Rheumatoid Arthritis

BARCELONA — Anti-tumor necrosis factor-α drugs may aid insulin resistance in rheumatoid arthritis, according to studies presented at the annual European Congress of Rheumatology.

Traditional and nontraditional risk factors, like systemic inflammation and insulin resistance, have been implicated in cardio-vascular disease in RA, said Dr. Sabrina Paolino of the University of Genova, Italy. Insulin resistance also has been shown to influence the development and progression of atherosclerotic lesions in rheumatic diseases and RA.

Dr. Paolino and colleagues compared 32 patients with active RA who were treated with either infliximab (3 mg/kg at week 0, 2, 6, and every 8 weeks thereafter) or etanercept (25 mg twice per week), with 20 RA patients not on anti-TNF-α drugs. All patients received prednisone (maximum of 7.5 mg/day) and methotrexate (10 mg/week). Subjects with frank diabetes; viral hepatitis B or C infection; any malignancy; liver or kidney disease; or endocrine or metabolic disorders, or who took medications that influence glucose metabolism were excluded.

At 24 weeks, patients on anti-TNF-α therapy had significantly greater improvement in disease activity score using 28 joint counts, the Quantitive Insulin Sensitivity Check Index, and the homeostasis model assessment of insulin resistance (HOMA) than those not on anti-TNF-α drugs. There were no differences in insulin resistance between patients on etanercept and those on infliximab.

In a poster presented at the Congress, insulin resistance as calculated on the HOMA index and hemoglobin A_1c were significantly lower in 16 nondiabetic RA patients after 1 year of anti-TNF-α therapy. No significant changes occurred during follow-up on dietary questionnaires, physical activity levels, anthropometric measurements, body mass index, or fat mass to confound the anti-TNF-α and insulin resistance link. Cholesterol and triglyceride levels did not change, said Dr. Sigrid Talaverano and associates at the University Hospital of the Canary Islands, La Cuesta, Spain.

BARCELONA — Anti-tumor necrosis factor-α drugs may aid insulin resistance in rheumatoid arthritis, according to studies presented at the annual European Congress of Rheumatology.

Traditional and nontraditional risk factors, like systemic inflammation and insulin resistance, have been implicated in cardio-vascular disease in RA, said Dr. Sabrina Paolino of the University of Genova, Italy. Insulin resistance also has been shown to influence the development and progression of atherosclerotic lesions in rheumatic diseases and RA.

Dr. Paolino and colleagues compared 32 patients with active RA who were treated with either infliximab (3 mg/kg at week 0, 2, 6, and every 8 weeks thereafter) or etanercept (25 mg twice per week), with 20 RA patients not on anti-TNF-α drugs. All patients received prednisone (maximum of 7.5 mg/day) and methotrexate (10 mg/week). Subjects with frank diabetes; viral hepatitis B or C infection; any malignancy; liver or kidney disease; or endocrine or metabolic disorders, or who took medications that influence glucose metabolism were excluded.

At 24 weeks, patients on anti-TNF-α therapy had significantly greater improvement in disease activity score using 28 joint counts, the Quantitive Insulin Sensitivity Check Index, and the homeostasis model assessment of insulin resistance (HOMA) than those not on anti-TNF-α drugs. There were no differences in insulin resistance between patients on etanercept and those on infliximab.

In a poster presented at the Congress, insulin resistance as calculated on the HOMA index and hemoglobin A_1c were significantly lower in 16 nondiabetic RA patients after 1 year of anti-TNF-α therapy. No significant changes occurred during follow-up on dietary questionnaires, physical activity levels, anthropometric measurements, body mass index, or fat mass to confound the anti-TNF-α and insulin resistance link. Cholesterol and triglyceride levels did not change, said Dr. Sigrid Talaverano and associates at the University Hospital of the Canary Islands, La Cuesta, Spain.

BARCELONA — Anti-tumor necrosis factor-α drugs may aid insulin resistance in rheumatoid arthritis, according to studies presented at the annual European Congress of Rheumatology.

Traditional and nontraditional risk factors, like systemic inflammation and insulin resistance, have been implicated in cardio-vascular disease in RA, said Dr. Sabrina Paolino of the University of Genova, Italy. Insulin resistance also has been shown to influence the development and progression of atherosclerotic lesions in rheumatic diseases and RA.

Dr. Paolino and colleagues compared 32 patients with active RA who were treated with either infliximab (3 mg/kg at week 0, 2, 6, and every 8 weeks thereafter) or etanercept (25 mg twice per week), with 20 RA patients not on anti-TNF-α drugs. All patients received prednisone (maximum of 7.5 mg/day) and methotrexate (10 mg/week). Subjects with frank diabetes; viral hepatitis B or C infection; any malignancy; liver or kidney disease; or endocrine or metabolic disorders, or who took medications that influence glucose metabolism were excluded.

At 24 weeks, patients on anti-TNF-α therapy had significantly greater improvement in disease activity score using 28 joint counts, the Quantitive Insulin Sensitivity Check Index, and the homeostasis model assessment of insulin resistance (HOMA) than those not on anti-TNF-α drugs. There were no differences in insulin resistance between patients on etanercept and those on infliximab.

In a poster presented at the Congress, insulin resistance as calculated on the HOMA index and hemoglobin A_1c were significantly lower in 16 nondiabetic RA patients after 1 year of anti-TNF-α therapy. No significant changes occurred during follow-up on dietary questionnaires, physical activity levels, anthropometric measurements, body mass index, or fat mass to confound the anti-TNF-α and insulin resistance link. Cholesterol and triglyceride levels did not change, said Dr. Sigrid Talaverano and associates at the University Hospital of the Canary Islands, La Cuesta, Spain.

Drinking multiple cups of coffee each day may reduce the risk of gout in men, according to data from a prospective study of nearly 50,000 men.

Studies of coffee's effects on the body are important for public health, because so many people drink so much of it, wrote Dr. Hyon K. Choi of the University of British Columbia, Vancouver, and colleagues. “More than 50% of Americans drink coffee,” they noted, and the average per capita intake is approximately two cups per day.

Coffee is a major source of the phenol known as chlorogenic acid, which is a very powerful antioxidant (Arthritis Rheum. 2007;56:2049–55). Data from previous studies suggest that chlorogenic acid may reduce plasma glucose concentrations and interact with other antioxidants that are present in coffee to reduce oxidative stress and, consequently, reduce the risk of developing gout.

Other components of coffee may also play a role in reducing gout risk by affecting insulin resistance.

To determine the relationship between coffee consumption and gout, the investigators studied 45,869 adult men with no baseline history of gout. The men's coffee consumption was assessed at 4-year intervals over a 12-year follow-up period using a validated questionnaire. An additional questionnaire was used to determine whether the men met the American College of Rheumatology's criteria for gout.

The researchers identified 757 confirmed incident cases of gout, and found that the risk for gout was 59% lower in men who drank six or more cups of coffee per day and 40% lower among men who drank four to five cups of coffee per day.

The risk reduction was 8% among men who drank one to three cups of coffee per day, and 3% among men who drank less than one cup of coffee per day.

The association between increased coffee intake and reduced risk of gout was independent of dietary factors and other variables including body mass index, age, hypertension, alcohol consumption, diuretic use, and chronic renal failure. No significant associations were found between total caffeine intake and risk for gout, and there was no apparent effect on gout risk for men who consumed caffeine from noncoffee sources, the researchers noted.

A modest association was noted between decaffeinated coffee consumption and a reduced risk for gout (a 27% reduction in men who drank at least four cups per day), but tea consumption was not associated with a reduced risk.

Because individuals can develop a tolerance for caffeine over time with respect to variables such as blood pressure and heart rate, long-term caffeine intake alone may not have a significant effect on the risk for gout, the researchers noted.

The investigation was limited by its observational nature, and the findings may not be generalizable to women, they added.

The study was sponsored in part by TAP Pharmaceutical Products Inc.

Dr. Choi has served on the advisory boards of Savient Pharmaceuticals Inc. and TAP.

ELSEVIER GLOBAL MEDICAL NEWS

Men who drank one to three cups per day cut their gout risk by 8%. Lynda Banzi/Elsevier Global Medical News

Drinking multiple cups of coffee each day may reduce the risk of gout in men, according to data from a prospective study of nearly 50,000 men.

Studies of coffee's effects on the body are important for public health, because so many people drink so much of it, wrote Dr. Hyon K. Choi of the University of British Columbia, Vancouver, and colleagues. “More than 50% of Americans drink coffee,” they noted, and the average per capita intake is approximately two cups per day.

Coffee is a major source of the phenol known as chlorogenic acid, which is a very powerful antioxidant (Arthritis Rheum. 2007;56:2049–55). Data from previous studies suggest that chlorogenic acid may reduce plasma glucose concentrations and interact with other antioxidants that are present in coffee to reduce oxidative stress and, consequently, reduce the risk of developing gout.

Other components of coffee may also play a role in reducing gout risk by affecting insulin resistance.

To determine the relationship between coffee consumption and gout, the investigators studied 45,869 adult men with no baseline history of gout. The men's coffee consumption was assessed at 4-year intervals over a 12-year follow-up period using a validated questionnaire. An additional questionnaire was used to determine whether the men met the American College of Rheumatology's criteria for gout.

The researchers identified 757 confirmed incident cases of gout, and found that the risk for gout was 59% lower in men who drank six or more cups of coffee per day and 40% lower among men who drank four to five cups of coffee per day.

The risk reduction was 8% among men who drank one to three cups of coffee per day, and 3% among men who drank less than one cup of coffee per day.

The association between increased coffee intake and reduced risk of gout was independent of dietary factors and other variables including body mass index, age, hypertension, alcohol consumption, diuretic use, and chronic renal failure. No significant associations were found between total caffeine intake and risk for gout, and there was no apparent effect on gout risk for men who consumed caffeine from noncoffee sources, the researchers noted.

A modest association was noted between decaffeinated coffee consumption and a reduced risk for gout (a 27% reduction in men who drank at least four cups per day), but tea consumption was not associated with a reduced risk.

Because individuals can develop a tolerance for caffeine over time with respect to variables such as blood pressure and heart rate, long-term caffeine intake alone may not have a significant effect on the risk for gout, the researchers noted.

The investigation was limited by its observational nature, and the findings may not be generalizable to women, they added.

The study was sponsored in part by TAP Pharmaceutical Products Inc.

Dr. Choi has served on the advisory boards of Savient Pharmaceuticals Inc. and TAP.

ELSEVIER GLOBAL MEDICAL NEWS

Men who drank one to three cups per day cut their gout risk by 8%. Lynda Banzi/Elsevier Global Medical News

Drinking multiple cups of coffee each day may reduce the risk of gout in men, according to data from a prospective study of nearly 50,000 men.

Studies of coffee's effects on the body are important for public health, because so many people drink so much of it, wrote Dr. Hyon K. Choi of the University of British Columbia, Vancouver, and colleagues. “More than 50% of Americans drink coffee,” they noted, and the average per capita intake is approximately two cups per day.

Coffee is a major source of the phenol known as chlorogenic acid, which is a very powerful antioxidant (Arthritis Rheum. 2007;56:2049–55). Data from previous studies suggest that chlorogenic acid may reduce plasma glucose concentrations and interact with other antioxidants that are present in coffee to reduce oxidative stress and, consequently, reduce the risk of developing gout.

Other components of coffee may also play a role in reducing gout risk by affecting insulin resistance.

To determine the relationship between coffee consumption and gout, the investigators studied 45,869 adult men with no baseline history of gout. The men's coffee consumption was assessed at 4-year intervals over a 12-year follow-up period using a validated questionnaire. An additional questionnaire was used to determine whether the men met the American College of Rheumatology's criteria for gout.

The researchers identified 757 confirmed incident cases of gout, and found that the risk for gout was 59% lower in men who drank six or more cups of coffee per day and 40% lower among men who drank four to five cups of coffee per day.

The risk reduction was 8% among men who drank one to three cups of coffee per day, and 3% among men who drank less than one cup of coffee per day.

The association between increased coffee intake and reduced risk of gout was independent of dietary factors and other variables including body mass index, age, hypertension, alcohol consumption, diuretic use, and chronic renal failure. No significant associations were found between total caffeine intake and risk for gout, and there was no apparent effect on gout risk for men who consumed caffeine from noncoffee sources, the researchers noted.

A modest association was noted between decaffeinated coffee consumption and a reduced risk for gout (a 27% reduction in men who drank at least four cups per day), but tea consumption was not associated with a reduced risk.

Because individuals can develop a tolerance for caffeine over time with respect to variables such as blood pressure and heart rate, long-term caffeine intake alone may not have a significant effect on the risk for gout, the researchers noted.

The investigation was limited by its observational nature, and the findings may not be generalizable to women, they added.

The study was sponsored in part by TAP Pharmaceutical Products Inc.

Dr. Choi has served on the advisory boards of Savient Pharmaceuticals Inc. and TAP.

ELSEVIER GLOBAL MEDICAL NEWS

Men who drank one to three cups per day cut their gout risk by 8%. Lynda Banzi/Elsevier Global Medical News

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

NEW YORK — Replacing the enzyme uricase may offer a new means of treating intractable gout.

Uricase—present in most mammals but lacking in certain primates since the Miocene era, when three mutations in the uricase gene rendered it inoperative—is responsible for breaking down uric acid to the soluble and easily excreted compound allantoin as a final step in the catabolism of purines. Without this enzyme hyperuricemia can, and does, develop in humans, chimpanzees, gorillas, orangutans, and gibbons, Dr. Michael Pillinger said at a rheumatology meeting sponsored by New York University.

Studies are evaluating the possibility of giving a pegylated, recombinant form of uricase to patients whose urate levels are not controlled with conventional antigout therapies. In a phase I trial that included 24 patients, the mean plasma urate concentration fell from 11.1 mg/dL to 1 mg/dL within 24–72 hours after intravenous administration of 4–12 mg pegylated uricase (Arthritis Rheum. 2007;56:1021–8).

After a 40-year hiatus during which few advances occurred in treatment or understanding of the disease, novel approaches to the treatment of gout also are being evaluated. In a recent report, the interleukin-1 inhibitor anakinra was administered to 10 patients with gout that was unresponsive to conventional anti-inflammatory drugs. After only three 100-mg doses of the drug, all 10 patients responded rapidly, with a 79% mean reduction in pain (Arthritis Res. Ther. 2007;9:R28 [Epub doi:10.1186/ar2143]).

Teleologic insights into gout's origins also are emerging, with consideration of questions about why uric acid should have been conserved through evolution at all, and why it is present in higher levels in humans and other primates than in other mammals, Dr. Pillinger said.

An explanation for evolutionary conservation of uric acid can be seen in the process of vaccination, where an adjuvant is needed to trigger the innate immune system to respond to the presence of a foreign antigen and overcome tolerance. Freund's adjuvant, for example, contains mycobacterial debris that provides this stimulus. Mammalian cell debris also can be used in an adjuvant capacity.

But there may be another means of providing the adjuvant stimulation, through endogenous “danger” signals from distressed or injured cells, a theory proposed by Dr. Polly Metzinger of the National Institute of Allergy and Infectious Diseases. In this hypothesis, infection or other cellular injury causes the secretion of some cellular danger signal that stimulates maturation of dendritic cells, upregulation of costimulatory molecules such as CD28, and antigen presentation. The result is an immunogenic response to an endogenous signal, said Dr. Pillinger of New York University, New York.

The precise nature of this danger signal remained unclear until a group of researchers from the University of Massachusetts conducted experiments in which they fractionated cytosol from ultraviolet-irradiated mouse fibroblasts. These researchers were able to identify a low-molecular-weight compound secreted in large amounts by dying cells as nucleotides break down—which turned out to be uric acid.

They then confirmed the role of uric acid by administering uricase to mice who had been immunized with uric acid and demonstrating a reduction in adjuvant activity. The authors wrote, “Up until now, [monosodium urate] crystals were viewed solely as pathogenic and the biological response to them as pathological. Our findings suggest that the formation of these crystals and the ensuing host response could have an important role in immune surveillance and the generation of adaptive immunity” (Nature 2003;425:516–21).

It also turned out that there was a threshold level for uric acid to begin upregulating CD28 on dendritic cells, at approximately 7 mg/dL uric acid—the level at which crystals begin to form. “Nature seems to have evolved this system, including a safety threshold, to play an important role in cell damage and the immune response,” said Dr. Pillinger, who is also chief of rheumatology at the Veterans Administration Hospital and director of medical education, Hospital for Special Surgery, New York.

Support for the danger signal hypothesis also has been demonstrated in a mouse model, where uric acid levels were elevated during tumor rejection, and rejection was delayed if uric acid was inhibited by the administration of allopurinol or uricase (Cancer Res. 2004;64:5059–62).

“Another question is why we have so much more uric acid than other mammals,” he said. Dogs and cats, for example, typically have levels of approximately 1 mg/dL, compared with the 5 or 6 mg/dL in normouricemic humans.

An answer to this question, if somewhat speculative, can be found in mutations of the uricase gene that occurred between 10 and 20 million years ago, at a time when many species of primates became extinct. Fossil records suggest that the primate diet at that time, consisting largely of fruit and grasses, was extremely low in salt, at approximately 0.6 g sodium chloride per day. In effect, vegetarian mammals were in a dietary hypotensive crisis that could be most problematic for those who had evolved to stand upright, Dr. Pillinger said.

Texas nephrologist Dr. Richard J. Johnson, who developed this hypothesis, said, “The uricase mutation may have provided an evolutionary advantage to early hominoids by maintaining blood pressure under the low sodium dietary conditions of that period” (Hypertension 2003;41:1183–90).

An association of gout with elevated blood pressure has long been noted, but these new findings suggest a causative role for hyperuricemia in hypertension, Dr. Pillinger said. One study of five adolescents with essential hypertension found that aggressive treatment with allopurinol normalized their blood pressure. Whether a causal link with uric acid can be found in all patients with hypertension remains to be seen but is intriguing, he said. A blinded trial investigating this question is currently underway.

Uric acid crystals in the urine of a patient with gout. After decades of inactivity, treatment advances are on the horizon. ©Bostwick Laboratories

NEW YORK — Replacing the enzyme uricase may offer a new means of treating intractable gout.

Uricase—present in most mammals but lacking in certain primates since the Miocene era, when three mutations in the uricase gene rendered it inoperative—is responsible for breaking down uric acid to the soluble and easily excreted compound allantoin as a final step in the catabolism of purines. Without this enzyme hyperuricemia can, and does, develop in humans, chimpanzees, gorillas, orangutans, and gibbons, Dr. Michael Pillinger said at a rheumatology meeting sponsored by New York University.

Studies are evaluating the possibility of giving a pegylated, recombinant form of uricase to patients whose urate levels are not controlled with conventional antigout therapies. In a phase I trial that included 24 patients, the mean plasma urate concentration fell from 11.1 mg/dL to 1 mg/dL within 24–72 hours after intravenous administration of 4–12 mg pegylated uricase (Arthritis Rheum. 2007;56:1021–8).

After a 40-year hiatus during which few advances occurred in treatment or understanding of the disease, novel approaches to the treatment of gout also are being evaluated. In a recent report, the interleukin-1 inhibitor anakinra was administered to 10 patients with gout that was unresponsive to conventional anti-inflammatory drugs. After only three 100-mg doses of the drug, all 10 patients responded rapidly, with a 79% mean reduction in pain (Arthritis Res. Ther. 2007;9:R28 [Epub doi:10.1186/ar2143]).

Teleologic insights into gout's origins also are emerging, with consideration of questions about why uric acid should have been conserved through evolution at all, and why it is present in higher levels in humans and other primates than in other mammals, Dr. Pillinger said.

An explanation for evolutionary conservation of uric acid can be seen in the process of vaccination, where an adjuvant is needed to trigger the innate immune system to respond to the presence of a foreign antigen and overcome tolerance. Freund's adjuvant, for example, contains mycobacterial debris that provides this stimulus. Mammalian cell debris also can be used in an adjuvant capacity.

But there may be another means of providing the adjuvant stimulation, through endogenous “danger” signals from distressed or injured cells, a theory proposed by Dr. Polly Metzinger of the National Institute of Allergy and Infectious Diseases. In this hypothesis, infection or other cellular injury causes the secretion of some cellular danger signal that stimulates maturation of dendritic cells, upregulation of costimulatory molecules such as CD28, and antigen presentation. The result is an immunogenic response to an endogenous signal, said Dr. Pillinger of New York University, New York.

The precise nature of this danger signal remained unclear until a group of researchers from the University of Massachusetts conducted experiments in which they fractionated cytosol from ultraviolet-irradiated mouse fibroblasts. These researchers were able to identify a low-molecular-weight compound secreted in large amounts by dying cells as nucleotides break down—which turned out to be uric acid.

They then confirmed the role of uric acid by administering uricase to mice who had been immunized with uric acid and demonstrating a reduction in adjuvant activity. The authors wrote, “Up until now, [monosodium urate] crystals were viewed solely as pathogenic and the biological response to them as pathological. Our findings suggest that the formation of these crystals and the ensuing host response could have an important role in immune surveillance and the generation of adaptive immunity” (Nature 2003;425:516–21).

It also turned out that there was a threshold level for uric acid to begin upregulating CD28 on dendritic cells, at approximately 7 mg/dL uric acid—the level at which crystals begin to form. “Nature seems to have evolved this system, including a safety threshold, to play an important role in cell damage and the immune response,” said Dr. Pillinger, who is also chief of rheumatology at the Veterans Administration Hospital and director of medical education, Hospital for Special Surgery, New York.

Support for the danger signal hypothesis also has been demonstrated in a mouse model, where uric acid levels were elevated during tumor rejection, and rejection was delayed if uric acid was inhibited by the administration of allopurinol or uricase (Cancer Res. 2004;64:5059–62).

“Another question is why we have so much more uric acid than other mammals,” he said. Dogs and cats, for example, typically have levels of approximately 1 mg/dL, compared with the 5 or 6 mg/dL in normouricemic humans.

An answer to this question, if somewhat speculative, can be found in mutations of the uricase gene that occurred between 10 and 20 million years ago, at a time when many species of primates became extinct. Fossil records suggest that the primate diet at that time, consisting largely of fruit and grasses, was extremely low in salt, at approximately 0.6 g sodium chloride per day. In effect, vegetarian mammals were in a dietary hypotensive crisis that could be most problematic for those who had evolved to stand upright, Dr. Pillinger said.

Texas nephrologist Dr. Richard J. Johnson, who developed this hypothesis, said, “The uricase mutation may have provided an evolutionary advantage to early hominoids by maintaining blood pressure under the low sodium dietary conditions of that period” (Hypertension 2003;41:1183–90).

An association of gout with elevated blood pressure has long been noted, but these new findings suggest a causative role for hyperuricemia in hypertension, Dr. Pillinger said. One study of five adolescents with essential hypertension found that aggressive treatment with allopurinol normalized their blood pressure. Whether a causal link with uric acid can be found in all patients with hypertension remains to be seen but is intriguing, he said. A blinded trial investigating this question is currently underway.

Uric acid crystals in the urine of a patient with gout. After decades of inactivity, treatment advances are on the horizon. ©Bostwick Laboratories

NEW YORK — Replacing the enzyme uricase may offer a new means of treating intractable gout.

Uricase—present in most mammals but lacking in certain primates since the Miocene era, when three mutations in the uricase gene rendered it inoperative—is responsible for breaking down uric acid to the soluble and easily excreted compound allantoin as a final step in the catabolism of purines. Without this enzyme hyperuricemia can, and does, develop in humans, chimpanzees, gorillas, orangutans, and gibbons, Dr. Michael Pillinger said at a rheumatology meeting sponsored by New York University.

Studies are evaluating the possibility of giving a pegylated, recombinant form of uricase to patients whose urate levels are not controlled with conventional antigout therapies. In a phase I trial that included 24 patients, the mean plasma urate concentration fell from 11.1 mg/dL to 1 mg/dL within 24–72 hours after intravenous administration of 4–12 mg pegylated uricase (Arthritis Rheum. 2007;56:1021–8).

After a 40-year hiatus during which few advances occurred in treatment or understanding of the disease, novel approaches to the treatment of gout also are being evaluated. In a recent report, the interleukin-1 inhibitor anakinra was administered to 10 patients with gout that was unresponsive to conventional anti-inflammatory drugs. After only three 100-mg doses of the drug, all 10 patients responded rapidly, with a 79% mean reduction in pain (Arthritis Res. Ther. 2007;9:R28 [Epub doi:10.1186/ar2143]).

Teleologic insights into gout's origins also are emerging, with consideration of questions about why uric acid should have been conserved through evolution at all, and why it is present in higher levels in humans and other primates than in other mammals, Dr. Pillinger said.

An explanation for evolutionary conservation of uric acid can be seen in the process of vaccination, where an adjuvant is needed to trigger the innate immune system to respond to the presence of a foreign antigen and overcome tolerance. Freund's adjuvant, for example, contains mycobacterial debris that provides this stimulus. Mammalian cell debris also can be used in an adjuvant capacity.

But there may be another means of providing the adjuvant stimulation, through endogenous “danger” signals from distressed or injured cells, a theory proposed by Dr. Polly Metzinger of the National Institute of Allergy and Infectious Diseases. In this hypothesis, infection or other cellular injury causes the secretion of some cellular danger signal that stimulates maturation of dendritic cells, upregulation of costimulatory molecules such as CD28, and antigen presentation. The result is an immunogenic response to an endogenous signal, said Dr. Pillinger of New York University, New York.

The precise nature of this danger signal remained unclear until a group of researchers from the University of Massachusetts conducted experiments in which they fractionated cytosol from ultraviolet-irradiated mouse fibroblasts. These researchers were able to identify a low-molecular-weight compound secreted in large amounts by dying cells as nucleotides break down—which turned out to be uric acid.

They then confirmed the role of uric acid by administering uricase to mice who had been immunized with uric acid and demonstrating a reduction in adjuvant activity. The authors wrote, “Up until now, [monosodium urate] crystals were viewed solely as pathogenic and the biological response to them as pathological. Our findings suggest that the formation of these crystals and the ensuing host response could have an important role in immune surveillance and the generation of adaptive immunity” (Nature 2003;425:516–21).

It also turned out that there was a threshold level for uric acid to begin upregulating CD28 on dendritic cells, at approximately 7 mg/dL uric acid—the level at which crystals begin to form. “Nature seems to have evolved this system, including a safety threshold, to play an important role in cell damage and the immune response,” said Dr. Pillinger, who is also chief of rheumatology at the Veterans Administration Hospital and director of medical education, Hospital for Special Surgery, New York.

Support for the danger signal hypothesis also has been demonstrated in a mouse model, where uric acid levels were elevated during tumor rejection, and rejection was delayed if uric acid was inhibited by the administration of allopurinol or uricase (Cancer Res. 2004;64:5059–62).

“Another question is why we have so much more uric acid than other mammals,” he said. Dogs and cats, for example, typically have levels of approximately 1 mg/dL, compared with the 5 or 6 mg/dL in normouricemic humans.

An answer to this question, if somewhat speculative, can be found in mutations of the uricase gene that occurred between 10 and 20 million years ago, at a time when many species of primates became extinct. Fossil records suggest that the primate diet at that time, consisting largely of fruit and grasses, was extremely low in salt, at approximately 0.6 g sodium chloride per day. In effect, vegetarian mammals were in a dietary hypotensive crisis that could be most problematic for those who had evolved to stand upright, Dr. Pillinger said.

Texas nephrologist Dr. Richard J. Johnson, who developed this hypothesis, said, “The uricase mutation may have provided an evolutionary advantage to early hominoids by maintaining blood pressure under the low sodium dietary conditions of that period” (Hypertension 2003;41:1183–90).

An association of gout with elevated blood pressure has long been noted, but these new findings suggest a causative role for hyperuricemia in hypertension, Dr. Pillinger said. One study of five adolescents with essential hypertension found that aggressive treatment with allopurinol normalized their blood pressure. Whether a causal link with uric acid can be found in all patients with hypertension remains to be seen but is intriguing, he said. A blinded trial investigating this question is currently underway.

Uric acid crystals in the urine of a patient with gout. After decades of inactivity, treatment advances are on the horizon. ©Bostwick Laboratories

Osteoarthritis and psoriatic arthritis do share some simple clinical characteristics. Both commonly affect the spine. More importantly, in the hand both osteoarthritis and psoriatic arthritis show a very strong tendency to afflict the distal interphalangeal joints.

“So when you look at it from a very simplistic, clinical perspective, there are strong similarities between psoriatic arthritis and osteoarthritis,” said Dr. Dennis McGonagle of the University of Leeds (England).

Dr. McGonagle, Dr. Ai Lyn Tan, and their colleagues have used high-resolution magnetic resonance imaging to look more closely at how psoriatic arthritis (PsA) and osteoarthritis (OA) affect the distal interphalangeal (DIP) joints (Arthritis Rheum. 2006;54:1328–33). This type of imaging involves conventional 1.5-T MRI scanners coupled with coils that are designed specially for hand imaging that give very high quality images.

Seeing patients with definite OA or PsA, “the most striking abnormalities that we saw were related to the ligaments and the adjacent attachments or entheses,” he said.

Ligament and tendon insertions were involved in patients with either disease; however, enhancement on scanning (evidence of inflammation) of these structures was greater in patients with PsA. In these patients, ligament origins/insertions and extensor tendon insertions appeared to be the epicenter of the inflammatory response with diffuse involvement of adjacent structures. While ligaments tended to be thickened and abnormal in patients with OA, even when the cartilage appeared normal, there was less postcontrast enhancement compared with patients in the PsA group.

The ligaments are sites of very high mechanical stress, particularly in small joints. Both OA and PsA “are localized to sites of very high mechanical stress and 'wear and tear.' A simplistic explanation is that this mechanical stress leads to joint degeneration in osteoarthritis but joint inflammation in psoriatic arthritis,” said Dr. McGonagle.

“Inflammation is well recognized in osteoarthritis but it's thought to be secondary to mechanical factors. Psoriatic arthritis is much more an inflammatory disease. What we speculate is that normal or low levels of microdamage and repair of joints—that damage is misinterpreted by the immune system as some sort of severe damage and then you get this autoimmune reaction.”

There is evidence that most normal people walk around all of the time with low-grade microdamage of the joints, based on studies of insertions and ligaments, carried out in conjunction with Dr. Mike Benjamin of Cardiff University, Wales.

However, in the psoriatic phenotype, the body may misinterpret that damage, resulting in an overexaggerated immune response. After age 50 years, the cumulative microdamage to the joints becomes more pronounced, resulting in the secondary and less severe inflammation that accompanies wear and tear. This would fit with known data that PsA is a disease of younger individuals, while OA is a disease of older individuals said Dr. McGonagle.

It's unclear why the immune system is inadvertently activated in patients with PsA or why cumulative microdamage results in OA in some older individuals but not all. However, the hypothesis that microdamage may trigger both PsA and OA provides fertile ground for research. It is especially relevant for an appreciation that inflammation in the joints may not be primarily the result of immune system malfunction but could be a result of some intrinsic problem with the joints' response to normal locomotion.

Joint space in the distal interphalangeal PsA joint (left) is well preserved versus the OA joint (right). Photos courtesy Dr. Dennis McGonagle/Dr. Ai Lyn Tan

Osteoarthritis and psoriatic arthritis do share some simple clinical characteristics. Both commonly affect the spine. More importantly, in the hand both osteoarthritis and psoriatic arthritis show a very strong tendency to afflict the distal interphalangeal joints.

“So when you look at it from a very simplistic, clinical perspective, there are strong similarities between psoriatic arthritis and osteoarthritis,” said Dr. Dennis McGonagle of the University of Leeds (England).

Dr. McGonagle, Dr. Ai Lyn Tan, and their colleagues have used high-resolution magnetic resonance imaging to look more closely at how psoriatic arthritis (PsA) and osteoarthritis (OA) affect the distal interphalangeal (DIP) joints (Arthritis Rheum. 2006;54:1328–33). This type of imaging involves conventional 1.5-T MRI scanners coupled with coils that are designed specially for hand imaging that give very high quality images.

Seeing patients with definite OA or PsA, “the most striking abnormalities that we saw were related to the ligaments and the adjacent attachments or entheses,” he said.

Ligament and tendon insertions were involved in patients with either disease; however, enhancement on scanning (evidence of inflammation) of these structures was greater in patients with PsA. In these patients, ligament origins/insertions and extensor tendon insertions appeared to be the epicenter of the inflammatory response with diffuse involvement of adjacent structures. While ligaments tended to be thickened and abnormal in patients with OA, even when the cartilage appeared normal, there was less postcontrast enhancement compared with patients in the PsA group.

The ligaments are sites of very high mechanical stress, particularly in small joints. Both OA and PsA “are localized to sites of very high mechanical stress and 'wear and tear.' A simplistic explanation is that this mechanical stress leads to joint degeneration in osteoarthritis but joint inflammation in psoriatic arthritis,” said Dr. McGonagle.

“Inflammation is well recognized in osteoarthritis but it's thought to be secondary to mechanical factors. Psoriatic arthritis is much more an inflammatory disease. What we speculate is that normal or low levels of microdamage and repair of joints—that damage is misinterpreted by the immune system as some sort of severe damage and then you get this autoimmune reaction.”

There is evidence that most normal people walk around all of the time with low-grade microdamage of the joints, based on studies of insertions and ligaments, carried out in conjunction with Dr. Mike Benjamin of Cardiff University, Wales.

However, in the psoriatic phenotype, the body may misinterpret that damage, resulting in an overexaggerated immune response. After age 50 years, the cumulative microdamage to the joints becomes more pronounced, resulting in the secondary and less severe inflammation that accompanies wear and tear. This would fit with known data that PsA is a disease of younger individuals, while OA is a disease of older individuals said Dr. McGonagle.

It's unclear why the immune system is inadvertently activated in patients with PsA or why cumulative microdamage results in OA in some older individuals but not all. However, the hypothesis that microdamage may trigger both PsA and OA provides fertile ground for research. It is especially relevant for an appreciation that inflammation in the joints may not be primarily the result of immune system malfunction but could be a result of some intrinsic problem with the joints' response to normal locomotion.

Joint space in the distal interphalangeal PsA joint (left) is well preserved versus the OA joint (right). Photos courtesy Dr. Dennis McGonagle/Dr. Ai Lyn Tan

Osteoarthritis and psoriatic arthritis do share some simple clinical characteristics. Both commonly affect the spine. More importantly, in the hand both osteoarthritis and psoriatic arthritis show a very strong tendency to afflict the distal interphalangeal joints.

“So when you look at it from a very simplistic, clinical perspective, there are strong similarities between psoriatic arthritis and osteoarthritis,” said Dr. Dennis McGonagle of the University of Leeds (England).

Dr. McGonagle, Dr. Ai Lyn Tan, and their colleagues have used high-resolution magnetic resonance imaging to look more closely at how psoriatic arthritis (PsA) and osteoarthritis (OA) affect the distal interphalangeal (DIP) joints (Arthritis Rheum. 2006;54:1328–33). This type of imaging involves conventional 1.5-T MRI scanners coupled with coils that are designed specially for hand imaging that give very high quality images.

Seeing patients with definite OA or PsA, “the most striking abnormalities that we saw were related to the ligaments and the adjacent attachments or entheses,” he said.

Ligament and tendon insertions were involved in patients with either disease; however, enhancement on scanning (evidence of inflammation) of these structures was greater in patients with PsA. In these patients, ligament origins/insertions and extensor tendon insertions appeared to be the epicenter of the inflammatory response with diffuse involvement of adjacent structures. While ligaments tended to be thickened and abnormal in patients with OA, even when the cartilage appeared normal, there was less postcontrast enhancement compared with patients in the PsA group.

The ligaments are sites of very high mechanical stress, particularly in small joints. Both OA and PsA “are localized to sites of very high mechanical stress and 'wear and tear.' A simplistic explanation is that this mechanical stress leads to joint degeneration in osteoarthritis but joint inflammation in psoriatic arthritis,” said Dr. McGonagle.

“Inflammation is well recognized in osteoarthritis but it's thought to be secondary to mechanical factors. Psoriatic arthritis is much more an inflammatory disease. What we speculate is that normal or low levels of microdamage and repair of joints—that damage is misinterpreted by the immune system as some sort of severe damage and then you get this autoimmune reaction.”

There is evidence that most normal people walk around all of the time with low-grade microdamage of the joints, based on studies of insertions and ligaments, carried out in conjunction with Dr. Mike Benjamin of Cardiff University, Wales.

However, in the psoriatic phenotype, the body may misinterpret that damage, resulting in an overexaggerated immune response. After age 50 years, the cumulative microdamage to the joints becomes more pronounced, resulting in the secondary and less severe inflammation that accompanies wear and tear. This would fit with known data that PsA is a disease of younger individuals, while OA is a disease of older individuals said Dr. McGonagle.

It's unclear why the immune system is inadvertently activated in patients with PsA or why cumulative microdamage results in OA in some older individuals but not all. However, the hypothesis that microdamage may trigger both PsA and OA provides fertile ground for research. It is especially relevant for an appreciation that inflammation in the joints may not be primarily the result of immune system malfunction but could be a result of some intrinsic problem with the joints' response to normal locomotion.

Joint space in the distal interphalangeal PsA joint (left) is well preserved versus the OA joint (right). Photos courtesy Dr. Dennis McGonagle/Dr. Ai Lyn Tan

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

Patients with rheumatoid arthritis exhibited increased body fat for a given body mass index when compared with healthy controls in a recent study. This suggests that standard BMI cut-off points in those patients with rheumatoid arthritis should be reduced to more accurately reflect risk for cardiovascular disease, according to Dr. Antonios Stavropoulos-Kalinoglou of the University of Wolverhampton's Research Institute in Healthcare Science, England, and his associates.

BMI does not distinguish between fat and lean body mass when it uses height and weight to measure body mass. As a result, individuals with the same height and weight, but different muscle content, may have the same BMI but different levels of body fat. This shortcoming should be taken into consideration when determining risk for cardiovascular disease, especially with rheumatoid arthritis (RA) patients, who often experience involuntary loss of lean body mass and an increase of fat mass, according to the researchers (Ann Rheum Dis. 2007 Feb. 8 [Epub doi:10.1136/ ard.2006.060319]).

The study included 299 individuals: 174 with RA, 43 with osteoarthritis of the hip or knee, and 82 healthy, medication-free controls by self-report. Body fat was assessed in all participants by bioelectrical impedance using a body analyzer. BMI was calculated based on measured height and weight.

Body fat and BMI differed significantly between those with RA and healthy controls, judging from analyses of covariance findings. For a given BMI, patients with RA showed significantly increased levels of body fat percentage compared with the healthy participants. Patients with RA also showed BMI levels reduced by 1.83 kg/m

The study also found that when the widely accepted BMI cut-offs of 25 kg/m

These misclassifications were corrected when the proposed rheumatoid arthritis-specific BMI cut-offs of 23 kg/m

However, body fat percentage is a better way to assess fat measurement and risk for cardiovascular disease, according to the investigators. They developed a predictive model as part of the study to calculate body fat of RA patients without relying on the sophisticated equipment often needed to measure body fat.

The model, which uses BMI, age, gender, and disease status to determine body fat, was validated using Limits of Agreement Analysis against measured body fat in a group of 342 patients with RA. In that validation group, the model predicted body fat to be 0.4% higher than actual levels, but results were within suitable limits and the cross-validation was “reassuring,” according to the investigators.

Patients with rheumatoid arthritis exhibited increased body fat for a given body mass index when compared with healthy controls in a recent study. This suggests that standard BMI cut-off points in those patients with rheumatoid arthritis should be reduced to more accurately reflect risk for cardiovascular disease, according to Dr. Antonios Stavropoulos-Kalinoglou of the University of Wolverhampton's Research Institute in Healthcare Science, England, and his associates.

BMI does not distinguish between fat and lean body mass when it uses height and weight to measure body mass. As a result, individuals with the same height and weight, but different muscle content, may have the same BMI but different levels of body fat. This shortcoming should be taken into consideration when determining risk for cardiovascular disease, especially with rheumatoid arthritis (RA) patients, who often experience involuntary loss of lean body mass and an increase of fat mass, according to the researchers (Ann Rheum Dis. 2007 Feb. 8 [Epub doi:10.1136/ ard.2006.060319]).

The study included 299 individuals: 174 with RA, 43 with osteoarthritis of the hip or knee, and 82 healthy, medication-free controls by self-report. Body fat was assessed in all participants by bioelectrical impedance using a body analyzer. BMI was calculated based on measured height and weight.

Body fat and BMI differed significantly between those with RA and healthy controls, judging from analyses of covariance findings. For a given BMI, patients with RA showed significantly increased levels of body fat percentage compared with the healthy participants. Patients with RA also showed BMI levels reduced by 1.83 kg/m

The study also found that when the widely accepted BMI cut-offs of 25 kg/m

These misclassifications were corrected when the proposed rheumatoid arthritis-specific BMI cut-offs of 23 kg/m

However, body fat percentage is a better way to assess fat measurement and risk for cardiovascular disease, according to the investigators. They developed a predictive model as part of the study to calculate body fat of RA patients without relying on the sophisticated equipment often needed to measure body fat.

The model, which uses BMI, age, gender, and disease status to determine body fat, was validated using Limits of Agreement Analysis against measured body fat in a group of 342 patients with RA. In that validation group, the model predicted body fat to be 0.4% higher than actual levels, but results were within suitable limits and the cross-validation was “reassuring,” according to the investigators.

Patients with rheumatoid arthritis exhibited increased body fat for a given body mass index when compared with healthy controls in a recent study. This suggests that standard BMI cut-off points in those patients with rheumatoid arthritis should be reduced to more accurately reflect risk for cardiovascular disease, according to Dr. Antonios Stavropoulos-Kalinoglou of the University of Wolverhampton's Research Institute in Healthcare Science, England, and his associates.

BMI does not distinguish between fat and lean body mass when it uses height and weight to measure body mass. As a result, individuals with the same height and weight, but different muscle content, may have the same BMI but different levels of body fat. This shortcoming should be taken into consideration when determining risk for cardiovascular disease, especially with rheumatoid arthritis (RA) patients, who often experience involuntary loss of lean body mass and an increase of fat mass, according to the researchers (Ann Rheum Dis. 2007 Feb. 8 [Epub doi:10.1136/ ard.2006.060319]).

The study included 299 individuals: 174 with RA, 43 with osteoarthritis of the hip or knee, and 82 healthy, medication-free controls by self-report. Body fat was assessed in all participants by bioelectrical impedance using a body analyzer. BMI was calculated based on measured height and weight.

Body fat and BMI differed significantly between those with RA and healthy controls, judging from analyses of covariance findings. For a given BMI, patients with RA showed significantly increased levels of body fat percentage compared with the healthy participants. Patients with RA also showed BMI levels reduced by 1.83 kg/m

The study also found that when the widely accepted BMI cut-offs of 25 kg/m

These misclassifications were corrected when the proposed rheumatoid arthritis-specific BMI cut-offs of 23 kg/m

However, body fat percentage is a better way to assess fat measurement and risk for cardiovascular disease, according to the investigators. They developed a predictive model as part of the study to calculate body fat of RA patients without relying on the sophisticated equipment often needed to measure body fat.

The model, which uses BMI, age, gender, and disease status to determine body fat, was validated using Limits of Agreement Analysis against measured body fat in a group of 342 patients with RA. In that validation group, the model predicted body fat to be 0.4% higher than actual levels, but results were within suitable limits and the cross-validation was “reassuring,” according to the investigators.

SNOWMASS, COLO. — Unicompartmental knee and total knee arthroplasties provide good results in carefully selected patients, said Dr. Thomas S. Thornhill, chairman of orthopedic surgery at Brig-ham and Women's Hospital in Boston, at a symposium sponsored by the American College of Rheumatology.

UKA is indicated for degenerative arthritis in patients who are not good candidates for osteotomy or total knee replacement regardless of age. UKA might be the first option to consider in a younger patient because “it's much easier to convert a [UKA] to a total [knee arthroplasty] than a total to another total,” he said.

He estimates that the revision rate for UKAs at his facility is about 1% per year. Most problems are related to wear and progression of disease in the lateral compartment. UKA can be performed with a small incision, involves a shorter hospital stay, lower cost, and more rapid rehabilitation than does a total knee replacement.

In their defense, TKA procedures that are cruciate sparing have good to excellent results at 10–15 years. The major problems with failure of TKA still are related to wear, loosening, and infection. “I would submit to you that most of these failures can be attributed to technical issues and patient selection,” said Dr. Thornhill.

The most common cause of failure is instability. Surgeons think they need to put the knee in loosely so it will bend and flex better. Instead the looseness creates shearing when the knee moves, he said.

Dr. Thornhill disclosed that he receives royalties from DePuy Inc. He also has received research grants from DePuy Inc., Biomet Inc., and Smith & Nephew.

SNOWMASS, COLO. — Unicompartmental knee and total knee arthroplasties provide good results in carefully selected patients, said Dr. Thomas S. Thornhill, chairman of orthopedic surgery at Brig-ham and Women's Hospital in Boston, at a symposium sponsored by the American College of Rheumatology.

UKA is indicated for degenerative arthritis in patients who are not good candidates for osteotomy or total knee replacement regardless of age. UKA might be the first option to consider in a younger patient because “it's much easier to convert a [UKA] to a total [knee arthroplasty] than a total to another total,” he said.

He estimates that the revision rate for UKAs at his facility is about 1% per year. Most problems are related to wear and progression of disease in the lateral compartment. UKA can be performed with a small incision, involves a shorter hospital stay, lower cost, and more rapid rehabilitation than does a total knee replacement.

In their defense, TKA procedures that are cruciate sparing have good to excellent results at 10–15 years. The major problems with failure of TKA still are related to wear, loosening, and infection. “I would submit to you that most of these failures can be attributed to technical issues and patient selection,” said Dr. Thornhill.

The most common cause of failure is instability. Surgeons think they need to put the knee in loosely so it will bend and flex better. Instead the looseness creates shearing when the knee moves, he said.

Dr. Thornhill disclosed that he receives royalties from DePuy Inc. He also has received research grants from DePuy Inc., Biomet Inc., and Smith & Nephew.

SNOWMASS, COLO. — Unicompartmental knee and total knee arthroplasties provide good results in carefully selected patients, said Dr. Thomas S. Thornhill, chairman of orthopedic surgery at Brig-ham and Women's Hospital in Boston, at a symposium sponsored by the American College of Rheumatology.

UKA is indicated for degenerative arthritis in patients who are not good candidates for osteotomy or total knee replacement regardless of age. UKA might be the first option to consider in a younger patient because “it's much easier to convert a [UKA] to a total [knee arthroplasty] than a total to another total,” he said.

He estimates that the revision rate for UKAs at his facility is about 1% per year. Most problems are related to wear and progression of disease in the lateral compartment. UKA can be performed with a small incision, involves a shorter hospital stay, lower cost, and more rapid rehabilitation than does a total knee replacement.

In their defense, TKA procedures that are cruciate sparing have good to excellent results at 10–15 years. The major problems with failure of TKA still are related to wear, loosening, and infection. “I would submit to you that most of these failures can be attributed to technical issues and patient selection,” said Dr. Thornhill.

The most common cause of failure is instability. Surgeons think they need to put the knee in loosely so it will bend and flex better. Instead the looseness creates shearing when the knee moves, he said.

Dr. Thornhill disclosed that he receives royalties from DePuy Inc. He also has received research grants from DePuy Inc., Biomet Inc., and Smith & Nephew.

Cartilage loss and bone marrow lesions are shown on sagittal image of the knee.

Moderate effusion and medial and lateral patella osteophytes as seen on axial view.

Cartilage loss with macerated remnants of medial meniscus on coronal image.

Effusion, lateral patella osteophyte, and lateral patella displacement are seen. Dr. David J. Hunter

Patellae that are positioned centrally in the trochlear groove and are not malaligned are thought to be less susceptible to the development of osteoarthritis. Patellae that are chronically poorly aligned can place excess stress on the articular surfaces of the patellofemoral (PF) joints and possibly promote knee degeneration.

Most studies of patellar malalignment have used x-rays of the knee in the lateral plane and skyline view. Few studies have taken advantage of the increased resolution and three-dimensional visualization afforded by magnetic resonance imaging. One reason is that although MRIs of the knee in flexion are more useful in evaluating PF alignment, clinical MRI of the knee is most commonly acquired with the knee extended in the supine position.

Dr. David J. Hunter, a rheumatologist, and his colleagues at Boston University recently compared a number of measures of patellofemoral (PF) malalignment with radiographic indices of osteoarthritis (OA)–the presence of joint space narrowing and osteophytes—in patients with symptomatic and radiographic knee OA (Arthritis Res. Ther. 2007;9:R26).

Study participants were part of the Boston Osteoarthritis of the Knee Study, a cross-sectional larger natural history study of symptomatic knee OA.

“Admittedly, identifying cause from a cross-sectional study is a little bit of a leap, but our belief is that patellar malalignment actually predisposes to these changes,” Dr. Hunter said in an interview.

Not only did the researchers find significant associations between PF malalignment and radiographic features of OA, they demonstrated that indices of patellar alignment can be measured easily on standard knee MRI.

Participants suspected of knee OA underwent a series of x-rays. Those with a definite osteophyte on any view in the symptomatic knee were eligible for the study. The researchers evaluated 213 patients—126 men (average age 68 years) and 87 women (average age 65 years).

MRI studies were performed with a 1.5-T magnet, and a positioning device was used to ensure uniformity of the extended knee position. The imaging protocol included sagittal spin-echo proton density-weighted and T2-weighted images and coronal and axial spin-echo fat-suppressed proton density-weighted and T2-weighted images.

Use of MRI allowed the researchers to evaluate several indices of patellofemoral alignment. “For some of the measures that we wanted to take of patellofemoral alignment, we would not be able to get them from radiographic films alone,” said Dr. Hunter, an assistant professor of medicine at Boston University. “The resolution and the different planes that can be acquired on MRI do provide advantages over standard x-ray.”

The researchers measured patellar alignment in the sagittal and transverse (axial) planes. In the sagittal plane, they measured the patellar length ratio (PLR).

To do so, they used the slice with clearly recognizable patellar margins and in which patellar bone volume appeared to be maximal. PLR was calculated as the ratio of patellar length to patellar ligament length. Patellar length was measured from the upper to the lower point of the inner surface of the patella—excluding osteophytes. Patellar ligament length was measured from the lower inner point of the patella to the highest point of the tibial tuberosity.

In the transverse plane, the researchers measured the trochlear depth (trochlear sulcus angle) and two indices describing patellar position (lateral patellar tilt angle and bisect offset of the patella). Sulcus angle (SA) is an indicator of femoral trochlear dysplasia, which is associated with PF OA and patellar instability. To measure SA, the researchers used the axial slice that referred to the proximal one-third of the femoral trochlear curve.

SA is the angle between two lines: one radiating from the lowest point of the trochlear sulcus along the lateral bony margin and the other from the lowest point of the trochlear sulcus along the medial bony margin.

For measurements of patellar alignment, the researchers used the axial slice that refers to the middle of the patella. The LPTA, which is the angle between the posterior condylar line and a line through the lateral interior bony margin of the patella, shows the angle of patellar inclination, which indicates the tightness or laxity of the lateral stabilizing mechanism of the patella.

Bisect offset (BO) indicates the lateral displacement of the patella in relation to the deepest part of the femoral sulcus. For the BO of the patella, the researchers used a line perpendicular to the posterior condylar line that runs through the lowest point of the femoral sulcus and up through the patella.

They then measured the distance between this line and the lateral border of the patella (a). They also measured the distance between this line and the medial border of the patella (b). BO was calculated as the formula: 100a/(a + b).

Participants had weight-bearing skyline radiography, and the x-rays were read by a rheumatologist who used a four-point scale to grade the presence of osteophytes in the medial and lateral parts of the patella and femur and the joint space narrowing in the medial and lateral parts of the PF joint.

There was a statistically significant association between PLR and both osteophytes and joint space narrowing in the lateral compartment. With increasing PLR, there was an increased risk of lateral joint space narrowing. A similar trend was found between increasing PLR and increasing lateral patellar osteophytosis. There was no significant association between PLR and indices of radiographic PF OA in the medial PF compartment.

SA showed a statistically significant association with medial joint space narrowing and lateral and medial patellar osteophytosis—with increasing SA, there was increased risk of medial joint space narrowing. LPTA showed a statistically significant association with joint space narrowing and osteophytosis of the lateral PF compartment. A more laterally displaced patella was positively associated with increased lateral joint space narrowing and also with lateral patellar osteophytosis. In contrast, lateral patella displacement was negatively associated with medial joint space narrowing—increased medial displacement of the patella was associated with medial joint space narrowing.

The findings suggest that alignment of the patella may be an important factor influencing PF joint degeneration, due to the aberrant distribution of forces with activity. “I think that the important message for clinicians here is that to date, the majority of people really haven't considered problems of malalignment of the patellofemoral joint as important features in patellofemoral osteoarthritis. This study suggests that they're strongly associated,” said Dr. Hunter.

The fact that MRI was performed with the knee placed in a supine position likely means that the findings from this analysis are conservative for measures that could potentially change with weight bearing (LPTA and BO).

Cartilage loss and bone marrow lesions are shown on sagittal image of the knee.

Moderate effusion and medial and lateral patella osteophytes as seen on axial view.

Cartilage loss with macerated remnants of medial meniscus on coronal image.

Effusion, lateral patella osteophyte, and lateral patella displacement are seen. Dr. David J. Hunter

Patellae that are positioned centrally in the trochlear groove and are not malaligned are thought to be less susceptible to the development of osteoarthritis. Patellae that are chronically poorly aligned can place excess stress on the articular surfaces of the patellofemoral (PF) joints and possibly promote knee degeneration.

Most studies of patellar malalignment have used x-rays of the knee in the lateral plane and skyline view. Few studies have taken advantage of the increased resolution and three-dimensional visualization afforded by magnetic resonance imaging. One reason is that although MRIs of the knee in flexion are more useful in evaluating PF alignment, clinical MRI of the knee is most commonly acquired with the knee extended in the supine position.

Dr. David J. Hunter, a rheumatologist, and his colleagues at Boston University recently compared a number of measures of patellofemoral (PF) malalignment with radiographic indices of osteoarthritis (OA)–the presence of joint space narrowing and osteophytes—in patients with symptomatic and radiographic knee OA (Arthritis Res. Ther. 2007;9:R26).

Study participants were part of the Boston Osteoarthritis of the Knee Study, a cross-sectional larger natural history study of symptomatic knee OA.

“Admittedly, identifying cause from a cross-sectional study is a little bit of a leap, but our belief is that patellar malalignment actually predisposes to these changes,” Dr. Hunter said in an interview.

Not only did the researchers find significant associations between PF malalignment and radiographic features of OA, they demonstrated that indices of patellar alignment can be measured easily on standard knee MRI.

Participants suspected of knee OA underwent a series of x-rays. Those with a definite osteophyte on any view in the symptomatic knee were eligible for the study. The researchers evaluated 213 patients—126 men (average age 68 years) and 87 women (average age 65 years).

MRI studies were performed with a 1.5-T magnet, and a positioning device was used to ensure uniformity of the extended knee position. The imaging protocol included sagittal spin-echo proton density-weighted and T2-weighted images and coronal and axial spin-echo fat-suppressed proton density-weighted and T2-weighted images.

Use of MRI allowed the researchers to evaluate several indices of patellofemoral alignment. “For some of the measures that we wanted to take of patellofemoral alignment, we would not be able to get them from radiographic films alone,” said Dr. Hunter, an assistant professor of medicine at Boston University. “The resolution and the different planes that can be acquired on MRI do provide advantages over standard x-ray.”

The researchers measured patellar alignment in the sagittal and transverse (axial) planes. In the sagittal plane, they measured the patellar length ratio (PLR).

To do so, they used the slice with clearly recognizable patellar margins and in which patellar bone volume appeared to be maximal. PLR was calculated as the ratio of patellar length to patellar ligament length. Patellar length was measured from the upper to the lower point of the inner surface of the patella—excluding osteophytes. Patellar ligament length was measured from the lower inner point of the patella to the highest point of the tibial tuberosity.

In the transverse plane, the researchers measured the trochlear depth (trochlear sulcus angle) and two indices describing patellar position (lateral patellar tilt angle and bisect offset of the patella). Sulcus angle (SA) is an indicator of femoral trochlear dysplasia, which is associated with PF OA and patellar instability. To measure SA, the researchers used the axial slice that referred to the proximal one-third of the femoral trochlear curve.

SA is the angle between two lines: one radiating from the lowest point of the trochlear sulcus along the lateral bony margin and the other from the lowest point of the trochlear sulcus along the medial bony margin.

For measurements of patellar alignment, the researchers used the axial slice that refers to the middle of the patella. The LPTA, which is the angle between the posterior condylar line and a line through the lateral interior bony margin of the patella, shows the angle of patellar inclination, which indicates the tightness or laxity of the lateral stabilizing mechanism of the patella.

Bisect offset (BO) indicates the lateral displacement of the patella in relation to the deepest part of the femoral sulcus. For the BO of the patella, the researchers used a line perpendicular to the posterior condylar line that runs through the lowest point of the femoral sulcus and up through the patella.

They then measured the distance between this line and the lateral border of the patella (a). They also measured the distance between this line and the medial border of the patella (b). BO was calculated as the formula: 100a/(a + b).

Participants had weight-bearing skyline radiography, and the x-rays were read by a rheumatologist who used a four-point scale to grade the presence of osteophytes in the medial and lateral parts of the patella and femur and the joint space narrowing in the medial and lateral parts of the PF joint.

There was a statistically significant association between PLR and both osteophytes and joint space narrowing in the lateral compartment. With increasing PLR, there was an increased risk of lateral joint space narrowing. A similar trend was found between increasing PLR and increasing lateral patellar osteophytosis. There was no significant association between PLR and indices of radiographic PF OA in the medial PF compartment.

SA showed a statistically significant association with medial joint space narrowing and lateral and medial patellar osteophytosis—with increasing SA, there was increased risk of medial joint space narrowing. LPTA showed a statistically significant association with joint space narrowing and osteophytosis of the lateral PF compartment. A more laterally displaced patella was positively associated with increased lateral joint space narrowing and also with lateral patellar osteophytosis. In contrast, lateral patella displacement was negatively associated with medial joint space narrowing—increased medial displacement of the patella was associated with medial joint space narrowing.

The findings suggest that alignment of the patella may be an important factor influencing PF joint degeneration, due to the aberrant distribution of forces with activity. “I think that the important message for clinicians here is that to date, the majority of people really haven't considered problems of malalignment of the patellofemoral joint as important features in patellofemoral osteoarthritis. This study suggests that they're strongly associated,” said Dr. Hunter.

The fact that MRI was performed with the knee placed in a supine position likely means that the findings from this analysis are conservative for measures that could potentially change with weight bearing (LPTA and BO).

Cartilage loss and bone marrow lesions are shown on sagittal image of the knee.

Moderate effusion and medial and lateral patella osteophytes as seen on axial view.

Cartilage loss with macerated remnants of medial meniscus on coronal image.

Effusion, lateral patella osteophyte, and lateral patella displacement are seen. Dr. David J. Hunter

Patellae that are positioned centrally in the trochlear groove and are not malaligned are thought to be less susceptible to the development of osteoarthritis. Patellae that are chronically poorly aligned can place excess stress on the articular surfaces of the patellofemoral (PF) joints and possibly promote knee degeneration.

Most studies of patellar malalignment have used x-rays of the knee in the lateral plane and skyline view. Few studies have taken advantage of the increased resolution and three-dimensional visualization afforded by magnetic resonance imaging. One reason is that although MRIs of the knee in flexion are more useful in evaluating PF alignment, clinical MRI of the knee is most commonly acquired with the knee extended in the supine position.

Dr. David J. Hunter, a rheumatologist, and his colleagues at Boston University recently compared a number of measures of patellofemoral (PF) malalignment with radiographic indices of osteoarthritis (OA)–the presence of joint space narrowing and osteophytes—in patients with symptomatic and radiographic knee OA (Arthritis Res. Ther. 2007;9:R26).

Study participants were part of the Boston Osteoarthritis of the Knee Study, a cross-sectional larger natural history study of symptomatic knee OA.

“Admittedly, identifying cause from a cross-sectional study is a little bit of a leap, but our belief is that patellar malalignment actually predisposes to these changes,” Dr. Hunter said in an interview.

Not only did the researchers find significant associations between PF malalignment and radiographic features of OA, they demonstrated that indices of patellar alignment can be measured easily on standard knee MRI.

Participants suspected of knee OA underwent a series of x-rays. Those with a definite osteophyte on any view in the symptomatic knee were eligible for the study. The researchers evaluated 213 patients—126 men (average age 68 years) and 87 women (average age 65 years).

MRI studies were performed with a 1.5-T magnet, and a positioning device was used to ensure uniformity of the extended knee position. The imaging protocol included sagittal spin-echo proton density-weighted and T2-weighted images and coronal and axial spin-echo fat-suppressed proton density-weighted and T2-weighted images.

Use of MRI allowed the researchers to evaluate several indices of patellofemoral alignment. “For some of the measures that we wanted to take of patellofemoral alignment, we would not be able to get them from radiographic films alone,” said Dr. Hunter, an assistant professor of medicine at Boston University. “The resolution and the different planes that can be acquired on MRI do provide advantages over standard x-ray.”

The researchers measured patellar alignment in the sagittal and transverse (axial) planes. In the sagittal plane, they measured the patellar length ratio (PLR).

To do so, they used the slice with clearly recognizable patellar margins and in which patellar bone volume appeared to be maximal. PLR was calculated as the ratio of patellar length to patellar ligament length. Patellar length was measured from the upper to the lower point of the inner surface of the patella—excluding osteophytes. Patellar ligament length was measured from the lower inner point of the patella to the highest point of the tibial tuberosity.

In the transverse plane, the researchers measured the trochlear depth (trochlear sulcus angle) and two indices describing patellar position (lateral patellar tilt angle and bisect offset of the patella). Sulcus angle (SA) is an indicator of femoral trochlear dysplasia, which is associated with PF OA and patellar instability. To measure SA, the researchers used the axial slice that referred to the proximal one-third of the femoral trochlear curve.

SA is the angle between two lines: one radiating from the lowest point of the trochlear sulcus along the lateral bony margin and the other from the lowest point of the trochlear sulcus along the medial bony margin.

For measurements of patellar alignment, the researchers used the axial slice that refers to the middle of the patella. The LPTA, which is the angle between the posterior condylar line and a line through the lateral interior bony margin of the patella, shows the angle of patellar inclination, which indicates the tightness or laxity of the lateral stabilizing mechanism of the patella.

Bisect offset (BO) indicates the lateral displacement of the patella in relation to the deepest part of the femoral sulcus. For the BO of the patella, the researchers used a line perpendicular to the posterior condylar line that runs through the lowest point of the femoral sulcus and up through the patella.

They then measured the distance between this line and the lateral border of the patella (a). They also measured the distance between this line and the medial border of the patella (b). BO was calculated as the formula: 100a/(a + b).

Participants had weight-bearing skyline radiography, and the x-rays were read by a rheumatologist who used a four-point scale to grade the presence of osteophytes in the medial and lateral parts of the patella and femur and the joint space narrowing in the medial and lateral parts of the PF joint.

There was a statistically significant association between PLR and both osteophytes and joint space narrowing in the lateral compartment. With increasing PLR, there was an increased risk of lateral joint space narrowing. A similar trend was found between increasing PLR and increasing lateral patellar osteophytosis. There was no significant association between PLR and indices of radiographic PF OA in the medial PF compartment.

SA showed a statistically significant association with medial joint space narrowing and lateral and medial patellar osteophytosis—with increasing SA, there was increased risk of medial joint space narrowing. LPTA showed a statistically significant association with joint space narrowing and osteophytosis of the lateral PF compartment. A more laterally displaced patella was positively associated with increased lateral joint space narrowing and also with lateral patellar osteophytosis. In contrast, lateral patella displacement was negatively associated with medial joint space narrowing—increased medial displacement of the patella was associated with medial joint space narrowing.

The findings suggest that alignment of the patella may be an important factor influencing PF joint degeneration, due to the aberrant distribution of forces with activity. “I think that the important message for clinicians here is that to date, the majority of people really haven't considered problems of malalignment of the patellofemoral joint as important features in patellofemoral osteoarthritis. This study suggests that they're strongly associated,” said Dr. Hunter.

The fact that MRI was performed with the knee placed in a supine position likely means that the findings from this analysis are conservative for measures that could potentially change with weight bearing (LPTA and BO).

DESTIN, FLA. — The incidence of gout is on the rise, and lifestyle factors are largely to blame, Dr. N. Lawrence Edwards said at the annual Rheumatology on the Beach.

For example, one study showed that between 1977–1978 and 1995–1996, the annual rate of primary gout more than doubled, from about 16 cases/100,000 population to nearly 42 cases/100,000 population. Factors that appear to play a role in this incidence spike are greater longevity, widespread diuretic and aspirin use, hypertension incidence, obesity, metabolic syndrome, and dietary trends, said Dr. Edwards, professor and vice chairman of the department of medicine at the University of Florida, Gainesville.

Certain dietary factors affect the risk for gout (high consumption of meat, seafood, and beer increase risk, and high intake of dairy is protective, for example); other risk factors are modifiable (such as obesity and hypertension). However, despite the association between lifestyle factors and risk, their modification will not eliminate existing gout. Weight reduction, decreased alcohol consumption, and reduced intake of purine-rich foods will reduce urate levels only by about 1 mg/dL. Medical treatment should be considered early in patients presenting with acute attacks, he said.

Urate-lowering therapy, which 15 years ago was reserved for use only in patients with chronic gout, now is considered warranted following the first one or two acute attacks, he noted.

Treatment goals for gout include termination of the attack as rapidly as possible, prevention of future attacks by reducing the chance of crystal-induced inflammation, and long-term correction of metabolic problems with a goal of lowering serum urate to below 6 mg/dL to allow depletion of the total body uric acid pool.

Uricosuric agents, such a probenecid, and the xanthine oxidase inhibitor allopurinol are used for this purpose.

These agents are used for reducing urate levels but uricosuric agents increase the risk of uric acid crystallization in the urine and associated stone formation. A number of other agents, such as ampicillin, penicillin, cephradine, heparin, and rifampicin, can potentially affect the action of uricosuric agents, Dr. Edwards said.

Allopurinol, which is a purine analog that is both a substrate and inhibitor of xanthine oxidase, is effective both for people who over produce and for those who underexcrete xanthine oxidase. The drug also has the convenience of single daily dosing, and it can be efficacious in patients with renal insufficiency.

However, allopurinol isn't always effective for achieving target serum urate levels. In one study of patients treated daily with a 300-mg dose, only about half achieved a serum urate level of 6 mg/dL, and in a large observational study of nearly 6,000 patients, median serum urate levels decreased from 8.7 mg/dL to 7.1 mg/dL. Although dosing up to 800 mg/day is acceptable, concerns about intolerance based on reports of severe hypersensitivity syndrome, rash, gastrointestinal problems, increases in liver enzymes, and rare bone marrow suppression tend to scare physicians away from prescribing higher doses, he noted. As with uricosuric agents, drug-drug interactions also are a problem with allopurinol.

Keys to effective treatment with this drug include dosing allopurinol to achieve a serum urate level between 5.0 and 6.0 mg/dL, which allows reduction of total body urate pool and mobilization of deposited crystals, Dr. Edwards said, stressing the need to start at a low dose of 50–100 mg/day, with close monitoring of escalation.

If the target serum urate level is reached, therapy should be ongoing; intermittent therapy or withdrawal will lead to recurrence of acute attacks within 6 months, and development of tophi within a few years.

Allopurinol shouldn't be started during an acute gouty attack and shouldn't be stopped in those already on treatment, he added. Also keep in mind that these medications will not control the pain of gout, and pain medications will do nothing to reduce serum urate, he advised.

New urate-lowering agents that improve compliance and are useful in those with allopurinol intolerance and renal failure, and who require treatment with other drugs that interact with allopurinol and uricosuric agents are needed, he concluded.

DESTIN, FLA. — The incidence of gout is on the rise, and lifestyle factors are largely to blame, Dr. N. Lawrence Edwards said at the annual Rheumatology on the Beach.

For example, one study showed that between 1977–1978 and 1995–1996, the annual rate of primary gout more than doubled, from about 16 cases/100,000 population to nearly 42 cases/100,000 population. Factors that appear to play a role in this incidence spike are greater longevity, widespread diuretic and aspirin use, hypertension incidence, obesity, metabolic syndrome, and dietary trends, said Dr. Edwards, professor and vice chairman of the department of medicine at the University of Florida, Gainesville.

Certain dietary factors affect the risk for gout (high consumption of meat, seafood, and beer increase risk, and high intake of dairy is protective, for example); other risk factors are modifiable (such as obesity and hypertension). However, despite the association between lifestyle factors and risk, their modification will not eliminate existing gout. Weight reduction, decreased alcohol consumption, and reduced intake of purine-rich foods will reduce urate levels only by about 1 mg/dL. Medical treatment should be considered early in patients presenting with acute attacks, he said.

Urate-lowering therapy, which 15 years ago was reserved for use only in patients with chronic gout, now is considered warranted following the first one or two acute attacks, he noted.

Treatment goals for gout include termination of the attack as rapidly as possible, prevention of future attacks by reducing the chance of crystal-induced inflammation, and long-term correction of metabolic problems with a goal of lowering serum urate to below 6 mg/dL to allow depletion of the total body uric acid pool.

Uricosuric agents, such a probenecid, and the xanthine oxidase inhibitor allopurinol are used for this purpose.

These agents are used for reducing urate levels but uricosuric agents increase the risk of uric acid crystallization in the urine and associated stone formation. A number of other agents, such as ampicillin, penicillin, cephradine, heparin, and rifampicin, can potentially affect the action of uricosuric agents, Dr. Edwards said.

Allopurinol, which is a purine analog that is both a substrate and inhibitor of xanthine oxidase, is effective both for people who over produce and for those who underexcrete xanthine oxidase. The drug also has the convenience of single daily dosing, and it can be efficacious in patients with renal insufficiency.

However, allopurinol isn't always effective for achieving target serum urate levels. In one study of patients treated daily with a 300-mg dose, only about half achieved a serum urate level of 6 mg/dL, and in a large observational study of nearly 6,000 patients, median serum urate levels decreased from 8.7 mg/dL to 7.1 mg/dL. Although dosing up to 800 mg/day is acceptable, concerns about intolerance based on reports of severe hypersensitivity syndrome, rash, gastrointestinal problems, increases in liver enzymes, and rare bone marrow suppression tend to scare physicians away from prescribing higher doses, he noted. As with uricosuric agents, drug-drug interactions also are a problem with allopurinol.

Keys to effective treatment with this drug include dosing allopurinol to achieve a serum urate level between 5.0 and 6.0 mg/dL, which allows reduction of total body urate pool and mobilization of deposited crystals, Dr. Edwards said, stressing the need to start at a low dose of 50–100 mg/day, with close monitoring of escalation.

If the target serum urate level is reached, therapy should be ongoing; intermittent therapy or withdrawal will lead to recurrence of acute attacks within 6 months, and development of tophi within a few years.

Allopurinol shouldn't be started during an acute gouty attack and shouldn't be stopped in those already on treatment, he added. Also keep in mind that these medications will not control the pain of gout, and pain medications will do nothing to reduce serum urate, he advised.

New urate-lowering agents that improve compliance and are useful in those with allopurinol intolerance and renal failure, and who require treatment with other drugs that interact with allopurinol and uricosuric agents are needed, he concluded.

DESTIN, FLA. — The incidence of gout is on the rise, and lifestyle factors are largely to blame, Dr. N. Lawrence Edwards said at the annual Rheumatology on the Beach.

For example, one study showed that between 1977–1978 and 1995–1996, the annual rate of primary gout more than doubled, from about 16 cases/100,000 population to nearly 42 cases/100,000 population. Factors that appear to play a role in this incidence spike are greater longevity, widespread diuretic and aspirin use, hypertension incidence, obesity, metabolic syndrome, and dietary trends, said Dr. Edwards, professor and vice chairman of the department of medicine at the University of Florida, Gainesville.

Certain dietary factors affect the risk for gout (high consumption of meat, seafood, and beer increase risk, and high intake of dairy is protective, for example); other risk factors are modifiable (such as obesity and hypertension). However, despite the association between lifestyle factors and risk, their modification will not eliminate existing gout. Weight reduction, decreased alcohol consumption, and reduced intake of purine-rich foods will reduce urate levels only by about 1 mg/dL. Medical treatment should be considered early in patients presenting with acute attacks, he said.

Urate-lowering therapy, which 15 years ago was reserved for use only in patients with chronic gout, now is considered warranted following the first one or two acute attacks, he noted.

Treatment goals for gout include termination of the attack as rapidly as possible, prevention of future attacks by reducing the chance of crystal-induced inflammation, and long-term correction of metabolic problems with a goal of lowering serum urate to below 6 mg/dL to allow depletion of the total body uric acid pool.

Uricosuric agents, such a probenecid, and the xanthine oxidase inhibitor allopurinol are used for this purpose.

These agents are used for reducing urate levels but uricosuric agents increase the risk of uric acid crystallization in the urine and associated stone formation. A number of other agents, such as ampicillin, penicillin, cephradine, heparin, and rifampicin, can potentially affect the action of uricosuric agents, Dr. Edwards said.

Allopurinol, which is a purine analog that is both a substrate and inhibitor of xanthine oxidase, is effective both for people who over produce and for those who underexcrete xanthine oxidase. The drug also has the convenience of single daily dosing, and it can be efficacious in patients with renal insufficiency.

However, allopurinol isn't always effective for achieving target serum urate levels. In one study of patients treated daily with a 300-mg dose, only about half achieved a serum urate level of 6 mg/dL, and in a large observational study of nearly 6,000 patients, median serum urate levels decreased from 8.7 mg/dL to 7.1 mg/dL. Although dosing up to 800 mg/day is acceptable, concerns about intolerance based on reports of severe hypersensitivity syndrome, rash, gastrointestinal problems, increases in liver enzymes, and rare bone marrow suppression tend to scare physicians away from prescribing higher doses, he noted. As with uricosuric agents, drug-drug interactions also are a problem with allopurinol.

Keys to effective treatment with this drug include dosing allopurinol to achieve a serum urate level between 5.0 and 6.0 mg/dL, which allows reduction of total body urate pool and mobilization of deposited crystals, Dr. Edwards said, stressing the need to start at a low dose of 50–100 mg/day, with close monitoring of escalation.

If the target serum urate level is reached, therapy should be ongoing; intermittent therapy or withdrawal will lead to recurrence of acute attacks within 6 months, and development of tophi within a few years.

Allopurinol shouldn't be started during an acute gouty attack and shouldn't be stopped in those already on treatment, he added. Also keep in mind that these medications will not control the pain of gout, and pain medications will do nothing to reduce serum urate, he advised.

New urate-lowering agents that improve compliance and are useful in those with allopurinol intolerance and renal failure, and who require treatment with other drugs that interact with allopurinol and uricosuric agents are needed, he concluded.