folic acid, multivitamins, a baby aspirin, furosemide, hydralazine, metoprolol, enalapril, insulins, thyroid replacement, and pravastatin. Examination was notable for heart rate of 66

with blood pressure of 142/88. The above-mentioned joints had cool proliferative synovium with a generally symmetric distribution. There was slight bilateral, cool, and nontender olecranon bursal distention; the left bursa contained several small nodules. The skin was dry, there was no psoriasis, and the left thumb pad had a nontender intradermal nodule (shown in Fig. 22-1). Hand radiographs from 2 years previously reported osteoarthritis of the finger PIP and distal interphalangeal (DIP) joints, normal joint spaces of the MCP and intercarpal joints, several carpal bone cysts, but no erosions. Discussion of Differential Diagnosis This patient was referred for management of seropositive rheumatoid arthritis (RA) and osteoarthritis; she had experienced a less than ideal response to methotrexate, and now was experiencing greater difficulties in performing daily activities due to joint stiffness. The presence of diabetes and CKD complicated the choice of medications. The symmetrical polyarthritis is consistent with rheumatoid disease, as is the positive rheumatoid factor in the past. A positive ANA can be found in patients with RA as well as in those with autoimmune thyroid disease. The radiographs were consistent with

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Figure 22-1.  Intradermal urate deposit (tophus).

­ steoarthritis but did not exclude the coexistence of o RA or an alternative inflammatory arthritis affecting the wrists. The lack of a complete response to methotrexate does not exclude the diagnosis of RA. Chronic hepatitis C, which can cause a “pseudorheumatoid” polyarthritis without erosions, was excluded by the absence of viral antibodies. There was nothing in the history or on examination to suggest psoriatic, enteropathic, or spondylitis-associated peripheral arthritis (these entities often, although not always, cause a fairly more asymmetric arthritis). The time course and examination did not suggest bacterial infection. The clinical wrist involvement, in the absence of a history of wrist trauma, made the diagnosis of generalized osteoarthritis affecting the wrists unlikely. The arthropathy preceded the dialysis; hence, dialysisassociated amyloidosis was not tenable. Although no calcinosis was seen on radiographs, the diagnoses of chronic pseudogout and hemochromatosis were considered. However, the olecranon nodules (thought to be tophi) and the thumb lesion, a characteristic intradermal deposit of urate, strongly suggested

TREATMENT OF THE ACUTE ATTACK The acute gout attack is a dramatic inflammatory response to urate crystals. In addition to being membranolytic, recent studies have elucidated a mechanism by which crystals trigger inflammatory cells to release interleukin 1 (IL-1) via a toll-like receptor (Fig. 22-2), which then activates a polymeric protein complex in the cytoplasm (inflammasome). The inflammasome generates active IL-1 beta, which then triggers and amplifies the local and systemic inflammatory response to crystals. The primary role of IL-1 can be demonstrated by the ability of

that the arthritis was due to chronic progressive gout with likely coexistent osteoarthritis. On careful questioning, most patients with chronic gout, or their family members, will recall a history of intermittent flares at the outset of the arthritis. As in this case, occasional patients with chronic established disease have symptoms and findings of chronic swelling and discomfort which can mimic rheumatoid or psoriatic (more asymmetric) arthritis. The diagnosis of gout was confirmed by aspiration of a few drops of fluid from the olecranon bursa demonstrating monosodium urate crystals. Retrospective studies suggest that the frequency of gout flares may decrease with the development of end stage renal disease,7 perhaps due to decreased inflammatory cell reactivity to the crystals. But as in this patient, symptoms from chronic proliferative gouty synovitis may not abate. The serum urate level was between 9 and 10 mg/dL on two occasions. Because renal transplantation was being considered and it was believed that the use of calcineurin antagonist therapy would likely accelerate the gouty arthritis, it was believed that it was imperative to initiate hypouricemic therapy. She was started on celecoxib prophylactically to reduce the likelihood of a gout flare with the introduction of hypouricemic therapy. A cyclooxygenase-2 (COX-2) selective NSAID was chosen because of its slightly decreased gastrointestinal (GI) bleeding risk and lack of antiplatelet effect compared with a nonselective NSAID in a patient taking (cardioprotective) aspirin and likely having kidney failure– associated platelet dysfunction. Because the patient was already on dialysis, there was no concern over worsening the renal function with celecoxib. Lowdose allopurinol (50 mg) was subsequently added and increased to a dose that decreased the serum urate to less than 6.0 mg/dL. The patient was monitored for systemic hypersensitivity reaction or rash as the dose of allopurinol was increased. It has been suggested by some (but not all) authors that the risk of hypersensitivity reactions is higher in patients with renal dysfunction.8 It should be noted that the promulgated guidelines for allopurinol dosing in patients with renal insufficiency have not been rigorously validated9 and, if adhered to, will result in suboptimal control of serum urate levels in a significant majority of patients.

IL-1 antagonists to block animal responses to urate crystals and it has been used to successfully treat human gout. Downstream from the effect of IL-1, other inflammatory mediators are released including prostaglandins, leukotrienes, and interleukin 8. Acute attacks of gout are generally responsive to high doses of several different anti-inflammatory therapies. The clinical choice of therapeutic agents is generally dependent on the risk of side effects in a given patient based on his or her ­comorbidities and concomitant medications, as well as the personal preferences of the prescribing physician (and patient). It has been

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TLR2/4 MSU crystals

CD14

MYD88

NFkB mediated cell activation Phagocytosis

Pro-IL1β NALP3 Caspase-1

Caspase 1 ASC

IL1β

Monocyte

IL1R Endothelial activation

Endothelium/leukocyte

Figure 22-2.  Uric acid crystals activate mononuclear cells to release interleukin 1 via toll-like receptor and the NALP3 inflammasome. (From So A. Uric acid crystals ­activate mononuclear cells to release interleukin 1 via toll like receptor and the NALP3 inflammasome. Arth Res Therapy 2008;10:221-7.)

s­ uggested that the earlier an attack is treated, the easier it is to treat. Some authors have described their experience with having patients abort an incipient attack if low doses of oral colchicine or an NSAID are taken at the first twinge of joint pain that can be recognized by the patient as gout. Once established, an attack may need to be treated for a longer period of time until it completely resolves and does not recur when the treatment is discontinued. In one retrospective review of 90 hospitalized patients treated with intravenous colchicine, the duration of symptoms before therapy did not influence the response (Khurana, PS and Mandell, BF presented at the Soc Gen Int Med annual meeting, 1999), but there is little other information to refute the common concept that the longer an attack persists, the harder it is to quickly get it to resolve. Agents that are effective in treating the acute gout attack include virtually all NSAIDs (aspirin is generally not used for this) including some COX-2 selective ones, corticosteroids (oral, parenteral and intra-articular), and colchicine (oral and previously intravenous). Narcotics blunt some of the pain but will not resolve the attack, and some clinicians (including myself) believe that they are not as effective as the anti-inflammatory medications in relieving the pain. Recently, there have been a few case reports on the efficacy of specific biologic therapies including anti-tumor necrosis factor (TNF) and anti-IL1 agents. These are briefly discussed later in this chapter. There have been few controlled trials studying acute gout; even fewer have included a placebo (or narcotic) arm. The historic approach to the treatment of gout attacks with repeated hourly (or bihourly) doses of oral colchicine was demonstrated to be more effective than placebo within 24 hours.10 However, virtually all patients suffered GI side effects with this regimen, and most clinicians avoid this approach. Using just a few

oral colchicine pills (one taken hourly) at the first onset of an attack can be effective, without GI side effects, according to some authors (and patients). Intravenous colchicine was safe and effective in several retrospective studies (one published in full form11) totaling approximately 250 patients. Despite some benefits of using low dose intravenous (IV) administration (limited GI side effects with appropriate dosing; no effect on bleeding; no general antipyretic effect; no leukocytosis, which can cause diagnostic confusion; and no effect on glucose levels or renal function); the multiple published case reports of morbidity and deaths attributed to IV colchicine use (many with therapeutic overdose) have led to removal of this formulation from the marketplace. NSAIDs have been a popular choice for treating acute gout attacks. Indomethacin has had a time­honored role as the gold standard therapy. It is believed to be quickly absorbed and rapidly effective. But given its proclivity to cause headache and confusion in the elderly, as well as gastric bleeding, and its potency in adversely affecting renal function, it has slowly and partially been replaced in general use by other NSAIDs. In a controlled double-blind comparison between indomethacin (50 mg every 8 hours) and the COX-2 selective NSAID etoricoxib (120 mg), significant pain relief was achieved with both agents by 4 hours after the first dose.12 Naproxen (500 mg twice daily) was shown in a different controlled trial as equivalent in efficacy to prednisolone (35 mg once daily).13 Pain was reduced to 50% of baseline with both agents by approximately 48 hours. NSAID therapy should be continued for several days after complete resolution of the attack to avoid resumption of the inflammation and pain. The well-accepted efficacy of NSAIDs in treating acute gout is tempered by the frequent presence of comorbidities in gouty patients, which often make the use of high-dose NSAIDs less than ideal. The demography of patients with gout includes a high prevalence of hypertension, renal insufficiency, metabolic syndrome, coronary disease and alcohol use. Owing to this situation and the increased awareness of the gastric toxicity of NSAIDs, many clinicians now use corticosteroids as first-line therapy for acute attacks of gout, particularly in hospitalized patients. For years, there was a dearth of data supporting what clinicians already knew, that steroids effectively can treat the acute gout attack.13 Textbooks stated that use of corticosteroids was associated with “rebound” attacks of gout on discontinuation. My own interpretation of this hackneyed caveat is that steroid therapy was frequently used for too short of a period of time, and if therapy (steroids or NSAIDs) of an attack of gout is stopped too soon, the attack is not resolved and symptoms resume. In 1990, a small experience was reviewed that documented the efficacy and lack of rebound attacks with steroid therapy.14 There is still no uniformly accepted dose, and many clinicians use some permutation of a scheme that involves initial treatment with approximately 40 mg daily of ­prednisone or the equivalent until symptoms resolve and then slowly taper the steroid over another 7 days.

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Adrenocorticotropic hormone is also effective,15 with animal models suggesting that its mechanisms of action include a direct peripheral anti-inflammatory effect as well as eliciting cortisol release from the adrenal gland. A single dose is generally not sufficient for the reasons noted earlier, and it is expensive therapy. Intra-articular steroid is effective, assuming the joint is accessible to injection. But, even though some animal studies and a study in pediatric patients with septic arthritis16 suggest that systemic steroids are not harmful, and may be beneficial when provided with appropriate antibiotics, there remains a strong theoretical concern with injecting a deposit formulation of steroid into an infected joint because once injected, it cannot be removed. The difficulties in rapidly and reliably distinguishing infection from crystal-induced arthritis were discussed earlier. Thus, I have some reluctance to use intra-articular steroids to treat gout attacks if there is any increased concern over the possibility of coexistent infection.

TREATMENT OF HYPERURICEMIA A biologic prerequisite for the development of gouty arthritis is a persistent serum urate level above 6.7 mg/dL, the concentration at which urate begins to crystallize in connective tissue. By maintaining the urate below this level, urate deposits will dissolve, pass into the serum, and be excreted into urine. Based on the pathophysiology alone, it thus makes sense to treat everyone who has experienced a gout attack with hypouricemic medication in order to prevent future attacks or progression to chronic polyarticular gout, as in Case Study 2 earlier. However, most patients with gout do not progress to severe disease, and some patients only have rare repeated attacks over years and do not wish to take on the cost and even minimal risk of taking a medication for the rest of their life. It is impossible to predict with certainty at the time of the first attack the disease course in a given patient, although repeated attacks at a young age, the presence of a transplanted organ with cyclosporine therapy, and early formation of tophi or erosions presage a more difficult course. Controlled interventional studies have not been conducted to compare the different approaches of early hypouricemic therapy versus treating the inflammatory episodes without addressing the hyperuricemia in terms of patient quality of life, medical and social costs and function. Authors have advocated, without hard data, initiating hypouricemic therapy following a defined number of gouty attacks (sometimes two or three) or the presence of visible or radiographic tophi. The first suggestion seems overly arbitrary. I favor instead to use the following points when discussing this treatment decision with patients: How disruptive will attacks of gout be if they continue to occur (does the patient travel a lot)? Are there relative contraindications to the use of medications needed to treat acute attacks (renal

insufficiency, peptic ulcer disease, diabetes, etc.)? Is it likely that the attack frequency will increase over time (presence of tophi, attacks began at a young age or are increasing in frequency, the likely need for medication that may increase urate levels further). Multiple studies and clinical experience have shown that the maintenance of low serum urate (< 6.0 mg/ dL) reduces the frequency of gout attacks as patients are followed over a long period of time. When making the decision to institute hypouricemic therapy for the purpose of controlling the progression of gouty arthritis and ultimately eliminate attacks of gout, it is critical that both physician and patient recognize that these goals can be reached only after many months of therapy as the total urate burden in the body is reduced. It is also critical to recognize (and inform the patient) that if the urate level is abruptly reduced for any reason, including with medication, that there is a significant risk of inducing an attack of gout within the first several months of therapy. There is a suggestion that the more the urate is lowered, the greater the chance of inducing an attack.17 Hence, it is reasonable practice to use a prophylactic anti-inflammatory therapy such as low dose oral colchicine or an NSAID for the initial months of hypouricemic therapy. The presence of renal insufficiency can complicate the decision regarding prophylaxis, requiring a decrease in the colchicine dose to below the oftenused dose of 0.6 mg twice daily and avoidance of NSAIDs entirely. In patients with severe gout, the likelihood of an attack may be as high as 40% over the 8 weeks following the start of hypouricemic therapy, even with prophylaxis. It has been recognized for more than 100 years that hyperuricemia, as defined by a level greater than population normal (which is higher than the biologically relevant level of 6.7 mg/dL at which urate is saturated in biologic fluids), is associated with a number of other conditions. Hyperuricemia was strongly linked as a causative agent of gout, LeschNyhan syndrome, tumor lysis syndrome, and uric acid nephrolithiasis. Hyperuricemia has also been associated with CKD, CAD, hypertension, and components of the metabolic syndrome including diabetes. However, several analyses of the epidemiologic data led authors to conclude that the urate was more likely a consequence than a cause of these latter conditions, and the general teaching for the past few decades had been that hyperuricemia is “benign” and does not in and of itself require treatment. Re-examination of this association in large observational and retrospective studies, other than the Framingham database, has led to a growing opinion that hyperuricemia may be a proximate cause of cardiovascular disease, and not simply an innocent bystander or epiphenomenon.18,19 Serum urate has even been suggested as an ­independent predictor of all-cause as well as cardiovascular mortality.20 Stronger evidence for a direct role of urate in the development of hypertension and cardiovascular disease comes from the rat model of mild

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hyperuricemia developed by Johnson and colleagues.21 Moderate acute hyperuricemia induced by inhibition of endogenous uricase in rats induces reversible hypertension in the absence of crystal deposition or acute renal injury. If left untreated, the hyperuricemia induces microvascular disease and a salt-sensitive hypertension that no longer can be reversed by normalization of the hyperuricemia. If this pathophysiology is mimicked in humans, it could explain why patients with longstanding hypertension and hyperuricemia do not normalize their blood pressure with treatment of the hyperuricemia. In an attempt to mimic the timing of hypouricemic therapy in the animal studies, Feig and colleagues22 followed up on observations that hyperuricemia in adolescents and young adults predicts the future development of hypertension and in a placebo-controlled crossover design trial treated adolescents with new-onset primary hypertension and hyperuricemia with allopurinol. Treatment with allopurinol, but not placebo, reversibly and significantly lowered the blood pressure. Some, but not all, interventional studies in patients with chronic kidney disease have shown that administering allopurinol can slow the progression of kidney dysfunction.23,24 In a parallel body of data, there is growing recognition that high-fructose intake, as is common in the United States, predisposes to glucose intolerance, weight gain, and the complete metabolic syndrome.25 It has been proposed that this contributes to the obesity epidemic in young Americans, and may also contribute to the rising prevalence of hyperuricemia and gout. Experimental data in rats have been published supporting the hypothesis that fructose contributes to the development of all of these outcomes via an increase in serum urate levels.26 Conclusive data in humans, however, have not yet been published. Inhibition of xanthine oxidase with allopurinol has been the most used, best tolerated, and most effective hypouricemic therapy in the United States. It has been shown to be effective in “inefficient renal excretors” of uric acid (probably > 90% of hyperuricemic patients), as well as “hyperproducers.” If allopurinol is used, there is no necessity in obtaining a 24-hour urinary uric acid excretion before starting therapy. However, in very young patients, in patients with a striking family history of gout, or in those patients likely to be provided a uricosuric agent to lower their serum urate, two 24-hour urine uric acid excretion tests should be performed. Some authors have recommended in the absence of nephrolithiasis that a spot urine uric acid/creatinine excretion should be measured, and if it is low, then a 24-hour excretion does not need to be evaluated. (Simkin, P letter to editor Arth Rheum 49:735, 2003). This is a reasonable approach, although one not yet prospectively validated. In the United States, probenecid is the generally used uricosuric agent, but in general, most clini-

cians prefer to start with allopurinol because it is easier to take (once daily), does not require extra water intake, works in the setting of renal insufficiency (see comments regarding use of allopurinol in the setting of renal insufficiency), and tends to be more effective. The angiotensin receptor blocker losartan is unique in its probenecid-like uricosuric effect but is generally less effective than fulldose probenecid. It can be used in conjunction with allopurinol and is a reasonable adjunct therapy in the hypertensive hyperuricemic patient. Uricosurics should be avoided in patients excreting more than 1 g of uric acid daily and those with a history of nephrolithiasis because increasing uric acid excretion in these patients may increase the chance of further stone formation. Outside of the United States, some countries have access to benzbromarone, a uricosuric with greater efficacy than probenecid. However there have been difficulties with hepatotoxicity. Allopurinol is generally well tolerated. It should be started at a low dose, perhaps at one half of a 100 mg tablet once daily to avoid a rapid fall in the urate level, which seems more likely to induce a gouty attack. Perhaps 8% experience a rash, and a small percentage of those patients develop StevensJohnson syndrome or a systemic hypersensitivity reaction, which can be serious and life threatening. Hence, any rash, fever or elevations in transaminases in a patient taking allopurinol must be taken seriously. It has been suggested that severe hypersensitivity reactions are more common in patients with renal insufficiency. However, it is not certain that adjusting the dose of allopurinol in patients with CKD reduces the risk of adverse reactions. Patients with mild skin reactions can be desensitized to allopurinol,28 but a new xanthine oxidase inhibitor (febuxostat) was approved by the FDA and this will make desensitization unnecessary for these relatively few patients. Studies with febuxostat suggest a daily dose of 80 or 120 mg has an equal if not greater hypouricemic effect than 300 mg allopurinol. Once hypouricemic therapy is initiated as part of a total program to lower the serum urate, reduce the total body uric acid load, and reduce the frequency of gout attacks, it is generally a life-long therapy. The urate level should be checked a few weeks after each change in dose until the target level is achieved, and then approximately every 6 months. The target urate level should be approximately 6.0 mg/dL to maintain the urate level below its saturation point of ∼6.7 mg/dL. Over time, urate crystals will disappear from the synovial fluid and presumably from the synovial tissue.29 Although the current trend of thought in 2009 is moving toward the concept that hyperuricemia is deleterious and a primary mediator of several aspects of cardiovascular disease morbidity and mortality, there are as yet no data of sufficient strength in humans to warrant a paradigm shift toward routinely treating asymptomatic hyperuricemia. There are also conceptually conflicting data that suggest

Chapter 22 urate can be biologically beneficial to endothelial function27 and that elevated urate levels perhaps act as a circulating antioxidant.30 Although these data need to be addressed, I believe that the weight of information supports trying to avoid hyperuricemia and that controlled interventional trials are warranted to guide our clinical decision making. In the meantime, as I counsel patients on ways to limit cardiovascular risk and limit progression of CKD, I  note the growing amount of information on the adverse effects of hyperuricemia. I also am particularly attentive to treating the comorbid, potentially unrecognized, cardiovascular risk in patients who have known gouty arthritis.

TREATMENT OF INTERCRITICAL GOUT Gouty arthritis, for most untreated patients, is characterized by intermittent flares separated by periods of time (“intercritical-gout”) when there are no joint symptoms. Over time, these intercritical periods may become shorter as the flare frequency increases. However, this time course is notoriously difficult to predict for most patients. In a few patients, chronic gout develops, as in Case Study 2. If attacks are few, intercritical periods very long and the attacks are easy to treat then it is a reasonable strategy for many patients to simply treat the attacks as they arise. It must be remembered, however, that with this approach the uric acid burden in the body is likely increasing, and tophi, joint damage, or an increase in attack frequency may occur (as may other complications of hyperuricemia—see earlier discussion). Clinician and patient must be vigilant for evidence of tophi deposition or worsening joint symptoms. Lowering the serum urate will, over time, lengthen periods of intercritical gout as it decreases the frequency of attacks. But, this may not be apparent for close to a year. Gout flare frequency may also be decreased by chronic suppressive anti-inflammatory therapy, independent of urate lowering therapy. NSAIDs or prednisone would likely decrease attack frequency (never tested in a formal way in a large study), but the side effects of chronic therapy with these agents in gouty patients would likely be fraught with side effects. Low-dose colchicine (0.6 mg tablets once or twice daily) is generally well tolerated as a chronic therapy, and can decrease the frequency of gout flares, but without lowering the uric acid burden in the body. Loose stools and occasionally intolerable diarrhea may necessitate reduction in dose or discontinuation of therapy. A toxicity of concern in patients on long-term low-dose colchicine prophylactic therapy is some combination of a vacuolar myopathy and axonal neuropathy.31 It may be painful and associated with weakness, pain, and reduced deep tendon reflexes as well as elevated CPK values. It is reversible over weeks to months if it is recognized and

the drug is stopped. It is more common in patients with a reduced glomerular filtration rate (GFR), but can also occur suddenly due to the addition of drugs that influence colchicine metabolism or intracellular distribution (macrolide antibiotics, most statins, cyclosporine and some calcium channel blockers). A long-term comparative study between the strategies of urate-lowering versus long-term suppressive therapy has never been undertaken. Experience has informed us that patients with tophacious or severe recurrent gout do better with hypouricemic therapy plus prophylactic anti-inflammatory therapy in an effort to reduce attacks and reduce uric acid burden, including visible tophi. However, in the middleaged to older patient with their first flare, or in older healthy patients with a few intermittent attacks, the ideal strategic approach must be empiric and based on discussion between patient and physician.

TREATMENT CONSIDERATIONS IN SPECIAL PATIENT GROUPS There are several special patient groups that warrant specific comment because of unique aspects of their presentation or difficulties in therapeutic management. Gout is generally thought of as a disease of men. There is a striking male predominance, but women do get gout. I have a sense that it is underrecognized by primary care physicians. Women develop gout later in life, generally after menopause, when their serum urate levels increase to a range comparable to males. The postmenopausal increase in urate is due to the loss of estrogen, and estrogen (in animal studies) suppresses the transporter responsible for uric acid reabsorption in the proximal tubule.32 Perhaps due to late recognition, women more commonly have tophi and multiple joint involvement at the time of ­initial diagnosis of gout than men. Additionally, there seems to be frequent involvement of the finger DIP joints. Red, tender Heberden’s nodes from gout can be misdiagnosed as acute inflammatory osteoarthritis.33 As ­discussed earlier, once the correct diagnosis is made, treatment is based on the patient’s comorbidities and the clinician’s estimated likelihood that the disease will progress or cause ­significant morbidity. Patients who have received solid organ transplants and are prescribed a calcineurin antagonist, particularly cyclosporine, to prevent rejection are especially prone to develop rapidly progressive tophacious gout. The exact mechanisms by which cyclosporine exacerbates gout and hyperuricemia is not totally clear, but the rapidity of tophi formation and polyarticular joint involvement suggest something more than just a reduction in the GFR, or altered tubular handling of uric acid with resultant hyperuricemia. Diuretics, which are frequently required in heart and kidney transplant patients,

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exacerbate the hyperuricemia and gout. Because xanthine oxidase metabolizes azathioprine, allopurinol (or febuxostat) must be used with extreme caution and lowered azathioprine doses must be used when the patient is receiving azathioprine. Because of the background immunosuppression, the risk for infection is always present, and joints should be aspirated rather than assuming the etiology of an acute arthritis is gout. Gout usually starts within 5 years of the transplant,34 if there is no prior history of gout. Patients with hyperuricemia at the time of transplantation are at greater risk to develop gout following the transplant. Management is complicated by the many drug interactions and the likelihood of some degree of renal impairment. Gout may be manifest primarily in tendons or as an enthesitis. If possible, in patients with known gout who are expecting a transplant, I try to reduce their serum urate before transplantation. Discussion with the transplant team is of value because antirejection regimens avoiding azathioprine can be utilized if the continued use of allopurinol is desired. Gout occurs frequently following surgery, generally in patients who have a prior history of gout attacks (often not asked about on admission to the hospital). The likely reasons for postoperative flares include fluid shifts that alter the serum urate level and may favor new crystal formation in the joint fluid, as well as new medications that may elicit increases or decreases in serum urate. Additionally, allopurinol and prophylactic anti-inflammatory medications are often held before surgeries when the patient is not eating. The average time following surgery before an attack of gout is about 4 days,35 and multiple joints are frequently involved. Treatment is complicated by the many potential drug interactions. Postoperative gout (or pseudogout) can be a vexing cause of postoperative fever, especially in the intubated or otherwise noncommunicating patient. The patient with CKD and gout was discussed above (see Case Study 2), but a few points are worth reiterating. It was observed that the frequency of allopurinol hypersensitivity reactions seemed to be increased in patients with renal insufficiency. Because allopurinol’s key active metabolite oxypurinol is cleared by the kidney, it was proposed that allopurinol dosing be adjusted based on the estimated GFR.36 However the data to support that these “guidelines” reduce the frequency of hypersensitivity reactions are scant, and there are data refuting this premise.8 Treating hyperuricemia with a uricosuric drug is not likely to be effective in the setting of a reduced GFR. A nonpurine inhibitor of xanthine oxidase (febuxostat), which is not cleared by the kidney, has been approved by the FDA. There are only limited data available on its use in patients with severe CKD. NSAIDs are relatively contraindicated in the setting of severe kidney disease, although once the patient is on dialysis, these agents can be used (some form of gastric protection should be considered). Use of colchicine in the

setting of CKD or end-stage renal disease (ESRD) is potentially dangerous, and full-dose treatment of an acute attack or chronic full-dose prophylactic dosing should be avoided because there is a high risk for colchicine toxicity. The patient with severe tophacious gout and a history of allopurinol intolerance had posed a special set of problems because there was not another extremely efficacious hypouricemic agent. If the intolerance was a mild skin reaction, desensitization therapy may be effective.37 However, if the intolerance was demonstrated as GI symptoms, severe rash, or a systemic hypersensitivity reaction, there was no satisfactory treatment. Probenecid or other uricosurics are often not extremely effective, and even with a severe low purine diet, they are not likely to lower the serum urate sufficiently. Febuxostat may provide the alternative to this small group of patients, but information on the tolerance of this drug by patients who had an allopurinol systemic hypersensitivity reaction is still limited. We have utilized the drug successfully in 8 such patients.

EXPERIMENTAL APPROACHES AND DRUGS IN DEVELOPMENT FOR GOUT Gout is generally not an extremely difficult condition to treat, even with currently available agents. The major problems seem to be related to patient compliance and physician education regarding the treatment of this disease. As noted earlier, there are certain groups of patients with gout who pose special management problems with our current available drugs. There are specific situations in which the drugs used to treat the acute attack (i.e., NSAIDs, corticosteroids, and colchicine) are relatively strongly contraindicated or even ineffective. Based on current knowledge of the mediators of the acute gouty attack, several investigators have published their experiences using targeted biological therapy to treat the acute attack. Antagonizing IL-1 with anakinra,37 as expected from the data on crystal activation of IL-1 via the inflammasome discussed earlier, or TNF-α38 has been successful. There are a number of published and unpublished anecdotal successes in difficult or refractory gout patients using these currently available agents. Despite the very significant expense, these may be extremely useful drugs in highly selected patients. One personal caveat to these successes, I have cared for three patients on chronic anti-TNF therapy for nongouty diseases (two with etanercept and one with adalimumab) who have experienced continued intermittent attacks of gout (two patients) and pseudogout. An additional problematic issue with the use of these targeted therapies is that they are likely contraindicated in the setting of infection, a situation when an alternative to corticosteroids would be of real value.

Chapter 22

Humans lack a functional (enzyme) uricase, which degrades urate into the more soluble allantoin. Raspuricase is a preparation of uricase available for clinical use in the treatment of the tumor lysis syndrome, and it has been used anecdotally to try to dissolve tophi and reduce the total body burden of uric acid in order to prevent further attacks of gout. It is antigenic, however, and cannot be used on a long-term basis. In an effort to limit the antigenicity and allergic potential, pegylated uricase has been developed and has been utilized in clinical trials in patients with severe tophacious gout and allopurinol intolerance.39 It has been effective when infused every 2 or 4 weeks at lowering the serum urate and dramatically dissolving tophi. A plenary report at the annual 2008 scientific meeting of the American College of Rheumatology included data describing the efficacy, but also raised some concerns regarding potential cardiac toxicity. At the present time, it has not been resolved whether this is a significant issue of concern.40

PSEUDOGOUT (CALCIUM PYROPHOSPHATE DEPOSITION DISEASE) Other naturally occurring crystals can elicit an acute or chronic arthritis. Calcium pyrophosphate deposition disease (CPPD) can result in an acute inflammatory arthritis that is clinically indistinguishable from gout; hence, the term “pseudogout.” The biochemical inflammatory cascade may be similar to that triggered by monosodium urate,41,42 and the acute inflammatory response may respond to the same anti-inflammatory agents, including colchicine and an IL-1 antagonist.43 The joint distribution and demographics are somewhat different in patients with CPPD as compared with those with gout. More women get CPPD, and the wrists (knees and MCPs) are far more common than the first metatarsophalangeal (MTP) joint. Patients with CPPD only extremely rarely get visible/palpable crystal masses or radiographically visible erosive tophi. Instead, they frequently get calcification of cartilaginous structures, including the menisci and fibrocartilage. It should be noted that this “chondrocalcinosis” can be seen radiographically in patients who have had no clinical inflammatory arthritis, and in this case, the condition requires no therapy. Multiple bone cysts may be prominent findings on radiographs, initially in the absence of joint space narrowing. A myriad of metabolic and other disorders have been associated with CPPD, but the association may be tenuous with many. However, hyperparathyroidism is an important consideration, particularly because pseudogout attacks are strikingly common immediately following curative parathyroid surgery. Distinguishing CPPD from gout is important; although the acute attacks can be treated similarly, the chronic disease ­management

is different because patients with CPPD do not need their serum urate levels lowered. The serum urate level should not be used to distinguish CPPD from gout because patients with pseudogout may have hyperuricemia for unrelated reasons. There are fewer reported studies, but many (not all) patients with chronic, recurrent pseudogout respond to prophylactic therapy with colchicine and/or NSAIDs.

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