Cleveland Clinic Journal of Medicine

Both the incidence and the prevalence of gout appear to be increasing worldwide.^1,2 Risk factors for the development of gout are related to our increasing longevity, dietary and lifestyle changes, and an increased prevalence of comorbid conditions. Patients with conditions such as hypertension, diabetes, cardiovascular disease, and the metabolic syndrome have an increased risk of developing hyperuricemia and gout,^1,2 and such conditions are frequently managed by primary care physicians. This paper discusses how these conditions, along with diet, alcohol intake, and lifestyle, contribute to the increasing prevalence of hyperuricemia and gout.¹

PREVALENCE AND INCIDENCE: BOTH ARE RISING

The Third National Health and Nutrition Examination Survey (NHANES III) estimated the prevalence of gout in the US population to be 5.1 million between 1988 and 1994.³ Data from a US managed care claims database revealed an increase in gout prevalence from 2.9 cases per 1,000 persons in 1990 to 5.2 cases per 1,000 persons in 1999.⁴ Other studies indicate that gout is becoming more prevalent in societies such as New Zealand and Taiwan as well as in the United States.^5,6

The NHANES III data show that gout affected more than 3 million men aged 40 years or older, and 1.7 million women aged 40 years or older, in the period from 1988 to 1994.³ The estimated prevalence of gout among men aged 40 years or older makes this disease more common than rheumatoid arthritis and the most common form of inflammatory arthritis in adult men.^7–9

Reprinted, with permission, from Journal of Rheumatology (Arromdee E, et al. J Rheumatol 2002; 29:2403–2406).

RISK FACTORS FOR GOUT DEVELOPMENT

Sex and age

Reprinted from Annals of Rheumatic Diseases (Mikuls TR, et al. Ann Rheum Dis 2005; 64:267–272) with permission from the BMJ Publishing Group.

Men have higher serum urate levels than women do, which increases their risk of developing gout. Development of gout before age 30 years is overwhelmingly more likely in men than in women.^7,9,10 The prevalence of gout in men increases with advancing age and peaks between ages 75 and 84 years.⁶ Women have an increased risk of developing gout after menopause; the risk begins to rise at about age 45 years with the decrease in estrogen levels.^10,11 The incidence of gout becomes approximately equal between the sexes after age 60 years.^10,12

It is important for clinicians to bear these factors in mind when taking the patient history and considering gout in the differential diagnosis. Although gout is more common in men, the diagnosis of gout should still be considered in women, particularly postmenopausal women.^10,11

Medications

The use of diuretics is a significant risk factor for the development of gout. Diuretic use results in increased reabsorption of uric acid in the kidney, leading to hyperuricemia.^1,7,10,13 If reasonable, an alternative antihypertensive agent should be prescribed. Low-dose aspirin, commonly prescribed for cardioprotection, also increases urate levels slightly in elderly patients,¹⁴ but should not be discontinued if indicated. Cyclosporine, which increases tubular reabsorption of urate,¹ can result in a type of rapidly ascending gout that frequently is polyarticular.^1,15 This is often encountered in transplant patients taking cyclosporine as an immunosuppressant. Hyperuricemia is also seen in patients taking pyrazinamide, ethambutol, and niacin. Physicians should be aware of the risks and benefits of prescribing any of these drugs to a patient with gout and consider that they may precipitate a gout flare in a previously unaffected patient.

Comorbidities

Primary care physicians regularly see patients with hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease, and the metabolic syndrome. As patients with these comorbidities are at an increased risk for developing gout,^1,10,11 it may be beneficial in these patients to inquire whether they have had any bouts of arthritic pain and periodically evaluate the serum urate level (which is no longer included on chemistry profiles).

Obesity/high body mass index

Obesity and high body mass index significantly contribute to the risk of developing gout.^13,16 Choi and colleagues observed that the risk of gout is very low for men with a body mass index between 21 and 22 but is increased threefold for men whose body mass index is 35 or greater.¹³ Obesity is associated with increased serum urate levels attributable to increased urate production and decreased renal urate excretion. A weight loss program may reduce the risk of gout by decreasing urate levels over time.^13,16

Diet and alcohol consumption

A study by Choi and colleagues found that high intake of alcohol (beer more so than hard liquor or wine) and a diet rich in meat (particularly red meat, wild game, or organ meat) and seafood (particularly shellfish and some larger saltwater fish) increase the risk for developing gout.^17,18 Purine-rich vegetables, which were previously eliminated in low-purine diets, were found not to have any association with hyperuricemia and did not increase the risk of gout.^17,18 Frequent consumption of dairy products was found to slightly reduce the risk of gout and hyperuricemia.^17,18

Although manipulation of diet and alcohol consumption alone rarely achieves the desired degree of serum urate reduction, adherence to changes in diet and alcohol intake will reduce flares of gout and assist in lowering serum urate levels.

CONCLUSIONS

Diet, alcohol consumption, and lifestyle choices can increase the risk of developing gout, but making recommended lifestyle changes does not replace pharmacologic treatments for existing gout or associated comorbidities. Furthermore, very few patients are likely to follow through with lifestyle changes such as weight reduction and a low-cholesterol diet.19–21 Therefore, physician awareness of the factors that contribute to the development of gout is important, as is identification of at-risk patients before they develop manifestations of the disease. Increased vigilance in monitoring serum urate levels and monitoring for gout development in at-risk patients may help to improve the standard of care for gout.

Acknowledgment

Dr. Weaver thanks Kenneth G. Saag, MD, MSc, for his contributions to the lecture on which this paper is based.

Both the incidence and the prevalence of gout appear to be increasing worldwide.^1,2 Risk factors for the development of gout are related to our increasing longevity, dietary and lifestyle changes, and an increased prevalence of comorbid conditions. Patients with conditions such as hypertension, diabetes, cardiovascular disease, and the metabolic syndrome have an increased risk of developing hyperuricemia and gout,^1,2 and such conditions are frequently managed by primary care physicians. This paper discusses how these conditions, along with diet, alcohol intake, and lifestyle, contribute to the increasing prevalence of hyperuricemia and gout.¹

PREVALENCE AND INCIDENCE: BOTH ARE RISING

The Third National Health and Nutrition Examination Survey (NHANES III) estimated the prevalence of gout in the US population to be 5.1 million between 1988 and 1994.³ Data from a US managed care claims database revealed an increase in gout prevalence from 2.9 cases per 1,000 persons in 1990 to 5.2 cases per 1,000 persons in 1999.⁴ Other studies indicate that gout is becoming more prevalent in societies such as New Zealand and Taiwan as well as in the United States.^5,6

The NHANES III data show that gout affected more than 3 million men aged 40 years or older, and 1.7 million women aged 40 years or older, in the period from 1988 to 1994.³ The estimated prevalence of gout among men aged 40 years or older makes this disease more common than rheumatoid arthritis and the most common form of inflammatory arthritis in adult men.^7–9

Reprinted, with permission, from Journal of Rheumatology (Arromdee E, et al. J Rheumatol 2002; 29:2403–2406).

RISK FACTORS FOR GOUT DEVELOPMENT

Sex and age

Reprinted from Annals of Rheumatic Diseases (Mikuls TR, et al. Ann Rheum Dis 2005; 64:267–272) with permission from the BMJ Publishing Group.

Men have higher serum urate levels than women do, which increases their risk of developing gout. Development of gout before age 30 years is overwhelmingly more likely in men than in women.^7,9,10 The prevalence of gout in men increases with advancing age and peaks between ages 75 and 84 years.⁶ Women have an increased risk of developing gout after menopause; the risk begins to rise at about age 45 years with the decrease in estrogen levels.^10,11 The incidence of gout becomes approximately equal between the sexes after age 60 years.^10,12

It is important for clinicians to bear these factors in mind when taking the patient history and considering gout in the differential diagnosis. Although gout is more common in men, the diagnosis of gout should still be considered in women, particularly postmenopausal women.^10,11

Medications

The use of diuretics is a significant risk factor for the development of gout. Diuretic use results in increased reabsorption of uric acid in the kidney, leading to hyperuricemia.^1,7,10,13 If reasonable, an alternative antihypertensive agent should be prescribed. Low-dose aspirin, commonly prescribed for cardioprotection, also increases urate levels slightly in elderly patients,¹⁴ but should not be discontinued if indicated. Cyclosporine, which increases tubular reabsorption of urate,¹ can result in a type of rapidly ascending gout that frequently is polyarticular.^1,15 This is often encountered in transplant patients taking cyclosporine as an immunosuppressant. Hyperuricemia is also seen in patients taking pyrazinamide, ethambutol, and niacin. Physicians should be aware of the risks and benefits of prescribing any of these drugs to a patient with gout and consider that they may precipitate a gout flare in a previously unaffected patient.

Comorbidities

Primary care physicians regularly see patients with hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease, and the metabolic syndrome. As patients with these comorbidities are at an increased risk for developing gout,^1,10,11 it may be beneficial in these patients to inquire whether they have had any bouts of arthritic pain and periodically evaluate the serum urate level (which is no longer included on chemistry profiles).

Obesity/high body mass index

Obesity and high body mass index significantly contribute to the risk of developing gout.^13,16 Choi and colleagues observed that the risk of gout is very low for men with a body mass index between 21 and 22 but is increased threefold for men whose body mass index is 35 or greater.¹³ Obesity is associated with increased serum urate levels attributable to increased urate production and decreased renal urate excretion. A weight loss program may reduce the risk of gout by decreasing urate levels over time.^13,16

Diet and alcohol consumption

A study by Choi and colleagues found that high intake of alcohol (beer more so than hard liquor or wine) and a diet rich in meat (particularly red meat, wild game, or organ meat) and seafood (particularly shellfish and some larger saltwater fish) increase the risk for developing gout.^17,18 Purine-rich vegetables, which were previously eliminated in low-purine diets, were found not to have any association with hyperuricemia and did not increase the risk of gout.^17,18 Frequent consumption of dairy products was found to slightly reduce the risk of gout and hyperuricemia.^17,18

Although manipulation of diet and alcohol consumption alone rarely achieves the desired degree of serum urate reduction, adherence to changes in diet and alcohol intake will reduce flares of gout and assist in lowering serum urate levels.

CONCLUSIONS

Diet, alcohol consumption, and lifestyle choices can increase the risk of developing gout, but making recommended lifestyle changes does not replace pharmacologic treatments for existing gout or associated comorbidities. Furthermore, very few patients are likely to follow through with lifestyle changes such as weight reduction and a low-cholesterol diet.19–21 Therefore, physician awareness of the factors that contribute to the development of gout is important, as is identification of at-risk patients before they develop manifestations of the disease. Increased vigilance in monitoring serum urate levels and monitoring for gout development in at-risk patients may help to improve the standard of care for gout.

Acknowledgment

Dr. Weaver thanks Kenneth G. Saag, MD, MSc, for his contributions to the lecture on which this paper is based.

Both the incidence and the prevalence of gout appear to be increasing worldwide.^1,2 Risk factors for the development of gout are related to our increasing longevity, dietary and lifestyle changes, and an increased prevalence of comorbid conditions. Patients with conditions such as hypertension, diabetes, cardiovascular disease, and the metabolic syndrome have an increased risk of developing hyperuricemia and gout,^1,2 and such conditions are frequently managed by primary care physicians. This paper discusses how these conditions, along with diet, alcohol intake, and lifestyle, contribute to the increasing prevalence of hyperuricemia and gout.¹

PREVALENCE AND INCIDENCE: BOTH ARE RISING

The Third National Health and Nutrition Examination Survey (NHANES III) estimated the prevalence of gout in the US population to be 5.1 million between 1988 and 1994.³ Data from a US managed care claims database revealed an increase in gout prevalence from 2.9 cases per 1,000 persons in 1990 to 5.2 cases per 1,000 persons in 1999.⁴ Other studies indicate that gout is becoming more prevalent in societies such as New Zealand and Taiwan as well as in the United States.^5,6

The NHANES III data show that gout affected more than 3 million men aged 40 years or older, and 1.7 million women aged 40 years or older, in the period from 1988 to 1994.³ The estimated prevalence of gout among men aged 40 years or older makes this disease more common than rheumatoid arthritis and the most common form of inflammatory arthritis in adult men.^7–9

Reprinted, with permission, from Journal of Rheumatology (Arromdee E, et al. J Rheumatol 2002; 29:2403–2406).

RISK FACTORS FOR GOUT DEVELOPMENT

Sex and age

Reprinted from Annals of Rheumatic Diseases (Mikuls TR, et al. Ann Rheum Dis 2005; 64:267–272) with permission from the BMJ Publishing Group.

Men have higher serum urate levels than women do, which increases their risk of developing gout. Development of gout before age 30 years is overwhelmingly more likely in men than in women.^7,9,10 The prevalence of gout in men increases with advancing age and peaks between ages 75 and 84 years.⁶ Women have an increased risk of developing gout after menopause; the risk begins to rise at about age 45 years with the decrease in estrogen levels.^10,11 The incidence of gout becomes approximately equal between the sexes after age 60 years.^10,12

It is important for clinicians to bear these factors in mind when taking the patient history and considering gout in the differential diagnosis. Although gout is more common in men, the diagnosis of gout should still be considered in women, particularly postmenopausal women.^10,11

Medications

The use of diuretics is a significant risk factor for the development of gout. Diuretic use results in increased reabsorption of uric acid in the kidney, leading to hyperuricemia.^1,7,10,13 If reasonable, an alternative antihypertensive agent should be prescribed. Low-dose aspirin, commonly prescribed for cardioprotection, also increases urate levels slightly in elderly patients,¹⁴ but should not be discontinued if indicated. Cyclosporine, which increases tubular reabsorption of urate,¹ can result in a type of rapidly ascending gout that frequently is polyarticular.^1,15 This is often encountered in transplant patients taking cyclosporine as an immunosuppressant. Hyperuricemia is also seen in patients taking pyrazinamide, ethambutol, and niacin. Physicians should be aware of the risks and benefits of prescribing any of these drugs to a patient with gout and consider that they may precipitate a gout flare in a previously unaffected patient.

Comorbidities

Primary care physicians regularly see patients with hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease, and the metabolic syndrome. As patients with these comorbidities are at an increased risk for developing gout,^1,10,11 it may be beneficial in these patients to inquire whether they have had any bouts of arthritic pain and periodically evaluate the serum urate level (which is no longer included on chemistry profiles).

Obesity/high body mass index

Obesity and high body mass index significantly contribute to the risk of developing gout.^13,16 Choi and colleagues observed that the risk of gout is very low for men with a body mass index between 21 and 22 but is increased threefold for men whose body mass index is 35 or greater.¹³ Obesity is associated with increased serum urate levels attributable to increased urate production and decreased renal urate excretion. A weight loss program may reduce the risk of gout by decreasing urate levels over time.^13,16

Diet and alcohol consumption

A study by Choi and colleagues found that high intake of alcohol (beer more so than hard liquor or wine) and a diet rich in meat (particularly red meat, wild game, or organ meat) and seafood (particularly shellfish and some larger saltwater fish) increase the risk for developing gout.^17,18 Purine-rich vegetables, which were previously eliminated in low-purine diets, were found not to have any association with hyperuricemia and did not increase the risk of gout.^17,18 Frequent consumption of dairy products was found to slightly reduce the risk of gout and hyperuricemia.^17,18

Although manipulation of diet and alcohol consumption alone rarely achieves the desired degree of serum urate reduction, adherence to changes in diet and alcohol intake will reduce flares of gout and assist in lowering serum urate levels.

CONCLUSIONS

Diet, alcohol consumption, and lifestyle choices can increase the risk of developing gout, but making recommended lifestyle changes does not replace pharmacologic treatments for existing gout or associated comorbidities. Furthermore, very few patients are likely to follow through with lifestyle changes such as weight reduction and a low-cholesterol diet.19–21 Therefore, physician awareness of the factors that contribute to the development of gout is important, as is identification of at-risk patients before they develop manifestations of the disease. Increased vigilance in monitoring serum urate levels and monitoring for gout development in at-risk patients may help to improve the standard of care for gout.

Acknowledgment

Dr. Weaver thanks Kenneth G. Saag, MD, MSc, for his contributions to the lecture on which this paper is based.

Hyperuricemia is a metabolic problem that has become quite common over the past several decades. The main clinical issues associated with hyperuricemia are gouty arthritis, gouty tophi, and uric acid kidney stones. For decades, these have been the main indications for lowering serum urate levels. Well-established nonarticular associations of hyperuricemia in gout include chronic kidney disease, coronary artery disease, and hypertension.¹ Recent animal studies and epidemiologic studies have shed new light on the relationship between urate and comorbid disease processes. This article describes our evolving understanding of the association of hyperuricemia and gout with kidney disease, hypertension, and cardiovascular disease, and also reviews the kidney’s role in regulation of urate levels in the body.

SOURCES, DISTRIBUTION, AND ELIMINATION OF URATE

Uric acid is the end product of purine metabolism in humans. Sources of purine are either endogenous, from de novo synthesis and nucleic acid breakdown (approximately 600 mg/day), or exogenous, from dietary purine intake (approximately 100 mg/day).² In the steady state, this daily production and ingestion of approximately 700 mg of uric acid is balanced by daily elimination of an equal amount of uric acid from the body. Approximately 30% of this daily loss is through the gut, with subsequent bacterial intestinal uricolysis. The other 70% (roughly 500 mg daily) needs to be excreted by the kidneys.

In humans, plasma urate is freely filtered at the glomerulus, but the fractional excretion of the filtered uric acid is less than 10%. This demonstrates a dominance of reabsorptive processes in humans, and these processes are handled primarily by the selective urate transport protein known as URAT1 in the proximal convoluted tubules. In normouricemic individuals, there is a balance between the daily production and ingestion of uric acid and the daily excretion of it. In most patients with primary hyperuricemia and gout, the fractional excretion of uric acid by the kidneys is relatively diminished, resulting in an imbalance of uric acid homeostasis, and serum urate exceeds saturability (6.8 mg/dL at physiologic temperature and pH). As this imbalance persists over years and decades, the miscible serum uric acid pool expands and urate may be deposited as part of an insoluble urate pool in the joints and soft tissues, referred to as tophi.

In the past, most investigators have focused on the destructive and proinflammatory role of insoluble deposited urate crystals, but new evidence is accumulating that rising levels of soluble urate in body fluids may also be harmful and lead to kidney disease, hypertension, and cardiovascular disease.

RENAL MANIFESTATIONS OF HYPERURICEMIA

Urate is strongly associated with renal disease but traditionally has not been considered to have a causal role in kidney dysfunction. The exceptions have been uric acid kidney stones and the acute uric acid nephropathy associated with chemotherapy and tumor lysis syndrome. New epidemiologic studies in humans, as well as an animal model of mild hyperuricemia leading to microvascular changes in the glomerular afferent arterioles, shed new light on a possible direct role of urate in the genesis of idiopathic chronic kidney disease.

Longstanding reluctance to implicate urate in kidney disease

Significant impairment of renal function was reported in up to 40% of patients with gout in studies conducted before the advent of effective urate-lowering therapies.^3,4 In these older studies, renal failure was the eventual cause of death in 18% to 25% of patients with gout.^3,4 However, any primary causal relationship for urate in this very high incidence of kidney disease was questioned for decades in light of the many other conditions and factors associated with hyperuricemia and gout that may contribute to kidney disease, such as hypertension, diabetes mellitus, alcohol abuse, non-steroidal anti-inflammatory drug use, and lead toxicity.

Recent epidemiologic studies establish the connection

More recently, two large prospective population studies from Japan examined the relationship between serum urate level and development of kidney disease using multiple covariate analysis to adjust for age, blood pressure, body mass index, proteinuria, hematocrit, hyperlipidemia, fasting glucose, and serum creatinine.^5,6

Reprinted from American Journal of Kidney Diseases (Iseki K, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004; 44:642–650), copyright 2004, with permission from Elsevier.

The strong association between hypertension and hyperuricemia has been recognized for more than a century. In his original description of essential hypertension in 1879, Frederick A. Mohamed noted that many of his subjects came from gouty families.⁷ Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive subjects to be between 20% and 40%.^8,9 The prevalence of hypertension among gouty patients is Hyperuricemia predicts ESRD between 25% and 50%.¹⁰ In 1972, Kahn et al found that a rising level of serum urate is an independent risk factor for hypertension.¹¹ A year later, Klein et al demonstrated a linear relationship between serum urate level and systolic blood pressure in both black and white subjects.¹²

Six large epidemiologic studies published over the past 7 years have found that serum urate level predicts the later development of hypertension.^13–18 The most recent of these is the Normative Aging Study,¹⁸ which showed that the serum urate level independently predicts the development of hypertension when using age-adjusted and multivariate models that include body mass, abdominal girth, alcohol use, serum lipid levels, plasma glucose level, and smoking status.

A potential mechanism emerges

No clear causal or mechanistic link between elevated serum urate and the development of hypertension was evident until a rat model of mild hyperuricemia was found to be associated with the development of an initial salt-insensitive hypertension that was reversible with restoration of normal urate levels.¹⁹ However, if the urate-induced hypertension was allowed to persist, the rat would develop a salt-sensitive hypertension that was irreversible even if normouricemia was reestablished.¹⁹

This mechanism was tested in a small pilot study of 5 children with previously untreated essential hypertension who received monotherapy with allopurinol for 1 month.²⁰ All 5 children had substantial drops in their continuously monitored ambulatory blood pressure, and 4 of the 5 developed normal blood pressure (as assessed by continuous monitoring). After the allopurinol was stopped, the blood pressure of all 5 children rebounded to baseline levels.²⁰ A larger blinded, randomized, placebo-controlled crossover trial using the same intervention with similar results has been presented recently at national meetings.²¹

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND HYPERURICEMIA

There is considerable documentation that urate levels correlate with many recognized cardiovascular risk factors, including age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. Because of these relationships, the observed association between serum urate elevations and cardiovascular disease was considered to be “epiphenomenal” and not causal. Many older epidemiologic studies that demonstrated the increased cardiovascular risk associated with higher urate levels used traditional statistical techniques that could not prove the “independence” of urate as a risk factor.²²

An independent effect is finally documented

Three studies published in the past several years demonstrate an independent risk relationship between hyperuricemia and cardiovascular disease, including acute myocardial infarction.^23–25

Multivariate regression analysis of the Multiple Risk Factor Intervention Trial (MRFIT) database demonstrated hyperuricemia to be an independent risk factor for acute myocardial infarction.²³

Similarly, the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study showed that after adjustment for age, sex, diabetes, serum lipid levels, serum creatinine, left ventricular hypertrophy, blood pressure, and diuretic use, serum urate levels in the highest quartile were associated with increased risk of all cardiovascular events (relative risk [RR] = 1.73) and fatal cardiovascular events (RR = 1.96) compared with urate levels in the second quartile.²⁴

Finally, follow-up of 4,385 participants in the Rotterdam Study over an average of 8.4 years revealed that high urate levels were a strong predictor of both myocardial infarction and stroke, even after adjustment for other vascular risk factors.²⁵

CONCLUSIONS

Based on the preponderance of recent epidemiologic studies, it appears that an elevated serum urate level is an independent risk factor for kidney disease, hypertension, and cardiovascular disease. The precise mechanisms for urate-induced tissue injury remain unclear, and no large study to date has convincingly demonstrated that lowering serum urate levels can prevent or lessen the risk of these potentially severe complications of hyperuricemia.

It should also be emphasized that the treatment of hyperuricemia with medications such as allopurinol or probenecid is currently not indicated in patients with hypertension, kidney disease, or heart disease. The use of these agents is supported only in the treatment of gout, the treatment of uric acid kidney stones, and the prevention of tumor lysis syndrome.

Hyperuricemia is a metabolic problem that has become quite common over the past several decades. The main clinical issues associated with hyperuricemia are gouty arthritis, gouty tophi, and uric acid kidney stones. For decades, these have been the main indications for lowering serum urate levels. Well-established nonarticular associations of hyperuricemia in gout include chronic kidney disease, coronary artery disease, and hypertension.¹ Recent animal studies and epidemiologic studies have shed new light on the relationship between urate and comorbid disease processes. This article describes our evolving understanding of the association of hyperuricemia and gout with kidney disease, hypertension, and cardiovascular disease, and also reviews the kidney’s role in regulation of urate levels in the body.

SOURCES, DISTRIBUTION, AND ELIMINATION OF URATE

Uric acid is the end product of purine metabolism in humans. Sources of purine are either endogenous, from de novo synthesis and nucleic acid breakdown (approximately 600 mg/day), or exogenous, from dietary purine intake (approximately 100 mg/day).² In the steady state, this daily production and ingestion of approximately 700 mg of uric acid is balanced by daily elimination of an equal amount of uric acid from the body. Approximately 30% of this daily loss is through the gut, with subsequent bacterial intestinal uricolysis. The other 70% (roughly 500 mg daily) needs to be excreted by the kidneys.

In humans, plasma urate is freely filtered at the glomerulus, but the fractional excretion of the filtered uric acid is less than 10%. This demonstrates a dominance of reabsorptive processes in humans, and these processes are handled primarily by the selective urate transport protein known as URAT1 in the proximal convoluted tubules. In normouricemic individuals, there is a balance between the daily production and ingestion of uric acid and the daily excretion of it. In most patients with primary hyperuricemia and gout, the fractional excretion of uric acid by the kidneys is relatively diminished, resulting in an imbalance of uric acid homeostasis, and serum urate exceeds saturability (6.8 mg/dL at physiologic temperature and pH). As this imbalance persists over years and decades, the miscible serum uric acid pool expands and urate may be deposited as part of an insoluble urate pool in the joints and soft tissues, referred to as tophi.

In the past, most investigators have focused on the destructive and proinflammatory role of insoluble deposited urate crystals, but new evidence is accumulating that rising levels of soluble urate in body fluids may also be harmful and lead to kidney disease, hypertension, and cardiovascular disease.

RENAL MANIFESTATIONS OF HYPERURICEMIA

Urate is strongly associated with renal disease but traditionally has not been considered to have a causal role in kidney dysfunction. The exceptions have been uric acid kidney stones and the acute uric acid nephropathy associated with chemotherapy and tumor lysis syndrome. New epidemiologic studies in humans, as well as an animal model of mild hyperuricemia leading to microvascular changes in the glomerular afferent arterioles, shed new light on a possible direct role of urate in the genesis of idiopathic chronic kidney disease.

Longstanding reluctance to implicate urate in kidney disease

Significant impairment of renal function was reported in up to 40% of patients with gout in studies conducted before the advent of effective urate-lowering therapies.^3,4 In these older studies, renal failure was the eventual cause of death in 18% to 25% of patients with gout.^3,4 However, any primary causal relationship for urate in this very high incidence of kidney disease was questioned for decades in light of the many other conditions and factors associated with hyperuricemia and gout that may contribute to kidney disease, such as hypertension, diabetes mellitus, alcohol abuse, non-steroidal anti-inflammatory drug use, and lead toxicity.

Recent epidemiologic studies establish the connection

More recently, two large prospective population studies from Japan examined the relationship between serum urate level and development of kidney disease using multiple covariate analysis to adjust for age, blood pressure, body mass index, proteinuria, hematocrit, hyperlipidemia, fasting glucose, and serum creatinine.^5,6

Reprinted from American Journal of Kidney Diseases (Iseki K, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004; 44:642–650), copyright 2004, with permission from Elsevier.

The strong association between hypertension and hyperuricemia has been recognized for more than a century. In his original description of essential hypertension in 1879, Frederick A. Mohamed noted that many of his subjects came from gouty families.⁷ Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive subjects to be between 20% and 40%.^8,9 The prevalence of hypertension among gouty patients is Hyperuricemia predicts ESRD between 25% and 50%.¹⁰ In 1972, Kahn et al found that a rising level of serum urate is an independent risk factor for hypertension.¹¹ A year later, Klein et al demonstrated a linear relationship between serum urate level and systolic blood pressure in both black and white subjects.¹²

Six large epidemiologic studies published over the past 7 years have found that serum urate level predicts the later development of hypertension.^13–18 The most recent of these is the Normative Aging Study,¹⁸ which showed that the serum urate level independently predicts the development of hypertension when using age-adjusted and multivariate models that include body mass, abdominal girth, alcohol use, serum lipid levels, plasma glucose level, and smoking status.

A potential mechanism emerges

No clear causal or mechanistic link between elevated serum urate and the development of hypertension was evident until a rat model of mild hyperuricemia was found to be associated with the development of an initial salt-insensitive hypertension that was reversible with restoration of normal urate levels.¹⁹ However, if the urate-induced hypertension was allowed to persist, the rat would develop a salt-sensitive hypertension that was irreversible even if normouricemia was reestablished.¹⁹

This mechanism was tested in a small pilot study of 5 children with previously untreated essential hypertension who received monotherapy with allopurinol for 1 month.²⁰ All 5 children had substantial drops in their continuously monitored ambulatory blood pressure, and 4 of the 5 developed normal blood pressure (as assessed by continuous monitoring). After the allopurinol was stopped, the blood pressure of all 5 children rebounded to baseline levels.²⁰ A larger blinded, randomized, placebo-controlled crossover trial using the same intervention with similar results has been presented recently at national meetings.²¹

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND HYPERURICEMIA

There is considerable documentation that urate levels correlate with many recognized cardiovascular risk factors, including age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. Because of these relationships, the observed association between serum urate elevations and cardiovascular disease was considered to be “epiphenomenal” and not causal. Many older epidemiologic studies that demonstrated the increased cardiovascular risk associated with higher urate levels used traditional statistical techniques that could not prove the “independence” of urate as a risk factor.²²

An independent effect is finally documented

Three studies published in the past several years demonstrate an independent risk relationship between hyperuricemia and cardiovascular disease, including acute myocardial infarction.^23–25

Multivariate regression analysis of the Multiple Risk Factor Intervention Trial (MRFIT) database demonstrated hyperuricemia to be an independent risk factor for acute myocardial infarction.²³

Similarly, the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study showed that after adjustment for age, sex, diabetes, serum lipid levels, serum creatinine, left ventricular hypertrophy, blood pressure, and diuretic use, serum urate levels in the highest quartile were associated with increased risk of all cardiovascular events (relative risk [RR] = 1.73) and fatal cardiovascular events (RR = 1.96) compared with urate levels in the second quartile.²⁴

Finally, follow-up of 4,385 participants in the Rotterdam Study over an average of 8.4 years revealed that high urate levels were a strong predictor of both myocardial infarction and stroke, even after adjustment for other vascular risk factors.²⁵

CONCLUSIONS

Based on the preponderance of recent epidemiologic studies, it appears that an elevated serum urate level is an independent risk factor for kidney disease, hypertension, and cardiovascular disease. The precise mechanisms for urate-induced tissue injury remain unclear, and no large study to date has convincingly demonstrated that lowering serum urate levels can prevent or lessen the risk of these potentially severe complications of hyperuricemia.

It should also be emphasized that the treatment of hyperuricemia with medications such as allopurinol or probenecid is currently not indicated in patients with hypertension, kidney disease, or heart disease. The use of these agents is supported only in the treatment of gout, the treatment of uric acid kidney stones, and the prevention of tumor lysis syndrome.

Hyperuricemia is a metabolic problem that has become quite common over the past several decades. The main clinical issues associated with hyperuricemia are gouty arthritis, gouty tophi, and uric acid kidney stones. For decades, these have been the main indications for lowering serum urate levels. Well-established nonarticular associations of hyperuricemia in gout include chronic kidney disease, coronary artery disease, and hypertension.¹ Recent animal studies and epidemiologic studies have shed new light on the relationship between urate and comorbid disease processes. This article describes our evolving understanding of the association of hyperuricemia and gout with kidney disease, hypertension, and cardiovascular disease, and also reviews the kidney’s role in regulation of urate levels in the body.

SOURCES, DISTRIBUTION, AND ELIMINATION OF URATE

Uric acid is the end product of purine metabolism in humans. Sources of purine are either endogenous, from de novo synthesis and nucleic acid breakdown (approximately 600 mg/day), or exogenous, from dietary purine intake (approximately 100 mg/day).² In the steady state, this daily production and ingestion of approximately 700 mg of uric acid is balanced by daily elimination of an equal amount of uric acid from the body. Approximately 30% of this daily loss is through the gut, with subsequent bacterial intestinal uricolysis. The other 70% (roughly 500 mg daily) needs to be excreted by the kidneys.

In humans, plasma urate is freely filtered at the glomerulus, but the fractional excretion of the filtered uric acid is less than 10%. This demonstrates a dominance of reabsorptive processes in humans, and these processes are handled primarily by the selective urate transport protein known as URAT1 in the proximal convoluted tubules. In normouricemic individuals, there is a balance between the daily production and ingestion of uric acid and the daily excretion of it. In most patients with primary hyperuricemia and gout, the fractional excretion of uric acid by the kidneys is relatively diminished, resulting in an imbalance of uric acid homeostasis, and serum urate exceeds saturability (6.8 mg/dL at physiologic temperature and pH). As this imbalance persists over years and decades, the miscible serum uric acid pool expands and urate may be deposited as part of an insoluble urate pool in the joints and soft tissues, referred to as tophi.

In the past, most investigators have focused on the destructive and proinflammatory role of insoluble deposited urate crystals, but new evidence is accumulating that rising levels of soluble urate in body fluids may also be harmful and lead to kidney disease, hypertension, and cardiovascular disease.

RENAL MANIFESTATIONS OF HYPERURICEMIA

Urate is strongly associated with renal disease but traditionally has not been considered to have a causal role in kidney dysfunction. The exceptions have been uric acid kidney stones and the acute uric acid nephropathy associated with chemotherapy and tumor lysis syndrome. New epidemiologic studies in humans, as well as an animal model of mild hyperuricemia leading to microvascular changes in the glomerular afferent arterioles, shed new light on a possible direct role of urate in the genesis of idiopathic chronic kidney disease.

Longstanding reluctance to implicate urate in kidney disease

Significant impairment of renal function was reported in up to 40% of patients with gout in studies conducted before the advent of effective urate-lowering therapies.^3,4 In these older studies, renal failure was the eventual cause of death in 18% to 25% of patients with gout.^3,4 However, any primary causal relationship for urate in this very high incidence of kidney disease was questioned for decades in light of the many other conditions and factors associated with hyperuricemia and gout that may contribute to kidney disease, such as hypertension, diabetes mellitus, alcohol abuse, non-steroidal anti-inflammatory drug use, and lead toxicity.

Recent epidemiologic studies establish the connection

More recently, two large prospective population studies from Japan examined the relationship between serum urate level and development of kidney disease using multiple covariate analysis to adjust for age, blood pressure, body mass index, proteinuria, hematocrit, hyperlipidemia, fasting glucose, and serum creatinine.^5,6

Reprinted from American Journal of Kidney Diseases (Iseki K, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004; 44:642–650), copyright 2004, with permission from Elsevier.

The strong association between hypertension and hyperuricemia has been recognized for more than a century. In his original description of essential hypertension in 1879, Frederick A. Mohamed noted that many of his subjects came from gouty families.⁷ Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive subjects to be between 20% and 40%.^8,9 The prevalence of hypertension among gouty patients is Hyperuricemia predicts ESRD between 25% and 50%.¹⁰ In 1972, Kahn et al found that a rising level of serum urate is an independent risk factor for hypertension.¹¹ A year later, Klein et al demonstrated a linear relationship between serum urate level and systolic blood pressure in both black and white subjects.¹²

Six large epidemiologic studies published over the past 7 years have found that serum urate level predicts the later development of hypertension.^13–18 The most recent of these is the Normative Aging Study,¹⁸ which showed that the serum urate level independently predicts the development of hypertension when using age-adjusted and multivariate models that include body mass, abdominal girth, alcohol use, serum lipid levels, plasma glucose level, and smoking status.

A potential mechanism emerges

No clear causal or mechanistic link between elevated serum urate and the development of hypertension was evident until a rat model of mild hyperuricemia was found to be associated with the development of an initial salt-insensitive hypertension that was reversible with restoration of normal urate levels.¹⁹ However, if the urate-induced hypertension was allowed to persist, the rat would develop a salt-sensitive hypertension that was irreversible even if normouricemia was reestablished.¹⁹

This mechanism was tested in a small pilot study of 5 children with previously untreated essential hypertension who received monotherapy with allopurinol for 1 month.²⁰ All 5 children had substantial drops in their continuously monitored ambulatory blood pressure, and 4 of the 5 developed normal blood pressure (as assessed by continuous monitoring). After the allopurinol was stopped, the blood pressure of all 5 children rebounded to baseline levels.²⁰ A larger blinded, randomized, placebo-controlled crossover trial using the same intervention with similar results has been presented recently at national meetings.²¹

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND HYPERURICEMIA

There is considerable documentation that urate levels correlate with many recognized cardiovascular risk factors, including age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. Because of these relationships, the observed association between serum urate elevations and cardiovascular disease was considered to be “epiphenomenal” and not causal. Many older epidemiologic studies that demonstrated the increased cardiovascular risk associated with higher urate levels used traditional statistical techniques that could not prove the “independence” of urate as a risk factor.²²

An independent effect is finally documented

Three studies published in the past several years demonstrate an independent risk relationship between hyperuricemia and cardiovascular disease, including acute myocardial infarction.^23–25

Multivariate regression analysis of the Multiple Risk Factor Intervention Trial (MRFIT) database demonstrated hyperuricemia to be an independent risk factor for acute myocardial infarction.²³

Similarly, the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study showed that after adjustment for age, sex, diabetes, serum lipid levels, serum creatinine, left ventricular hypertrophy, blood pressure, and diuretic use, serum urate levels in the highest quartile were associated with increased risk of all cardiovascular events (relative risk [RR] = 1.73) and fatal cardiovascular events (RR = 1.96) compared with urate levels in the second quartile.²⁴

Finally, follow-up of 4,385 participants in the Rotterdam Study over an average of 8.4 years revealed that high urate levels were a strong predictor of both myocardial infarction and stroke, even after adjustment for other vascular risk factors.²⁵

CONCLUSIONS

Based on the preponderance of recent epidemiologic studies, it appears that an elevated serum urate level is an independent risk factor for kidney disease, hypertension, and cardiovascular disease. The precise mechanisms for urate-induced tissue injury remain unclear, and no large study to date has convincingly demonstrated that lowering serum urate levels can prevent or lessen the risk of these potentially severe complications of hyperuricemia.

It should also be emphasized that the treatment of hyperuricemia with medications such as allopurinol or probenecid is currently not indicated in patients with hypertension, kidney disease, or heart disease. The use of these agents is supported only in the treatment of gout, the treatment of uric acid kidney stones, and the prevention of tumor lysis syndrome.

The presence of urate crystals in synovial fluid is the gold standard for diagnosing gout,¹ yet clinicians—both primary care physicians and rheumatologists—may not routinely perform synovial fluid analysis even when evaluating a patient who presents with an acute inflammatory arthritis.² This paper discusses the various reasons why this is so and reviews several important resulting clinical issues: how a presumptive diagnosis of gout is made, when to measure the serum urate level, and special considerations in the differential diagnosis.

SYNOVIAL FLUID ANALYSIS: WHY IS THE GOLD STANDARD NOT MORE ROUTINE?

Images courtesy of Brian F. Mandell, MD, PhD.

Occasionally, the aspirated joint does not appear to contain any joint fluid and the clinician may be concerned about the possibility of a “dry tap.” Other possible reasons include lack of experience with synovial fluid aspiration and evaluation, or limited access to the polarizing microscopes used to examine synovial fluid. Time is another factor; in a busy primary care practice, where patients are usually seen approximately every 7 to 11 minutes, there may not be time to aspirate a joint. The urgency of fluid examination is another issue, as synovial fluid must be examined immediately, since the crystals can become smaller, less numerous, and less birefringent with time.⁴

THE CLINICAL, OR PRESUMPTIVE, DIAGNOSIS

In the appropriate clinical scenario, a presumptive diagnosis of gout can be made on the basis of typical clinical features and the presence of hyperuricemia.^1,2

Expert societies offer guidance, but no validation studies to date

Evidence-based recommendations for the diagnosis of gout from the European League Against Rheumatism (EULAR) state that in acute attacks, the rapid development of severe pain, swelling, and tenderness that peaks within 6 to 12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation although not specific for gout.⁵ These recommendations further state that for typical presentations of gout (such as recurrent podagra [gouty pain in the great toe] with hyperuricemia), a clinical diagnosis alone is reasonably accurate.⁵

• The presence of urate crystals in joint fluid
• A tophus containing urate crystals
• Fulfillment of 6 or more of the criteria in Table 1.

No subsequent studies have been published on the validity or usefulness of any of these diagnostic criteria.

What must inform the presumptive diagnosis

Both the EULAR recommendations and the ACR criteria state that although the gold standard for diagnosing gout is the presence of urate crystals on synovial fluid analysis, a clinical diagnosis of gout can be made on the basis of certain patient criteria. This clinical, or presumptive, diagnosis of gout should be made based on the following:

• A careful patient and family history, including questions regarding comorbid conditions frequently associated with gout (such as hypertriglyceridemia, diabetes, coronary heart disease, hypertension, and the metabolic syndrome) and whether the patient has had previous similar episodes of acute joint pain and swelling in the absence of trauma
• Thorough identification of all current medications, some of which may be associated with hyperuricemia
• A thorough physical examination.

THE PHYSICAL EXAMINATION FOR GOUT

Examination of patients with a history suggestive of gout should include not only the joints but also the extensor surface of the forearms and feet. When patients are seen for a visit and gout is suspected, they should be instructed to remove their shoes and socks and roll up their sleeves to allow examination for evidence of tophi, which would suggest a past history of gouty arthritis. The ear, knee, and olecranon bursa are other common sites for tophi,³ so patients should also be asked to roll up their pants and sleeves and remove any head coverings.⁷ In the late stages of gouty arthritis, multiple joints may be involved, which can cause the condition to be confused with other diagnoses such as psoriatic arthritis or erosive osteoarthritis.⁷

ACUTE PRESENTATIONS OF GOUT

The typical gout presentation is remarkable for very intense pain that often occurs at night when the extremities are colder. Precipitation of urate in the distal extremities can occur when the extremities are horizontal and tend to become cold.⁸

Approximately 90% of initial gout attacks are monoarticular, leaving only 10% of cases that are oligoarticular or polyarticular.7 If more than one joint is involved, especially if the patient has a family history suggestive of gout or takes a medication that causes hyperuricemia, gout should be considered in the differential diagnosis even if the patient denies having a prior gout attack.

Frequently, patients will call their primary care physician during a gout attack but are not be able to schedule an appointment until after the attack has resolved. When possible, patients should be seen during the attack to confirm whether the attack is due to gout. A diagnosis of gout should not be made over the phone when a patient describes pain in the great toe, as only 50% of initial gout attacks occur in the great toe⁷ and it is not known what proportion of acute pain episodes in the great toe are attributable to gout. The most common cause of pain in the great toe is osteoarthritis.

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

How long have acute attacks been occurring?

In a clinical scenario in which synovial fluid aspiration cannot be performed, the appropriateness of a presumptive diagnosis can be assessed by a discussion with the patient about how long he or she has been experiencing acute attacks of joint pain. If the attacks have occurred for more than 10 years, tophi will likely be present.³ After even longer periods, gout may become polyarticular.⁷ In postmenopausal women, the distal interphalangeal joints may be involved,³ which may lead to a misdiagnosis of osteoarthritis, as these joints are typically affected by osteoarthritis.

Is the patient taking a urate-raising medication?

Certain medications have been associated with hyper-uricemia, including cyclosporine and thiazide diuretics.⁹ If a patient has been taking one of these medications, gout should be considered in the differential diagnosis if the patient presents with acute joint pain.

It has been argued that a reduction in joint pain and swelling after the use of colchicine confirms a diagnosis of gout. However, other conditions—such as tendonitis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (pseudogout),³ and rheumatoid arthritis (RA)—can also improve after treatment with colchicine.¹

Be vigilant for fever

Another consideration in making a clinical diagnosis of gout is the association with a low-grade fever; these patients may feel as if they have the flu.⁸ Acute gout may also cause a high fever and an elevated white blood cell (WBC) count;³ in this situation, synovial fluid aspiration must be performed to exclude septic arthritis, either alone or in the presence of gouty arthritis. In situations where septic arthritis is suspected, an emergency visit to a rheumatologist is indicated for synovial fluid aspiration to be performed, as gout and sepsis can coexist.⁵ In such instances, Gram staining and culture of the synovial fluid should still be performed even if monosodium urate crystals are identified.⁵

MEASUREMENT OF SERUM URATE LEVELS

Measuring serum urate levels during an acute attack, treating the acute attack with anti-inflammatory medications, and reevaluating the patient in the office 2 weeks after the acute attack are all recommended in the management of a patient with gout. If the serum urate level was not elevated during the acute attack, it is likely to be elevated 2 weeks later if the patient has gout.¹⁰ Elevated levels of serum urate during the intercritical periods are predictive of future gout attacks.¹¹ Measuring serum urate during the initial attack and then 2 weeks later yields two serum urate levels that can be compared to assist in considering a presumed diagnosis of gout. A study by Rigby and Wood concluded that in patients with low serum urate levels (< 4 mg/dL) 2 weeks following an inflammatory arthritis attack, a diagnosis of gout is unlikely.¹²

DIFFERENTIAL DIAGNOSIS OF GOUT

Rheumatoid arthritis

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

CPPD crystal deposition disease (pseudogout)

CPPD crystal deposition disease, or pseudogout, must also be included in the differential diagnosis of gout. This disease usually occurs in joints previously affected by osteoarthritis or joints that have been injured in the past.¹⁵ Attacks of CPPD crystal deposition disease commonly occur in the knee, in the wrist at the base of the thumb, or in the shoulder.¹⁵ Radiographic examination may reveal a line of calcification along the cartilage outlining the joint.¹⁵ Like gout, pseudogout attacks can occur spontaneously or after trauma, surgery, or a severe illness such as myocardial infarction or stroke.¹⁶

The presentation of pseudogout can be very similar to an acute attack of gout. The difference is seen when evaluating the crystals through a polarizing microscope. CPPD crystals are weakly positively birefringent (Figure 1B), in contrast to the negatively birefringent crystals seen with gout (Figure 1A).⁷ If a polarizing microscope is not available, the crystals usually can be distinguished by their differing shapes: urate crystals are fine and needlelike, whereas CPPD crystals are rhomboid (Figure 1).

Septic arthritis

When the differential diagnosis includes septic arthritis, the joint must be aspirated; a presumed diagnosis cannot be made. Among patients with an acute gouty attack, low-grade fever is reported during the attack in 29% of gout patients and 38% of patients with CPPD crystal deposition disease.¹⁴ Temperatures of 101°F or higher are not usually seen in patients with gout or CPPD crystal deposition disease and suggest an infection, although patients with septic arthritis may be afebrile, especially if they are taking immunosuppressive therapy or glucocorticoids, which can inhibit a febrile response. Synovial fluid analysis in patients with gout and septic arthritis can reveal WBC counts above 100,000 per mm³, whereas synovial fluid WBC counts above 50,000 per mm³ are more common in infection.

As noted earlier, gout and septic arthritis can coexist. In a patient presenting with a fever and a warm erythematous swollen joint, synovial fluid aspiration must be performed and evaluated for the presence of crystals and bacteria. The patient may require treatment for both causes of acute monoarticular arthritis.

In a patient undergoing renal dialysis, where gout or pseudogout can occur and where there is frequent intravascular manipulation, a septic joint can occur simultaneously.^3,14 In this situation, not only must joint aspiration be performed, but the synovial fluid also needs to be evaluated for both crystals and bacteria. Again, the patient may require treatment for both causes of acute monoarticular arthritis.

CONCLUSIONS

The gold standard for diagnosing gout remains synovial fluid aspiration and analysis. In clinical situations when joint aspiration cannot be performed, the EULAR recommendations⁵ and the ACR criteria⁶ provide guidance for making a clinical or presumptive diagnosis of gout. A thorough patient history—both personal and family—and physical examination are critical in making a presumed diagnosis of gout. If the patient presents during an acute attack, serum urate measurement may be useful in making a clinical diagnosis if it reveals an elevated level. When the patient returns for follow-up 2 weeks later, a second serum urate measurement should be taken to allow comparison of the two levels. If the serum urate level is elevated at the follow-up visit, the EULAR recommendations state that a clinical diagnosis of gout can be made if the patient had an acute attack of arthritis in the great toe.

As noted in the EULAR recommendations, the future research agenda should include validating the clinical manifestations of gout against a diagnosis established by identification of urate crystals on synovial fluid analysis.⁵ Until this task can be completed, clinicians should become familiarized with the technique of joint aspiration so that in situations where a clinical or presumptive diagnosis of gout cannot be made—including cases where the differential diagnosis includes a septic joint—clinicians will be able to perform aspiration with confidence.

The presence of urate crystals in synovial fluid is the gold standard for diagnosing gout,¹ yet clinicians—both primary care physicians and rheumatologists—may not routinely perform synovial fluid analysis even when evaluating a patient who presents with an acute inflammatory arthritis.² This paper discusses the various reasons why this is so and reviews several important resulting clinical issues: how a presumptive diagnosis of gout is made, when to measure the serum urate level, and special considerations in the differential diagnosis.

SYNOVIAL FLUID ANALYSIS: WHY IS THE GOLD STANDARD NOT MORE ROUTINE?

Images courtesy of Brian F. Mandell, MD, PhD.

Occasionally, the aspirated joint does not appear to contain any joint fluid and the clinician may be concerned about the possibility of a “dry tap.” Other possible reasons include lack of experience with synovial fluid aspiration and evaluation, or limited access to the polarizing microscopes used to examine synovial fluid. Time is another factor; in a busy primary care practice, where patients are usually seen approximately every 7 to 11 minutes, there may not be time to aspirate a joint. The urgency of fluid examination is another issue, as synovial fluid must be examined immediately, since the crystals can become smaller, less numerous, and less birefringent with time.⁴

THE CLINICAL, OR PRESUMPTIVE, DIAGNOSIS

In the appropriate clinical scenario, a presumptive diagnosis of gout can be made on the basis of typical clinical features and the presence of hyperuricemia.^1,2

Expert societies offer guidance, but no validation studies to date

Evidence-based recommendations for the diagnosis of gout from the European League Against Rheumatism (EULAR) state that in acute attacks, the rapid development of severe pain, swelling, and tenderness that peaks within 6 to 12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation although not specific for gout.⁵ These recommendations further state that for typical presentations of gout (such as recurrent podagra [gouty pain in the great toe] with hyperuricemia), a clinical diagnosis alone is reasonably accurate.⁵

• The presence of urate crystals in joint fluid
• A tophus containing urate crystals
• Fulfillment of 6 or more of the criteria in Table 1.

No subsequent studies have been published on the validity or usefulness of any of these diagnostic criteria.

What must inform the presumptive diagnosis

Both the EULAR recommendations and the ACR criteria state that although the gold standard for diagnosing gout is the presence of urate crystals on synovial fluid analysis, a clinical diagnosis of gout can be made on the basis of certain patient criteria. This clinical, or presumptive, diagnosis of gout should be made based on the following:

• A careful patient and family history, including questions regarding comorbid conditions frequently associated with gout (such as hypertriglyceridemia, diabetes, coronary heart disease, hypertension, and the metabolic syndrome) and whether the patient has had previous similar episodes of acute joint pain and swelling in the absence of trauma
• Thorough identification of all current medications, some of which may be associated with hyperuricemia
• A thorough physical examination.

THE PHYSICAL EXAMINATION FOR GOUT

Examination of patients with a history suggestive of gout should include not only the joints but also the extensor surface of the forearms and feet. When patients are seen for a visit and gout is suspected, they should be instructed to remove their shoes and socks and roll up their sleeves to allow examination for evidence of tophi, which would suggest a past history of gouty arthritis. The ear, knee, and olecranon bursa are other common sites for tophi,³ so patients should also be asked to roll up their pants and sleeves and remove any head coverings.⁷ In the late stages of gouty arthritis, multiple joints may be involved, which can cause the condition to be confused with other diagnoses such as psoriatic arthritis or erosive osteoarthritis.⁷

ACUTE PRESENTATIONS OF GOUT

The typical gout presentation is remarkable for very intense pain that often occurs at night when the extremities are colder. Precipitation of urate in the distal extremities can occur when the extremities are horizontal and tend to become cold.⁸

Approximately 90% of initial gout attacks are monoarticular, leaving only 10% of cases that are oligoarticular or polyarticular.7 If more than one joint is involved, especially if the patient has a family history suggestive of gout or takes a medication that causes hyperuricemia, gout should be considered in the differential diagnosis even if the patient denies having a prior gout attack.

Frequently, patients will call their primary care physician during a gout attack but are not be able to schedule an appointment until after the attack has resolved. When possible, patients should be seen during the attack to confirm whether the attack is due to gout. A diagnosis of gout should not be made over the phone when a patient describes pain in the great toe, as only 50% of initial gout attacks occur in the great toe⁷ and it is not known what proportion of acute pain episodes in the great toe are attributable to gout. The most common cause of pain in the great toe is osteoarthritis.

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

How long have acute attacks been occurring?

In a clinical scenario in which synovial fluid aspiration cannot be performed, the appropriateness of a presumptive diagnosis can be assessed by a discussion with the patient about how long he or she has been experiencing acute attacks of joint pain. If the attacks have occurred for more than 10 years, tophi will likely be present.³ After even longer periods, gout may become polyarticular.⁷ In postmenopausal women, the distal interphalangeal joints may be involved,³ which may lead to a misdiagnosis of osteoarthritis, as these joints are typically affected by osteoarthritis.

Is the patient taking a urate-raising medication?

Certain medications have been associated with hyper-uricemia, including cyclosporine and thiazide diuretics.⁹ If a patient has been taking one of these medications, gout should be considered in the differential diagnosis if the patient presents with acute joint pain.

It has been argued that a reduction in joint pain and swelling after the use of colchicine confirms a diagnosis of gout. However, other conditions—such as tendonitis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (pseudogout),³ and rheumatoid arthritis (RA)—can also improve after treatment with colchicine.¹

Be vigilant for fever

Another consideration in making a clinical diagnosis of gout is the association with a low-grade fever; these patients may feel as if they have the flu.⁸ Acute gout may also cause a high fever and an elevated white blood cell (WBC) count;³ in this situation, synovial fluid aspiration must be performed to exclude septic arthritis, either alone or in the presence of gouty arthritis. In situations where septic arthritis is suspected, an emergency visit to a rheumatologist is indicated for synovial fluid aspiration to be performed, as gout and sepsis can coexist.⁵ In such instances, Gram staining and culture of the synovial fluid should still be performed even if monosodium urate crystals are identified.⁵

MEASUREMENT OF SERUM URATE LEVELS

Measuring serum urate levels during an acute attack, treating the acute attack with anti-inflammatory medications, and reevaluating the patient in the office 2 weeks after the acute attack are all recommended in the management of a patient with gout. If the serum urate level was not elevated during the acute attack, it is likely to be elevated 2 weeks later if the patient has gout.¹⁰ Elevated levels of serum urate during the intercritical periods are predictive of future gout attacks.¹¹ Measuring serum urate during the initial attack and then 2 weeks later yields two serum urate levels that can be compared to assist in considering a presumed diagnosis of gout. A study by Rigby and Wood concluded that in patients with low serum urate levels (< 4 mg/dL) 2 weeks following an inflammatory arthritis attack, a diagnosis of gout is unlikely.¹²

DIFFERENTIAL DIAGNOSIS OF GOUT

Rheumatoid arthritis

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

CPPD crystal deposition disease (pseudogout)

CPPD crystal deposition disease, or pseudogout, must also be included in the differential diagnosis of gout. This disease usually occurs in joints previously affected by osteoarthritis or joints that have been injured in the past.¹⁵ Attacks of CPPD crystal deposition disease commonly occur in the knee, in the wrist at the base of the thumb, or in the shoulder.¹⁵ Radiographic examination may reveal a line of calcification along the cartilage outlining the joint.¹⁵ Like gout, pseudogout attacks can occur spontaneously or after trauma, surgery, or a severe illness such as myocardial infarction or stroke.¹⁶

The presentation of pseudogout can be very similar to an acute attack of gout. The difference is seen when evaluating the crystals through a polarizing microscope. CPPD crystals are weakly positively birefringent (Figure 1B), in contrast to the negatively birefringent crystals seen with gout (Figure 1A).⁷ If a polarizing microscope is not available, the crystals usually can be distinguished by their differing shapes: urate crystals are fine and needlelike, whereas CPPD crystals are rhomboid (Figure 1).

Septic arthritis

When the differential diagnosis includes septic arthritis, the joint must be aspirated; a presumed diagnosis cannot be made. Among patients with an acute gouty attack, low-grade fever is reported during the attack in 29% of gout patients and 38% of patients with CPPD crystal deposition disease.¹⁴ Temperatures of 101°F or higher are not usually seen in patients with gout or CPPD crystal deposition disease and suggest an infection, although patients with septic arthritis may be afebrile, especially if they are taking immunosuppressive therapy or glucocorticoids, which can inhibit a febrile response. Synovial fluid analysis in patients with gout and septic arthritis can reveal WBC counts above 100,000 per mm³, whereas synovial fluid WBC counts above 50,000 per mm³ are more common in infection.

As noted earlier, gout and septic arthritis can coexist. In a patient presenting with a fever and a warm erythematous swollen joint, synovial fluid aspiration must be performed and evaluated for the presence of crystals and bacteria. The patient may require treatment for both causes of acute monoarticular arthritis.

In a patient undergoing renal dialysis, where gout or pseudogout can occur and where there is frequent intravascular manipulation, a septic joint can occur simultaneously.^3,14 In this situation, not only must joint aspiration be performed, but the synovial fluid also needs to be evaluated for both crystals and bacteria. Again, the patient may require treatment for both causes of acute monoarticular arthritis.

CONCLUSIONS

The gold standard for diagnosing gout remains synovial fluid aspiration and analysis. In clinical situations when joint aspiration cannot be performed, the EULAR recommendations⁵ and the ACR criteria⁶ provide guidance for making a clinical or presumptive diagnosis of gout. A thorough patient history—both personal and family—and physical examination are critical in making a presumed diagnosis of gout. If the patient presents during an acute attack, serum urate measurement may be useful in making a clinical diagnosis if it reveals an elevated level. When the patient returns for follow-up 2 weeks later, a second serum urate measurement should be taken to allow comparison of the two levels. If the serum urate level is elevated at the follow-up visit, the EULAR recommendations state that a clinical diagnosis of gout can be made if the patient had an acute attack of arthritis in the great toe.

As noted in the EULAR recommendations, the future research agenda should include validating the clinical manifestations of gout against a diagnosis established by identification of urate crystals on synovial fluid analysis.⁵ Until this task can be completed, clinicians should become familiarized with the technique of joint aspiration so that in situations where a clinical or presumptive diagnosis of gout cannot be made—including cases where the differential diagnosis includes a septic joint—clinicians will be able to perform aspiration with confidence.

The presence of urate crystals in synovial fluid is the gold standard for diagnosing gout,¹ yet clinicians—both primary care physicians and rheumatologists—may not routinely perform synovial fluid analysis even when evaluating a patient who presents with an acute inflammatory arthritis.² This paper discusses the various reasons why this is so and reviews several important resulting clinical issues: how a presumptive diagnosis of gout is made, when to measure the serum urate level, and special considerations in the differential diagnosis.

SYNOVIAL FLUID ANALYSIS: WHY IS THE GOLD STANDARD NOT MORE ROUTINE?

Images courtesy of Brian F. Mandell, MD, PhD.

Occasionally, the aspirated joint does not appear to contain any joint fluid and the clinician may be concerned about the possibility of a “dry tap.” Other possible reasons include lack of experience with synovial fluid aspiration and evaluation, or limited access to the polarizing microscopes used to examine synovial fluid. Time is another factor; in a busy primary care practice, where patients are usually seen approximately every 7 to 11 minutes, there may not be time to aspirate a joint. The urgency of fluid examination is another issue, as synovial fluid must be examined immediately, since the crystals can become smaller, less numerous, and less birefringent with time.⁴

THE CLINICAL, OR PRESUMPTIVE, DIAGNOSIS

In the appropriate clinical scenario, a presumptive diagnosis of gout can be made on the basis of typical clinical features and the presence of hyperuricemia.^1,2

Expert societies offer guidance, but no validation studies to date

Evidence-based recommendations for the diagnosis of gout from the European League Against Rheumatism (EULAR) state that in acute attacks, the rapid development of severe pain, swelling, and tenderness that peaks within 6 to 12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation although not specific for gout.⁵ These recommendations further state that for typical presentations of gout (such as recurrent podagra [gouty pain in the great toe] with hyperuricemia), a clinical diagnosis alone is reasonably accurate.⁵

• The presence of urate crystals in joint fluid
• A tophus containing urate crystals
• Fulfillment of 6 or more of the criteria in Table 1.

No subsequent studies have been published on the validity or usefulness of any of these diagnostic criteria.

What must inform the presumptive diagnosis

Both the EULAR recommendations and the ACR criteria state that although the gold standard for diagnosing gout is the presence of urate crystals on synovial fluid analysis, a clinical diagnosis of gout can be made on the basis of certain patient criteria. This clinical, or presumptive, diagnosis of gout should be made based on the following:

• A careful patient and family history, including questions regarding comorbid conditions frequently associated with gout (such as hypertriglyceridemia, diabetes, coronary heart disease, hypertension, and the metabolic syndrome) and whether the patient has had previous similar episodes of acute joint pain and swelling in the absence of trauma
• Thorough identification of all current medications, some of which may be associated with hyperuricemia
• A thorough physical examination.

THE PHYSICAL EXAMINATION FOR GOUT

Examination of patients with a history suggestive of gout should include not only the joints but also the extensor surface of the forearms and feet. When patients are seen for a visit and gout is suspected, they should be instructed to remove their shoes and socks and roll up their sleeves to allow examination for evidence of tophi, which would suggest a past history of gouty arthritis. The ear, knee, and olecranon bursa are other common sites for tophi,³ so patients should also be asked to roll up their pants and sleeves and remove any head coverings.⁷ In the late stages of gouty arthritis, multiple joints may be involved, which can cause the condition to be confused with other diagnoses such as psoriatic arthritis or erosive osteoarthritis.⁷

ACUTE PRESENTATIONS OF GOUT

The typical gout presentation is remarkable for very intense pain that often occurs at night when the extremities are colder. Precipitation of urate in the distal extremities can occur when the extremities are horizontal and tend to become cold.⁸

Approximately 90% of initial gout attacks are monoarticular, leaving only 10% of cases that are oligoarticular or polyarticular.7 If more than one joint is involved, especially if the patient has a family history suggestive of gout or takes a medication that causes hyperuricemia, gout should be considered in the differential diagnosis even if the patient denies having a prior gout attack.

Frequently, patients will call their primary care physician during a gout attack but are not be able to schedule an appointment until after the attack has resolved. When possible, patients should be seen during the attack to confirm whether the attack is due to gout. A diagnosis of gout should not be made over the phone when a patient describes pain in the great toe, as only 50% of initial gout attacks occur in the great toe⁷ and it is not known what proportion of acute pain episodes in the great toe are attributable to gout. The most common cause of pain in the great toe is osteoarthritis.

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

How long have acute attacks been occurring?

In a clinical scenario in which synovial fluid aspiration cannot be performed, the appropriateness of a presumptive diagnosis can be assessed by a discussion with the patient about how long he or she has been experiencing acute attacks of joint pain. If the attacks have occurred for more than 10 years, tophi will likely be present.³ After even longer periods, gout may become polyarticular.⁷ In postmenopausal women, the distal interphalangeal joints may be involved,³ which may lead to a misdiagnosis of osteoarthritis, as these joints are typically affected by osteoarthritis.

Is the patient taking a urate-raising medication?

Certain medications have been associated with hyper-uricemia, including cyclosporine and thiazide diuretics.⁹ If a patient has been taking one of these medications, gout should be considered in the differential diagnosis if the patient presents with acute joint pain.

It has been argued that a reduction in joint pain and swelling after the use of colchicine confirms a diagnosis of gout. However, other conditions—such as tendonitis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (pseudogout),³ and rheumatoid arthritis (RA)—can also improve after treatment with colchicine.¹

Be vigilant for fever

Another consideration in making a clinical diagnosis of gout is the association with a low-grade fever; these patients may feel as if they have the flu.⁸ Acute gout may also cause a high fever and an elevated white blood cell (WBC) count;³ in this situation, synovial fluid aspiration must be performed to exclude septic arthritis, either alone or in the presence of gouty arthritis. In situations where septic arthritis is suspected, an emergency visit to a rheumatologist is indicated for synovial fluid aspiration to be performed, as gout and sepsis can coexist.⁵ In such instances, Gram staining and culture of the synovial fluid should still be performed even if monosodium urate crystals are identified.⁵

MEASUREMENT OF SERUM URATE LEVELS

Measuring serum urate levels during an acute attack, treating the acute attack with anti-inflammatory medications, and reevaluating the patient in the office 2 weeks after the acute attack are all recommended in the management of a patient with gout. If the serum urate level was not elevated during the acute attack, it is likely to be elevated 2 weeks later if the patient has gout.¹⁰ Elevated levels of serum urate during the intercritical periods are predictive of future gout attacks.¹¹ Measuring serum urate during the initial attack and then 2 weeks later yields two serum urate levels that can be compared to assist in considering a presumed diagnosis of gout. A study by Rigby and Wood concluded that in patients with low serum urate levels (< 4 mg/dL) 2 weeks following an inflammatory arthritis attack, a diagnosis of gout is unlikely.¹²

DIFFERENTIAL DIAGNOSIS OF GOUT

Rheumatoid arthritis

© 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

CPPD crystal deposition disease (pseudogout)

CPPD crystal deposition disease, or pseudogout, must also be included in the differential diagnosis of gout. This disease usually occurs in joints previously affected by osteoarthritis or joints that have been injured in the past.¹⁵ Attacks of CPPD crystal deposition disease commonly occur in the knee, in the wrist at the base of the thumb, or in the shoulder.¹⁵ Radiographic examination may reveal a line of calcification along the cartilage outlining the joint.¹⁵ Like gout, pseudogout attacks can occur spontaneously or after trauma, surgery, or a severe illness such as myocardial infarction or stroke.¹⁶

The presentation of pseudogout can be very similar to an acute attack of gout. The difference is seen when evaluating the crystals through a polarizing microscope. CPPD crystals are weakly positively birefringent (Figure 1B), in contrast to the negatively birefringent crystals seen with gout (Figure 1A).⁷ If a polarizing microscope is not available, the crystals usually can be distinguished by their differing shapes: urate crystals are fine and needlelike, whereas CPPD crystals are rhomboid (Figure 1).

Septic arthritis

When the differential diagnosis includes septic arthritis, the joint must be aspirated; a presumed diagnosis cannot be made. Among patients with an acute gouty attack, low-grade fever is reported during the attack in 29% of gout patients and 38% of patients with CPPD crystal deposition disease.¹⁴ Temperatures of 101°F or higher are not usually seen in patients with gout or CPPD crystal deposition disease and suggest an infection, although patients with septic arthritis may be afebrile, especially if they are taking immunosuppressive therapy or glucocorticoids, which can inhibit a febrile response. Synovial fluid analysis in patients with gout and septic arthritis can reveal WBC counts above 100,000 per mm³, whereas synovial fluid WBC counts above 50,000 per mm³ are more common in infection.

As noted earlier, gout and septic arthritis can coexist. In a patient presenting with a fever and a warm erythematous swollen joint, synovial fluid aspiration must be performed and evaluated for the presence of crystals and bacteria. The patient may require treatment for both causes of acute monoarticular arthritis.

In a patient undergoing renal dialysis, where gout or pseudogout can occur and where there is frequent intravascular manipulation, a septic joint can occur simultaneously.^3,14 In this situation, not only must joint aspiration be performed, but the synovial fluid also needs to be evaluated for both crystals and bacteria. Again, the patient may require treatment for both causes of acute monoarticular arthritis.

CONCLUSIONS

The gold standard for diagnosing gout remains synovial fluid aspiration and analysis. In clinical situations when joint aspiration cannot be performed, the EULAR recommendations⁵ and the ACR criteria⁶ provide guidance for making a clinical or presumptive diagnosis of gout. A thorough patient history—both personal and family—and physical examination are critical in making a presumed diagnosis of gout. If the patient presents during an acute attack, serum urate measurement may be useful in making a clinical diagnosis if it reveals an elevated level. When the patient returns for follow-up 2 weeks later, a second serum urate measurement should be taken to allow comparison of the two levels. If the serum urate level is elevated at the follow-up visit, the EULAR recommendations state that a clinical diagnosis of gout can be made if the patient had an acute attack of arthritis in the great toe.

As noted in the EULAR recommendations, the future research agenda should include validating the clinical manifestations of gout against a diagnosis established by identification of urate crystals on synovial fluid analysis.⁵ Until this task can be completed, clinicians should become familiarized with the technique of joint aspiration so that in situations where a clinical or presumptive diagnosis of gout cannot be made—including cases where the differential diagnosis includes a septic joint—clinicians will be able to perform aspiration with confidence.

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.

Q: Which condition is most likely?

• Rheumatoid arthritis with pulmonary involvement
• Hypertrophic pulmonary osteoarthropathy
• Polymyositis-dermatomyositis with pulmonary involvement
• Systemic lupus erythematosus with pulmonary involvement

A: The patient’s symptoms and physical findings suggest polymyositis-dermatomyositis with associated interstitial lung disease.

Rheumatoid arthritis can also cause lung disease and proximal myopathy, but early physical findings in the hands would include symmetrical joint effusions and soft tissue swelling of the metacarpophalangeal joints.

Patients with hypertrophic pulmonary osteoarthropathy present with arthralgias without weakness. Radiographic findings such as osteophytosis and tufting of terminal processes in the hands would support its diagnosis.

A small number of patients with systemic lupus erythematosus develop deforming arthritis with hand involvement that is either erosive (rhupus hand) or nonerosive (Jaccoud arthropathy, or lupus hand), but interstitial lung disease is rare in lupus, making this combination unlikely.

MULTIPLE PATHS TO DIAGNOSIS

Physical examination, review of systems, laboratory screening, radiographic findings, lung biopsy, electromyography, and muscle biopsy may be used in conjunction.

The criteria of Bohan and Peter are often used to diagnose polymyositis-dermatomyositis: symmetric proximal muscle weakness, elevated muscle enzymes, electromyographic changes consistent with myopathy, and compatible histologic findings on muscle biopsy, with or without the characteristic dermatologic manifestations.^1,2 However, the diagnosis can be made in the typical clinical setting on the basis of characteristic levels of anti-Jo-1 antinuclear antibody and elevated serum muscle enzyme.

Depending on the criteria used, the incidence of interstitial lung disease in various studies of polymyositis-dermatomyositis ranged from 5% to 46%.³ Pulmonary involvement can present in one of three forms:

• Sudden onset of dyspnea and fever with alveolar infiltrates on chest radiography and ground-glass opacities on high-resolution chest CT
• Progressive dyspnea with radiographic findings of chronic interstitial lung disease
• No clinical symptoms, but with abnormal findings on chest radiography.⁴

In a minority of patients, lung disease precedes the onset of muscle or skin disease. Much more commonly, patients present with skin and muscle involvement first. In these patients, pulmonary involvement is typically seen 2 to 5 years after the diagnosis.² Patients with interstitial lung disease are more likely to have arthralgias and arthritis than are those without lung involvement. Interestingly, the finding of microangiopathy on nail fold capillaroscopy strongly suggests pulmonary disease.³

Laboratory findings

Creatine kinase elevation is a marker of disease activity in the muscles. Aldolase, aspartate aminotransferase, and alanine aminotransferase levels may also be elevated but are not muscle-specific. Anti-Jo-1 antinuclear antibody is characteristic, although it can be negative in some patients.

Pulmonary function testing

Restrictive lung physiology with impaired diffusing capacity is the predominant pattern noted.

Lung biopsy findings

Polymyositis-dermatomyositis-associated interstitial lung disease is not limited to one histologic pattern. Nonspecific interstitial pneumonitis is the most common, but usual interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage are also described.² Patients with nonspecific interstitial pneumonitis and organizing pneumonia are suspected to have a better response to immunosuppression and better survival, although controlled studies are absent.

CT appearance

Polymyositis-dermatomyositis complicated by interstitial lung disease does not have a distinct appearance on high-resolution CT. However, the radiographic changes in most cases will suggest the underlying pathology, and this can be used to guide therapy. Most common are bibasilar subpleural ground-glass and reticular opacities that curiously spare the immediate 1 to 2 mm of subpleural parenchyma.^1,3 This pattern is very suggestive of fibrotic nonspecific interstitial pneumonitis. Patchy consolidations with air bronchograms suggest organizing pneumonia. Bibasilar, subpleural honeycomb cystic changes and traction bronchiectasis are noted in usual interstitial pneumonia and suggest fibrosis, which will not improve with therapy. In patients whose disease is progressive, the areas of consolidation often evolve into honeycomb cystic changes.^2,4

TREATMENT IS WITH STEROIDS AND OTHER IMMUNOSUPPRESSIVES

Oral corticosteroids in dosages of 0.5 to 1 mg/kg are first-line therapy. Clinically, muscle disease often improves before lung disease, and treatment may be extended to several months. The histologic pattern suggested by CT or by pathologic study of surgical lung biopsy specimens is a better predictor of treatment response than clinical presentation. Nonspecific interstitial pneumonitis and organizing pneumonia have the highest steroid response rates.³ However, many patients do not respond to steroids alone—only 44% in one study.⁵ Furthermore, treatment response does not indicate recovery, as the disease may relapse.

The addition of immunosuppressive therapy with cyclophosphamide (Cytoxan) may halt deterioration in patients with polymyositis-dermatomyositis-associated interstitial lung disease who are steroid-resistant or may be useful as a steroid-sparing agent in recurrent disease after initial steroid withdrawal. In some cases, therapy with cyclophosphamide improved oxygenation and led to resolution of abnormalities on chest radiography.^6,7

Azathioprine (Imuran), methotrexate, and hydroxychloroquine (Plaquenil) have all been used as part of a steroid-sparing regimen.¹ Tacrolimus (FK 506; Prograf) and rituximab (Rituxan) are emerging therapies, especially for patients who cannot tolerate cytotoxic immunosuppressive agents or who progress despite them.^8,9

PROGNOSIS IS WORSE IF LUNG DISEASE IS PRESENT

The presence of interstitial lung disease increases the risk of death in polymyositis-dermatomyositis. Additionally, clinicians must assess interstitial lung disease separately from muscle or skin disease, as there does not have to be correlation between the activity in the separate organs. Fortunately, the treatment for lung, muscle, and skin involvement is often the same.

Several elements suggest poor prognosis. An acute and aggressive presentation often heralds a poor outcome.¹ Neutrophil alveolitis on bronchoalveolar lavage and a very low diffusing capacity (< 45%) have both been associated with a poorer prognosis.³ The histologic pattern not only predicts treatment response but also prognosis. Patients whose lung biopsies reveal nonspecific interstitial pneumonitis or organizing pneumonia have a better outcome than do patients with usual interstitial pneumonia or diffuse alveolar damage.

In one study,¹ 36 patients with polymyositis-dermatomyositis and interstitial lung disease were followed for 5 years. Resolution was noted in 19.4%, improvement in 55.6%, and deterioration in 25%. Overall, the survival rate was 86.5% at 5 years, and the death rate attributable to pulmonary complications was 13.9% in patients with interstitial lung disease.¹

Q: Which condition is most likely?

• Rheumatoid arthritis with pulmonary involvement
• Hypertrophic pulmonary osteoarthropathy
• Polymyositis-dermatomyositis with pulmonary involvement
• Systemic lupus erythematosus with pulmonary involvement

A: The patient’s symptoms and physical findings suggest polymyositis-dermatomyositis with associated interstitial lung disease.

Rheumatoid arthritis can also cause lung disease and proximal myopathy, but early physical findings in the hands would include symmetrical joint effusions and soft tissue swelling of the metacarpophalangeal joints.

Patients with hypertrophic pulmonary osteoarthropathy present with arthralgias without weakness. Radiographic findings such as osteophytosis and tufting of terminal processes in the hands would support its diagnosis.

A small number of patients with systemic lupus erythematosus develop deforming arthritis with hand involvement that is either erosive (rhupus hand) or nonerosive (Jaccoud arthropathy, or lupus hand), but interstitial lung disease is rare in lupus, making this combination unlikely.

MULTIPLE PATHS TO DIAGNOSIS

Physical examination, review of systems, laboratory screening, radiographic findings, lung biopsy, electromyography, and muscle biopsy may be used in conjunction.

The criteria of Bohan and Peter are often used to diagnose polymyositis-dermatomyositis: symmetric proximal muscle weakness, elevated muscle enzymes, electromyographic changes consistent with myopathy, and compatible histologic findings on muscle biopsy, with or without the characteristic dermatologic manifestations.^1,2 However, the diagnosis can be made in the typical clinical setting on the basis of characteristic levels of anti-Jo-1 antinuclear antibody and elevated serum muscle enzyme.

Depending on the criteria used, the incidence of interstitial lung disease in various studies of polymyositis-dermatomyositis ranged from 5% to 46%.³ Pulmonary involvement can present in one of three forms:

• Sudden onset of dyspnea and fever with alveolar infiltrates on chest radiography and ground-glass opacities on high-resolution chest CT
• Progressive dyspnea with radiographic findings of chronic interstitial lung disease
• No clinical symptoms, but with abnormal findings on chest radiography.⁴

In a minority of patients, lung disease precedes the onset of muscle or skin disease. Much more commonly, patients present with skin and muscle involvement first. In these patients, pulmonary involvement is typically seen 2 to 5 years after the diagnosis.² Patients with interstitial lung disease are more likely to have arthralgias and arthritis than are those without lung involvement. Interestingly, the finding of microangiopathy on nail fold capillaroscopy strongly suggests pulmonary disease.³

Laboratory findings

Creatine kinase elevation is a marker of disease activity in the muscles. Aldolase, aspartate aminotransferase, and alanine aminotransferase levels may also be elevated but are not muscle-specific. Anti-Jo-1 antinuclear antibody is characteristic, although it can be negative in some patients.

Pulmonary function testing

Restrictive lung physiology with impaired diffusing capacity is the predominant pattern noted.

Lung biopsy findings

Polymyositis-dermatomyositis-associated interstitial lung disease is not limited to one histologic pattern. Nonspecific interstitial pneumonitis is the most common, but usual interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage are also described.² Patients with nonspecific interstitial pneumonitis and organizing pneumonia are suspected to have a better response to immunosuppression and better survival, although controlled studies are absent.

CT appearance

Polymyositis-dermatomyositis complicated by interstitial lung disease does not have a distinct appearance on high-resolution CT. However, the radiographic changes in most cases will suggest the underlying pathology, and this can be used to guide therapy. Most common are bibasilar subpleural ground-glass and reticular opacities that curiously spare the immediate 1 to 2 mm of subpleural parenchyma.^1,3 This pattern is very suggestive of fibrotic nonspecific interstitial pneumonitis. Patchy consolidations with air bronchograms suggest organizing pneumonia. Bibasilar, subpleural honeycomb cystic changes and traction bronchiectasis are noted in usual interstitial pneumonia and suggest fibrosis, which will not improve with therapy. In patients whose disease is progressive, the areas of consolidation often evolve into honeycomb cystic changes.^2,4

TREATMENT IS WITH STEROIDS AND OTHER IMMUNOSUPPRESSIVES

Oral corticosteroids in dosages of 0.5 to 1 mg/kg are first-line therapy. Clinically, muscle disease often improves before lung disease, and treatment may be extended to several months. The histologic pattern suggested by CT or by pathologic study of surgical lung biopsy specimens is a better predictor of treatment response than clinical presentation. Nonspecific interstitial pneumonitis and organizing pneumonia have the highest steroid response rates.³ However, many patients do not respond to steroids alone—only 44% in one study.⁵ Furthermore, treatment response does not indicate recovery, as the disease may relapse.

The addition of immunosuppressive therapy with cyclophosphamide (Cytoxan) may halt deterioration in patients with polymyositis-dermatomyositis-associated interstitial lung disease who are steroid-resistant or may be useful as a steroid-sparing agent in recurrent disease after initial steroid withdrawal. In some cases, therapy with cyclophosphamide improved oxygenation and led to resolution of abnormalities on chest radiography.^6,7

Azathioprine (Imuran), methotrexate, and hydroxychloroquine (Plaquenil) have all been used as part of a steroid-sparing regimen.¹ Tacrolimus (FK 506; Prograf) and rituximab (Rituxan) are emerging therapies, especially for patients who cannot tolerate cytotoxic immunosuppressive agents or who progress despite them.^8,9

PROGNOSIS IS WORSE IF LUNG DISEASE IS PRESENT

The presence of interstitial lung disease increases the risk of death in polymyositis-dermatomyositis. Additionally, clinicians must assess interstitial lung disease separately from muscle or skin disease, as there does not have to be correlation between the activity in the separate organs. Fortunately, the treatment for lung, muscle, and skin involvement is often the same.

Several elements suggest poor prognosis. An acute and aggressive presentation often heralds a poor outcome.¹ Neutrophil alveolitis on bronchoalveolar lavage and a very low diffusing capacity (< 45%) have both been associated with a poorer prognosis.³ The histologic pattern not only predicts treatment response but also prognosis. Patients whose lung biopsies reveal nonspecific interstitial pneumonitis or organizing pneumonia have a better outcome than do patients with usual interstitial pneumonia or diffuse alveolar damage.

In one study,¹ 36 patients with polymyositis-dermatomyositis and interstitial lung disease were followed for 5 years. Resolution was noted in 19.4%, improvement in 55.6%, and deterioration in 25%. Overall, the survival rate was 86.5% at 5 years, and the death rate attributable to pulmonary complications was 13.9% in patients with interstitial lung disease.¹

Q: Which condition is most likely?

• Rheumatoid arthritis with pulmonary involvement
• Hypertrophic pulmonary osteoarthropathy
• Polymyositis-dermatomyositis with pulmonary involvement
• Systemic lupus erythematosus with pulmonary involvement

A: The patient’s symptoms and physical findings suggest polymyositis-dermatomyositis with associated interstitial lung disease.

Rheumatoid arthritis can also cause lung disease and proximal myopathy, but early physical findings in the hands would include symmetrical joint effusions and soft tissue swelling of the metacarpophalangeal joints.

Patients with hypertrophic pulmonary osteoarthropathy present with arthralgias without weakness. Radiographic findings such as osteophytosis and tufting of terminal processes in the hands would support its diagnosis.

A small number of patients with systemic lupus erythematosus develop deforming arthritis with hand involvement that is either erosive (rhupus hand) or nonerosive (Jaccoud arthropathy, or lupus hand), but interstitial lung disease is rare in lupus, making this combination unlikely.

MULTIPLE PATHS TO DIAGNOSIS

Physical examination, review of systems, laboratory screening, radiographic findings, lung biopsy, electromyography, and muscle biopsy may be used in conjunction.

The criteria of Bohan and Peter are often used to diagnose polymyositis-dermatomyositis: symmetric proximal muscle weakness, elevated muscle enzymes, electromyographic changes consistent with myopathy, and compatible histologic findings on muscle biopsy, with or without the characteristic dermatologic manifestations.^1,2 However, the diagnosis can be made in the typical clinical setting on the basis of characteristic levels of anti-Jo-1 antinuclear antibody and elevated serum muscle enzyme.

Depending on the criteria used, the incidence of interstitial lung disease in various studies of polymyositis-dermatomyositis ranged from 5% to 46%.³ Pulmonary involvement can present in one of three forms:

• Sudden onset of dyspnea and fever with alveolar infiltrates on chest radiography and ground-glass opacities on high-resolution chest CT
• Progressive dyspnea with radiographic findings of chronic interstitial lung disease
• No clinical symptoms, but with abnormal findings on chest radiography.⁴

In a minority of patients, lung disease precedes the onset of muscle or skin disease. Much more commonly, patients present with skin and muscle involvement first. In these patients, pulmonary involvement is typically seen 2 to 5 years after the diagnosis.² Patients with interstitial lung disease are more likely to have arthralgias and arthritis than are those without lung involvement. Interestingly, the finding of microangiopathy on nail fold capillaroscopy strongly suggests pulmonary disease.³

Laboratory findings

Creatine kinase elevation is a marker of disease activity in the muscles. Aldolase, aspartate aminotransferase, and alanine aminotransferase levels may also be elevated but are not muscle-specific. Anti-Jo-1 antinuclear antibody is characteristic, although it can be negative in some patients.

Pulmonary function testing

Restrictive lung physiology with impaired diffusing capacity is the predominant pattern noted.

Lung biopsy findings

Polymyositis-dermatomyositis-associated interstitial lung disease is not limited to one histologic pattern. Nonspecific interstitial pneumonitis is the most common, but usual interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage are also described.² Patients with nonspecific interstitial pneumonitis and organizing pneumonia are suspected to have a better response to immunosuppression and better survival, although controlled studies are absent.

CT appearance

Polymyositis-dermatomyositis complicated by interstitial lung disease does not have a distinct appearance on high-resolution CT. However, the radiographic changes in most cases will suggest the underlying pathology, and this can be used to guide therapy. Most common are bibasilar subpleural ground-glass and reticular opacities that curiously spare the immediate 1 to 2 mm of subpleural parenchyma.^1,3 This pattern is very suggestive of fibrotic nonspecific interstitial pneumonitis. Patchy consolidations with air bronchograms suggest organizing pneumonia. Bibasilar, subpleural honeycomb cystic changes and traction bronchiectasis are noted in usual interstitial pneumonia and suggest fibrosis, which will not improve with therapy. In patients whose disease is progressive, the areas of consolidation often evolve into honeycomb cystic changes.^2,4

TREATMENT IS WITH STEROIDS AND OTHER IMMUNOSUPPRESSIVES

Oral corticosteroids in dosages of 0.5 to 1 mg/kg are first-line therapy. Clinically, muscle disease often improves before lung disease, and treatment may be extended to several months. The histologic pattern suggested by CT or by pathologic study of surgical lung biopsy specimens is a better predictor of treatment response than clinical presentation. Nonspecific interstitial pneumonitis and organizing pneumonia have the highest steroid response rates.³ However, many patients do not respond to steroids alone—only 44% in one study.⁵ Furthermore, treatment response does not indicate recovery, as the disease may relapse.

The addition of immunosuppressive therapy with cyclophosphamide (Cytoxan) may halt deterioration in patients with polymyositis-dermatomyositis-associated interstitial lung disease who are steroid-resistant or may be useful as a steroid-sparing agent in recurrent disease after initial steroid withdrawal. In some cases, therapy with cyclophosphamide improved oxygenation and led to resolution of abnormalities on chest radiography.^6,7

Azathioprine (Imuran), methotrexate, and hydroxychloroquine (Plaquenil) have all been used as part of a steroid-sparing regimen.¹ Tacrolimus (FK 506; Prograf) and rituximab (Rituxan) are emerging therapies, especially for patients who cannot tolerate cytotoxic immunosuppressive agents or who progress despite them.^8,9

PROGNOSIS IS WORSE IF LUNG DISEASE IS PRESENT

The presence of interstitial lung disease increases the risk of death in polymyositis-dermatomyositis. Additionally, clinicians must assess interstitial lung disease separately from muscle or skin disease, as there does not have to be correlation between the activity in the separate organs. Fortunately, the treatment for lung, muscle, and skin involvement is often the same.

Several elements suggest poor prognosis. An acute and aggressive presentation often heralds a poor outcome.¹ Neutrophil alveolitis on bronchoalveolar lavage and a very low diffusing capacity (< 45%) have both been associated with a poorer prognosis.³ The histologic pattern not only predicts treatment response but also prognosis. Patients whose lung biopsies reveal nonspecific interstitial pneumonitis or organizing pneumonia have a better outcome than do patients with usual interstitial pneumonia or diffuse alveolar damage.

In one study,¹ 36 patients with polymyositis-dermatomyositis and interstitial lung disease were followed for 5 years. Resolution was noted in 19.4%, improvement in 55.6%, and deterioration in 25%. Overall, the survival rate was 86.5% at 5 years, and the death rate attributable to pulmonary complications was 13.9% in patients with interstitial lung disease.¹

Children who undergo radiotherapy, chemotherapy, or surgery for cancer face a risk of complications later in life, including pulmonary fibrosis and pneumonitis.

These long-term cancer survivors need systematic, lifelong surveillance, in a program that takes into account their individual risk (based on therapeutic exposures, genetic predisposition, lifestyle behaviors, and comorbid health conditions).¹ Optimally, they would receive their care at multidisciplinary follow-up clinics organized by pediatric oncologists at tertiary care centers. However, access to such centers is limited, making this an option for relatively few. Consequently, as childhood cancer survivors age, internists and family practitioners may need to assume an increasing amount of responsibility for their follow-up care.

Because individual primary care providers are unlikely to follow more than a handful of survivors, specialists have developed guidelines for survivors of pediatric cancer. Working with established multidisciplinary clinics may help ensure appropriate follow-up for this population of patients.

This review summarizes the late effects of cancer therapy on the lungs and an approach to surveillance for the generalist or pulmonologist. We also review the quality of the evidence upon which these recommendations are based.

NUMBERS ON THE RISE

An estimated 1 of every 330 children develops cancer before age 19. With cure rates exceeding 75% for many pediatric malignancies, the number of survivors of childhood cancer, currently in excess of 270,000, will continue to increase.²

THE CHILDREN’S ONCOLOGY GROUP GUIDELINES

The Children’s Oncology Group (COG)³ released its first set of guidelines in 2003 for the follow-up care of patients treated for pediatric malignancies; the current version is available at www.survivorshipguidelines.org. The guidelines contain comprehensive screening recommendations, including those related to pulmonary toxicity, which can be used to standardize care.

Patient education materials accompany the guidelines, offering detailed information on guideline-specific topics in order to promote health maintenance.

HOW WE SEARCHED THE LITERATURE

We performed an extensive review of the literature via MEDLINE for the years 1975–2005. Key search terms were “childhood cancer,” “late effects,” and “pulmonary toxicity,” combined with keywords for each therapeutic exposure. References from selected articles were used to broaden the search. From several hundred citations, fewer than 30 were selected as best illustrating the relevant associations.

RISK IS THREE TIMES HIGHER IN CANCER SURVIVORS

The Childhood Cancer Survivor Study⁴ is the largest database of late effects, with more than 12,000 survivors of childhood cancer diagnosed between 1970 and 1986. Its data suggest that the risk of pulmonary conditions is more than three times higher in cancer survivors than in their siblings, as manifested by pulmonary signs (abnormal chest wall growth), symptoms (chronic cough, use of supplemental oxygen, exercise-induced shortness of breath), or specific diagnoses (lung fibrosis, recurrent pneumonia, pleurisy, bronchitis, recurrent sinus infection, or tonsillitis). Limitations: these data are retrospective, and the outcomes were detected by self-report and were not validated by review of medical records. Thus, the figures highlight the fact that pulmonary late effects are an important problem but do not give us a way to calculate risk exactly.

Other limitations of the literature: Treatments are constantly evolving, often in attempts to minimize late effects, and newer agents will need to be monitored for pulmonary toxicities. As noted, much of the available information is from studies of survivors of adult cancer; the potential for late effects of similar therapies in children is inferred. Most conclusions—and especially those based upon prospective serial evaluations—derive from small cohorts. For all treatments, the complications in the very long term remain undefined. What we know is summarized below.

CANCER THERAPY CAUSES FIBROSIS, PNEUMONITIS

The courses of these diseases are poorly characterized, since few longitudinal studies have been done. However, like most of the late effects of cancer therapy, pulmonary toxicity may first become apparent during the treatment and persist, or it may not appear until years later. Signs and symptoms may be static, progressive, or reversible.

ANGIOGENESIS MAY CONTRIBUTE TO FIBROSIS

On a microscopic level, pulmonary fibrosis is characterized by epithelial injury, fibroproliferation, and excessive extracellular matrix deposition.^6–8

Evidence is mounting that these findings result in part from angiogenesis. Although this has not been studied in long-term cancer survivors, evidence of neovascularization was seen both in an animal model of lung fibrosis and in patients with idiopathic pulmonary fibrosis.^6–8 High plasma concentrations of angiogenic cytokines (eg, tumor necrosis factor alpha, interleukin 8, and endothelin 1) have been found in these situations. Antiangiogenic agents and other immune modulators such as thalidomide may be beneficial in patients with lung fibrosis.⁷

On a macroscopic level, pulmonary fibrosis results in loss of lung volume in older children and in adults. In contrast, in younger children, interference with growth of both the lung and the chest wall may contribute to pulmonary dysfunction.

CANCER TYPES AND TREATMENTS VARY BY AGE

Cancers that commonly involve the thorax are listed in Table 2. Neuroblastoma, hepatoblastoma, extragonadal germ cell tumors, and Wilms tumor typically are diseases of young children; osteosarcoma, Ewing sarcoma, thyroid carcinoma, and Hodgkin disease are most common in older children and adolescents; soft tissue sarcoma and non-Hodgkin lymphoma span all age groups.

Surgery can, in some cases, control the cancer, as with mediastinal neuroblastoma and Ewing sarcoma of the chest wall.

Radiation to the chest remains a major component of treatment for Hodgkin disease, unresected thoracic Ewing sarcoma, soft tissue sarcoma with lung involvement or thyroid carcinoma, and Wilms tumor. Central nervous system tumors and leukemias, the most common pediatric malignancies, may require radiation to the spinal cord—with resulting radiation exposure of the lungs. Total-body irradiation is a component of many preparative regimens for stem cell transplantation.

Chemotherapy remains a mainstay for all types of tumors, and patients with germ cell tumors, Hodgkin disease, and brain tumors are at particular risk of pulmonary toxicity due to heavy reliance on bleomycin (Blenoxane) (for germ cell tumors, Hodgkin disease) and the nitrosoureas (for brain tumors).

RADIATION-INDUCED LUNG DAMAGE

The lungs are particularly sensitive to radiation, and pulmonary problems occur most often in patients with malignant diseases of the chest that are treated with radiation, ie, those involving the mediastinum, the lung parenchyma, or the chest wall.

Abnormal radiographic findings or restrictive changes on pulmonary function testing have been reported in more than 30% of patients who received radiation directly or indirectly to the lung.^9–12 These changes have been detected months to years after radiation therapy, most often in patients who suffered radiation pneumonitis as an acute toxicity.

The amount of damage depends on the cumulative dose, how many treatments (“fractions”) this cumulative dose was divided into (dividing the radiation dose into smaller dose fractions can reduce toxicity), the volume of lung tissue involved, and the patient’s age (the younger, the worse) at the time of treatment.

Cumulative dose. Whole-lung irradiation is limited to 12 Gy, although localized areas of cancer can be treated with much higher doses.

Clinically apparent pneumonitis with cough, fever, or dyspnea generally occurs only in survivors who received more than 30 Gy in standard fractions to more than 50% of the lung. However, in 12 survivors of Wilms tumor who received median total doses of approximately 20 Gy to both lungs 7 to 14 years previously, 8 patients had dyspnea on exertion and radiographic evidence of interstitial and pleural thickening.¹³ Mean total lung volumes and the diffusing capacity of the lung for carbon monoxide (DLCO) were reduced in all patients to approximately 60% of predicted values.

In a prospective study of adults with Hodgkin disease treated after 1980, 145 patients were examined 3 years after receiving more than 44 Gy limited to the mantle area.⁹ None were experiencing symptoms; however, 30% to 40% had a forced vital capacity (FVC) less than 80% of predicted, and 7% had a reduced DLCO. Some of these patients also had received bleomycin (see below), which may have exacerbated pulmonary toxicity. Asymptomatic restrictive and obstructive lung changes have been detected after lower doses of whole-lung radiation (11–14 Gy) were given for other malignant diseases.^11,14

In a recent study of adults and older adolescents with stage I and IIA Hodgkin disease treated with radiation alone (40–45 Gy to involved fields, including the mediastinum), late pulmonary effects observed were minimal.¹⁰ While FVC, residual volume, forced expiratory volume in 1 second (FEV₁), DLCO, and total lung capacity (TLC) were significantly lower at the end of radiation therapy than before treatment, all except DLCO returned nearly to normal within 1 year. The decrease in DLCO remained stable, but the forced expiratory flow rate between 25% and 75% of FVC (FEF 25%–75%) was significantly lower 3 years after treatment than at baseline.

The high doses of total lung irradiation cited in several of these reports are rarely used in today’s cancer protocols. For example, patients receiving radiation as adjunctive treatment for Hodgkin disease now receive lower doses (< 21 Gy), which are restricted to involved fields, and the pulmonary toxicity is less than in the past.

In one series, 159 children and adolescents with unfavorable Hodgkin disease treated from 1993 to 2000 received six cycles of chemotherapy followed by response-based, involved-field radiation therapy. Patients who achieved a complete response after the first two cycles of chemotherapy got 15 Gy, and those who achieved a partial response got 25.5 Gy to all sites of bulky lymphadenopathy.¹⁵ All patients underwent pulmonary function testing. Only 24 (30.8%) of them had pulmonary toxicity, which was limited to asymptomatic deficits of restriction and diffusion.

Nevertheless, the lungs receive some radiation even when they are not the target, such as in patients with malignant brain tumors, and this exposure can contribute to the development of lung disease, although these patients are likely to have no symptoms during day-to-day activities. Innovations in targeted radiation delivery (eg, conformal radiation) should further limit damage to normal lung tissue.

Age at the time of treatment also may influence the type and incidence of pulmonary sequelae. In older children and adults, radiation for thoracic malignancy results in pulmonary fibrosis with loss of lung volume. Similar injury can occur in younger children, but pulmonary function may also be compromised by inhibited growth of the supportive structures and the chest wall. One report suggests that children younger than 3 years at the time of therapy experience more chronic toxicity.¹¹

In contrast, after bone marrow transplantation, children seem to be at less risk of significant late pulmonary dysfunction than adults are, despite similar preparatory regimens.¹⁶ This may in part reflect a lower incidence of severe graft-vs-host disease involving the lung. Nonetheless, in a recent report of children treated with fractionated total-body irradiation between 1985 and 1993, restrictive pulmonary diseases were found in 30 of 42 patients at a median of 3.1 years after treatment (range 0.5–17 years).¹⁷ Most of these patients had asymptomatic mild restrictive disease, and the one patient with severe changes had previously received thoracic radiation for treatment of neuroblastoma. In about half of the cases, pulmonary function abnormalities were permanent although not progressive.

CHEMOTHERAPY-RELATED LUNG DAMAGE

A growing list of chemotherapeutic agents appears to cause pulmonary disease in long-term survivors.⁵

Bleomycin

Bleomycin toxicity is the prototype for chemotherapy-related lung injury: bleomycin was the first chemotherapy drug shown to cause lung injury, this effect is suggested by a large database, and the mechanism is typical.^5,18 Preclinical studies have attributed bleomycin’s toxicity to its tendency to promote free radicals.

Although interstitial pneumonitis and pulmonary fibrosis have been reported in children, clinically apparent bleomycin pneumonopathy is most frequent in older adults. Usually, the abnormalities began within 3 months of therapy and persisted or progressed. Like the acute toxicity, it is dose-dependent and more common above a threshold cumulative dose of 400 units/m². Above this dose, 10% of adult patients without other risk factors develop fibrosis; data are not available for these doses in children. At lower doses, fibrosis occurs sporadically in fewer than 5% of patients, with a 1% to 2% mortality rate. In some series, bleomycin toxicity was anticipated on the basis of DLCO abnormalities.

Bleomycin pulmonary toxicity is variably exacerbated by concurrent or previous radiation therapy.

Increased oxygen concentrations associated with general anesthesia have also been found to exacerbate prior bleomycin-induced pulmonary injury.^19,20 In one instance (reviewed by Zaniboni et al²⁰), the patient recovered with corticosteroid treatment.

Alkylating agents

Carmustine (also called BCNU; brand names BiCNU, Gliadel) and lomustine (CCNU; CeeNU) are thought to cause dose-related lung injury. When cumulative carmustine doses are greater than 1,500 mg/m², more than 50% of patients develop symptoms.²¹

In a careful clinicopathologic review of 31 children with brain tumors, restrictive changes with lung fibrosis were reported up to 17 years after treatment, most often with carmustine 100 mg/m² every 6 to 8 weeks for up to 2 years.²² Four of the 8 patients still alive at the time of study experienced shortness of breath and coughing; 6 showed a characteristic pattern of upper zone fibrosis on chest radiography and computed tomography; all 8 survivors had restrictive findings on pulmonary function testing, with vital capacities of about 50% of normal. Toxicity increases with more intensive dose-scheduling.

Cyclophosphamide (Cytoxan) may cause delayed-onset pulmonary fibrosis with severe restrictive lung disease in association with marked reductions in the anteroposterior diameter of the chest, although the evidence is less convincing than with carmustine and lomustine, coming from case reports and small series.²³

Melphalan (Alkeran), generally in doses used in stem cell transplant conditioning regimens, is also thought to cause pulmonary fibrosis.²⁴

Busulfan most predictably causes toxicity when it is used in transplantation doses (ie, more than 500 mg), and may be associated with a progressive, potentially fatal restrictive lung disease.²⁵ A current trend is to adjust the dose on the basis of pharmacokinetic analysis, which we hope will reduce toxicity.

Other agents

Methotrexate (MTX; Trexall) also has been associated with chronic pneumonitis and fibrosis.²⁶ This probably occurs with an incidence well below 1% and may be idiosyncratic and not dose-related. Asymptomatic changes in pulmonary function tests that do not predict clinically significant problems have most frequently been associated with low-dose oral administration during more than 3 years.²⁷ This is a treatment approach used in patients with psoriasis or rheumatoid arthritis, but is now obsolete for pediatric cancer. Intravenous and, rarely, intrathecal administration also have been associated with pulmonary toxicity.²⁸ A single report of two patients who developed diffuse interstitial pulmonary infiltrates and chronic pulmonary changes links vinblastine to these sequelae.²⁹

LUNG INJURY AFTER BONE MARROW TRANSPLANTATION

Hematopoietic stem cell transplantation is associated with various late pulmonary complications. The factors that influence these complications are similar to those discussed earlier. However, the intensity of therapy in patients undergoing transplantation and the additive effects of previous therapies magnify the risks.

Patients undergoing total-body irradiation as part of their preparation for transplantation have a high incidence of late pulmonary complications.^25,30–32 Busulfan, carmustine, bleomycin, and cyclophosphamide, also commonly used conditioning chemotherapies, are known to cause pneumonitis and fibrosis after transplantation.³³

Some acute pulmonary toxicities can have long-standing effects, including serious pulmonary infections, idiopathic pneumonia syndrome, bronchiolitis obliterans, acute respiratory distress syndrome, or other damage related to graft-vs-host disease.

OTHER RISK FACTORS FOR LUNG DAMAGE

Additional factors contributing to chronic pulmonary toxicity include superimposed infection, underlying pneumonopathy (eg, asthma), cigarette use, respirator toxicity, chronic graft-vs-host disease, and the effects of chronic pulmonary involvement by tumor or reaction to tumor. For example, a subset of patients with Langerhans cell histiocytosis can develop histiocytic pulmonary infiltrates or honeycombing with severe chronic restrictive lung disease unrelated to therapy or the presence of active tumor.

Although not well documented, scuba diving also has been said to exacerbate pulmonary fibrosis through increased underwater pressures and high oxygen levels.³⁴

Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function,^35–37 but the effect of lung surgery for children with cancer is not well defined.

GET THE PATIENT’S TREATMENT SUMMARY

Regardless of the setting for follow-up, the first step in any evaluation is to obtain the patient’s medical history and especially a treatment summary. The treatment summary should outline the cancer diagnosis, involved sites of disease, age at diagnosis, specific treatments (surgery, chemotherapy, radiation), and other key interventions and events during and after cancer therapy. Sample forms for physicians and patients are available at www.survivorshipguidelines.org.

Before the long-term survivor of childhood cancer graduates from the care of a pediatric oncologist, this treatment record and possible long-term problems should be reviewed with the family and, in the case of an adolescent, with the patient. Correspondence between the pediatric oncologist and subsequent caregivers should also include a treatment summary. The treatment summary allows the survivor or his health care provider to interface with the COG guidelines to determine recommended follow-up care. The primary care physician and the patient both should have copies of this document.

We are developing an interactive Web-based version of a standardized summary form, designed to interface with an automated version of the COG guidelines in order to generate individualized follow-up recommendations.

ASK ABOUT LUNG SYMPTOMS

We recommend that health care providers investigate symptoms of pulmonary dysfunction, and specifically ask about chronic cough with or without fever, shortness of breath, and dyspnea on exertion during yearly health care visits.

Baseline pulmonary function testing (including DLCO and spirometry) and chest radiography are recommended 2 or more years after completion of therapy to document persistent deficits and determine the need for continued monitoring. Reevaluation of pulmonary function should be considered in patients with established deficits who require general anesthesia and for those treated with bleomycin.

Scuba diving remains controversial for long-term survivors. Consequently, patients with risk factors for lung disease should be encouraged to consult with a pulmonary specialist to determine if diving poses a health threat to their pulmonary status. If clinical pulmonary dysfunction is identified, referral to colleagues in pulmonology for additional evaluation and treatment is essential. Increasing familiarity of primary care providers with surveillance concepts is a key element in survivorship care.

Smoking cessation can enhance the health of all patients and is particularly important among long-term survivors, especially those who received treatments predisposing to pulmonary injury. Strategies for cessation and patient information can be found at www.cdc.gov/tobacco/how2quit.htm.

Clinicians can take advantage of every patient interaction to assess readiness for smoking cessation and assist patients in this goal. Following the principles of patient-centered counseling, physicians can guide patients into considering a change of behavior with advice and encouragement. Whenever possible, physicians should personalize the risks of smoking as well as the short-term and long-term benefits. As smokers prepare to quit, their physicians can assist in developing a plan that includes a quit date.

Many pharmacologic agents are available to assist patients, ie, nicotine inhalers, sprays, gum, and transdermal patches; the antidepressants bupropion (Wellbutrin) and nortriptiline (Pamelor); the alpha-2 adrenergic agonist clonidine (Catapres); and, most recently, the nicotine receptor partial agonist varenicline (Chantix).³⁸

Follow-up to prevent relapse is an important part of this process.

Acknowledgment. This work was supported in part by the Swim Across America Foundation and the Campini Foundation.