Rheumatoid Arthritis

BIRMINGHAM, ENGLAND — One promising strategy for holding down the cost of biologic therapy for patients with rheumatic diseases is to prescribe low doses when possible, results from two new studies have suggested.

With infliximab, for example, the typical dosage regimen in ankylosing spondylitis (AS) is 5 mg/kg given by infusion at weeks 1, 2, and 6 and then every 8 weeks. This is higher than the usual regimen for rheumatoid arthritis (RA).

“Because of cost pressures, we tried using conventional RA doses of 3 mg/kg in 13 AS patients,” Ramesh N. Jois, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

All patients had Bath AS Disease Activity Index (BASDAI) scores greater than 4 at baseline. Mean disease duration of these patients, 12 of whom were male, was 16.9 years.

Clinical response was judged to be a 50% or greater reduction in the BASDAI score at 3 months.

One patient did not respond to the low-dose regimen and required an increase to the higher dose. All other patients showed statistically significant improvements across multiple measures of efficacy, said Dr. Jois of the department of rheumatology, Norfolk and Norwich (England) University Hospital.

Some patients now have been on the regimen for 12 months, with persisting benefits. (See chart.)

Five patients have been able to reduce their methotrexate dose (mean reduction 14 mg/wk). One stopped cyclosporine, another stopped sulfasalazine, and five discontinued nonsteroidal anti-inflammatory drugs altogether, he said.

No side effects were seen with the low-dose infliximab therapy.

Use of this regimen has led to a significant cost savings of approximately $29,000 per patient per year, for a total cost savings of $315,000 to the unit in the past year, Dr. Jois said in a poster session. “We advise starting all AS patients on low-dose infliximab. Consider increasing to the higher dose only if they fail to respond,” he said.

Dr. Jois disclosed that his department has received research grant support from Wyeth, Schering-Plough, and Abbott Pharmaceuticals.

In a second study, 36 patients with RA and 3 patients with AS were treated with the standard etanercept regimen of 25 mg twice weekly for at least 3 months. Those with RA who achieved a Disease Activity Score (DAS)-28 below 3.2 and those with AS who achieved a very good response then were asked to gradually increase the interval between their etanercept injections from twice weekly to once weekly, said Veronica E. Abernethy, M.D., of the rheumatology practice development unit, St. Helens and Knowsley NHS Hospitals, Merseyside, England.

Currently, 7 of the 39 have successfully reduced their etanercept to once weekly without any deterioration in disease activity, which has resulted in a cost savings of $67,675 per year. This figure represents 9% of the total etanercept cost for the 39 patients, Dr. Abernethy said in a poster session.

BIRMINGHAM, ENGLAND — One promising strategy for holding down the cost of biologic therapy for patients with rheumatic diseases is to prescribe low doses when possible, results from two new studies have suggested.

With infliximab, for example, the typical dosage regimen in ankylosing spondylitis (AS) is 5 mg/kg given by infusion at weeks 1, 2, and 6 and then every 8 weeks. This is higher than the usual regimen for rheumatoid arthritis (RA).

“Because of cost pressures, we tried using conventional RA doses of 3 mg/kg in 13 AS patients,” Ramesh N. Jois, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

All patients had Bath AS Disease Activity Index (BASDAI) scores greater than 4 at baseline. Mean disease duration of these patients, 12 of whom were male, was 16.9 years.

Clinical response was judged to be a 50% or greater reduction in the BASDAI score at 3 months.

One patient did not respond to the low-dose regimen and required an increase to the higher dose. All other patients showed statistically significant improvements across multiple measures of efficacy, said Dr. Jois of the department of rheumatology, Norfolk and Norwich (England) University Hospital.

Some patients now have been on the regimen for 12 months, with persisting benefits. (See chart.)

Five patients have been able to reduce their methotrexate dose (mean reduction 14 mg/wk). One stopped cyclosporine, another stopped sulfasalazine, and five discontinued nonsteroidal anti-inflammatory drugs altogether, he said.

No side effects were seen with the low-dose infliximab therapy.

Use of this regimen has led to a significant cost savings of approximately $29,000 per patient per year, for a total cost savings of $315,000 to the unit in the past year, Dr. Jois said in a poster session. “We advise starting all AS patients on low-dose infliximab. Consider increasing to the higher dose only if they fail to respond,” he said.

Dr. Jois disclosed that his department has received research grant support from Wyeth, Schering-Plough, and Abbott Pharmaceuticals.

In a second study, 36 patients with RA and 3 patients with AS were treated with the standard etanercept regimen of 25 mg twice weekly for at least 3 months. Those with RA who achieved a Disease Activity Score (DAS)-28 below 3.2 and those with AS who achieved a very good response then were asked to gradually increase the interval between their etanercept injections from twice weekly to once weekly, said Veronica E. Abernethy, M.D., of the rheumatology practice development unit, St. Helens and Knowsley NHS Hospitals, Merseyside, England.

Currently, 7 of the 39 have successfully reduced their etanercept to once weekly without any deterioration in disease activity, which has resulted in a cost savings of $67,675 per year. This figure represents 9% of the total etanercept cost for the 39 patients, Dr. Abernethy said in a poster session.

BIRMINGHAM, ENGLAND — One promising strategy for holding down the cost of biologic therapy for patients with rheumatic diseases is to prescribe low doses when possible, results from two new studies have suggested.

With infliximab, for example, the typical dosage regimen in ankylosing spondylitis (AS) is 5 mg/kg given by infusion at weeks 1, 2, and 6 and then every 8 weeks. This is higher than the usual regimen for rheumatoid arthritis (RA).

“Because of cost pressures, we tried using conventional RA doses of 3 mg/kg in 13 AS patients,” Ramesh N. Jois, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

All patients had Bath AS Disease Activity Index (BASDAI) scores greater than 4 at baseline. Mean disease duration of these patients, 12 of whom were male, was 16.9 years.

Clinical response was judged to be a 50% or greater reduction in the BASDAI score at 3 months.

One patient did not respond to the low-dose regimen and required an increase to the higher dose. All other patients showed statistically significant improvements across multiple measures of efficacy, said Dr. Jois of the department of rheumatology, Norfolk and Norwich (England) University Hospital.

Some patients now have been on the regimen for 12 months, with persisting benefits. (See chart.)

Five patients have been able to reduce their methotrexate dose (mean reduction 14 mg/wk). One stopped cyclosporine, another stopped sulfasalazine, and five discontinued nonsteroidal anti-inflammatory drugs altogether, he said.

No side effects were seen with the low-dose infliximab therapy.

Use of this regimen has led to a significant cost savings of approximately $29,000 per patient per year, for a total cost savings of $315,000 to the unit in the past year, Dr. Jois said in a poster session. “We advise starting all AS patients on low-dose infliximab. Consider increasing to the higher dose only if they fail to respond,” he said.

Dr. Jois disclosed that his department has received research grant support from Wyeth, Schering-Plough, and Abbott Pharmaceuticals.

In a second study, 36 patients with RA and 3 patients with AS were treated with the standard etanercept regimen of 25 mg twice weekly for at least 3 months. Those with RA who achieved a Disease Activity Score (DAS)-28 below 3.2 and those with AS who achieved a very good response then were asked to gradually increase the interval between their etanercept injections from twice weekly to once weekly, said Veronica E. Abernethy, M.D., of the rheumatology practice development unit, St. Helens and Knowsley NHS Hospitals, Merseyside, England.

Currently, 7 of the 39 have successfully reduced their etanercept to once weekly without any deterioration in disease activity, which has resulted in a cost savings of $67,675 per year. This figure represents 9% of the total etanercept cost for the 39 patients, Dr. Abernethy said in a poster session.

NEW ORLEANS — Psoriatic arthritis patients receiving etanercept reported sustained clinical benefits for up to 2 years, according to data from an open-label extension study.

Patients treated with the drug reported inhibition of disease as well as significant improvements in physical functioning and quality of life, Philip J. Mease, M.D., reported at the annual meeting of the American Academy of Dermatology.

After an initial 24-week blinded phase of the study and a maintenance phase of up to 24 weeks, during which patients were kept on their blinded drug, 169 patients received 25 mg of etanercept (Enbrel) twice weekly for an additional 48 weeks during the open-label extension phase.

Patient-reported outcomes included the physical and mental components of the Short-Form (SF-36) Health Survey and the Health Assessment Questionnaire-Disability Index (HAQ-DI). During the placebo-controlled phase, etanercept-treated patients had a mean improvement of 9.3 points on the SF-36 physical component summary scale; placebo patients improved only 0.7 on the scale.

In the open-label phase, patients originally randomized to etanercept maintained their improvements (mean 12.6 points), and patients switched to etanercept from placebo improved almost to the same level as those on continuous etanercept, said Dr. Mease, a rheumatologist at the Swedish Medical Center, the University of Washington, Seattle. Both groups had normal mental health at baseline and maintained it throughout the industry-sponsored trial.

In the placebo-controlled phase, the HAQ-DI improved from 1.1 to 0.5 in the etanercept group and from 1.1 to 1 in the placebo group. At 48 weeks, 40 (53%) of 75 patients originally randomized to etanercept had an HAQ-DI of zero, indicating no disability in performing activities of daily living. The mean HAQ-DI score at 48 weeks was 0.4 for patients continuously treated with etanercept and 0.6 for 70 patients switched from placebo to the drug.

NEW ORLEANS — Psoriatic arthritis patients receiving etanercept reported sustained clinical benefits for up to 2 years, according to data from an open-label extension study.

Patients treated with the drug reported inhibition of disease as well as significant improvements in physical functioning and quality of life, Philip J. Mease, M.D., reported at the annual meeting of the American Academy of Dermatology.

After an initial 24-week blinded phase of the study and a maintenance phase of up to 24 weeks, during which patients were kept on their blinded drug, 169 patients received 25 mg of etanercept (Enbrel) twice weekly for an additional 48 weeks during the open-label extension phase.

Patient-reported outcomes included the physical and mental components of the Short-Form (SF-36) Health Survey and the Health Assessment Questionnaire-Disability Index (HAQ-DI). During the placebo-controlled phase, etanercept-treated patients had a mean improvement of 9.3 points on the SF-36 physical component summary scale; placebo patients improved only 0.7 on the scale.

In the open-label phase, patients originally randomized to etanercept maintained their improvements (mean 12.6 points), and patients switched to etanercept from placebo improved almost to the same level as those on continuous etanercept, said Dr. Mease, a rheumatologist at the Swedish Medical Center, the University of Washington, Seattle. Both groups had normal mental health at baseline and maintained it throughout the industry-sponsored trial.

In the placebo-controlled phase, the HAQ-DI improved from 1.1 to 0.5 in the etanercept group and from 1.1 to 1 in the placebo group. At 48 weeks, 40 (53%) of 75 patients originally randomized to etanercept had an HAQ-DI of zero, indicating no disability in performing activities of daily living. The mean HAQ-DI score at 48 weeks was 0.4 for patients continuously treated with etanercept and 0.6 for 70 patients switched from placebo to the drug.

NEW ORLEANS — Psoriatic arthritis patients receiving etanercept reported sustained clinical benefits for up to 2 years, according to data from an open-label extension study.

Patients treated with the drug reported inhibition of disease as well as significant improvements in physical functioning and quality of life, Philip J. Mease, M.D., reported at the annual meeting of the American Academy of Dermatology.

After an initial 24-week blinded phase of the study and a maintenance phase of up to 24 weeks, during which patients were kept on their blinded drug, 169 patients received 25 mg of etanercept (Enbrel) twice weekly for an additional 48 weeks during the open-label extension phase.

Patient-reported outcomes included the physical and mental components of the Short-Form (SF-36) Health Survey and the Health Assessment Questionnaire-Disability Index (HAQ-DI). During the placebo-controlled phase, etanercept-treated patients had a mean improvement of 9.3 points on the SF-36 physical component summary scale; placebo patients improved only 0.7 on the scale.

In the open-label phase, patients originally randomized to etanercept maintained their improvements (mean 12.6 points), and patients switched to etanercept from placebo improved almost to the same level as those on continuous etanercept, said Dr. Mease, a rheumatologist at the Swedish Medical Center, the University of Washington, Seattle. Both groups had normal mental health at baseline and maintained it throughout the industry-sponsored trial.

In the placebo-controlled phase, the HAQ-DI improved from 1.1 to 0.5 in the etanercept group and from 1.1 to 1 in the placebo group. At 48 weeks, 40 (53%) of 75 patients originally randomized to etanercept had an HAQ-DI of zero, indicating no disability in performing activities of daily living. The mean HAQ-DI score at 48 weeks was 0.4 for patients continuously treated with etanercept and 0.6 for 70 patients switched from placebo to the drug.

BIRMINGHAM, ENGLAND — Tumor necrosis factor antagonists are the most effective treatment available for ankylosing spondylitis, according to the results of a systematic review of randomized placebo-controlled trials comparing the biologics with conventional drugs.

Prior to the introduction of biologic agents, treatment for ankylosing spondylitis (AS) was largely limited to physiotherapy and nonsteroidal antiinflammatory drugs (NSAIDs). Other drugs such as methotrexate and sulfasalazine have not shown the same efficacy for ankylosing spondylitis as they have for rheumatoid arthritis, Sarah Levy, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

From a search on Medline and Embase, Dr. Levy and her associates at University Hospital Lewisham, London, identified 14 trials of pharmacologic management of AS; 9 of the trials were of adequate quality and produced data that were comparable across all studies, she said. Two of the studies evaluated NSAIDs, three evaluated sulfasalazine, and four evaluated TNF-α blocking agents.

Spinal pain visual analog scale scores were available for all treatments, but the Bath Ankylosing Spondylitis Functional Index (BASFI) was available only for NSAIDs and anti-TNF-α treatment, said Dr. Levy, a rheumatologist at the hospital.

Treatment with NSAIDs and sulfasalazine did show significant benefit in BASFI and spinal pain, but the effect sizes were small. (See box.) Most of the effect of treatment with sulfasalazine was seen in patients with both axial and peripheral disease, rather than in those with axial disease alone. In contrast, anti-TNF-α treatment showed highly significant benefits and the largest effect size on both BASFI and spinal pain scores, she said in a poster session.

Four trials evaluating physical exercise regimens also were identified and showed no benefit in spinal pain scores compared with placebo.

BIRMINGHAM, ENGLAND — Tumor necrosis factor antagonists are the most effective treatment available for ankylosing spondylitis, according to the results of a systematic review of randomized placebo-controlled trials comparing the biologics with conventional drugs.

Prior to the introduction of biologic agents, treatment for ankylosing spondylitis (AS) was largely limited to physiotherapy and nonsteroidal antiinflammatory drugs (NSAIDs). Other drugs such as methotrexate and sulfasalazine have not shown the same efficacy for ankylosing spondylitis as they have for rheumatoid arthritis, Sarah Levy, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

From a search on Medline and Embase, Dr. Levy and her associates at University Hospital Lewisham, London, identified 14 trials of pharmacologic management of AS; 9 of the trials were of adequate quality and produced data that were comparable across all studies, she said. Two of the studies evaluated NSAIDs, three evaluated sulfasalazine, and four evaluated TNF-α blocking agents.

Spinal pain visual analog scale scores were available for all treatments, but the Bath Ankylosing Spondylitis Functional Index (BASFI) was available only for NSAIDs and anti-TNF-α treatment, said Dr. Levy, a rheumatologist at the hospital.

Treatment with NSAIDs and sulfasalazine did show significant benefit in BASFI and spinal pain, but the effect sizes were small. (See box.) Most of the effect of treatment with sulfasalazine was seen in patients with both axial and peripheral disease, rather than in those with axial disease alone. In contrast, anti-TNF-α treatment showed highly significant benefits and the largest effect size on both BASFI and spinal pain scores, she said in a poster session.

Four trials evaluating physical exercise regimens also were identified and showed no benefit in spinal pain scores compared with placebo.

BIRMINGHAM, ENGLAND — Tumor necrosis factor antagonists are the most effective treatment available for ankylosing spondylitis, according to the results of a systematic review of randomized placebo-controlled trials comparing the biologics with conventional drugs.

Prior to the introduction of biologic agents, treatment for ankylosing spondylitis (AS) was largely limited to physiotherapy and nonsteroidal antiinflammatory drugs (NSAIDs). Other drugs such as methotrexate and sulfasalazine have not shown the same efficacy for ankylosing spondylitis as they have for rheumatoid arthritis, Sarah Levy, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

From a search on Medline and Embase, Dr. Levy and her associates at University Hospital Lewisham, London, identified 14 trials of pharmacologic management of AS; 9 of the trials were of adequate quality and produced data that were comparable across all studies, she said. Two of the studies evaluated NSAIDs, three evaluated sulfasalazine, and four evaluated TNF-α blocking agents.

Spinal pain visual analog scale scores were available for all treatments, but the Bath Ankylosing Spondylitis Functional Index (BASFI) was available only for NSAIDs and anti-TNF-α treatment, said Dr. Levy, a rheumatologist at the hospital.

Treatment with NSAIDs and sulfasalazine did show significant benefit in BASFI and spinal pain, but the effect sizes were small. (See box.) Most of the effect of treatment with sulfasalazine was seen in patients with both axial and peripheral disease, rather than in those with axial disease alone. In contrast, anti-TNF-α treatment showed highly significant benefits and the largest effect size on both BASFI and spinal pain scores, she said in a poster session.

Four trials evaluating physical exercise regimens also were identified and showed no benefit in spinal pain scores compared with placebo.

BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.

Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.

The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.

Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.

“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.

“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.

Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.

An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.

“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.

The prevalence of HERV-K113 and HERV-K115 varies widely across countries. The top number is the prevalence of HERV-K113 in each country. Underneath is the prevalence of HERV-K115. Courtesy Dr. David Moyes

BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.

Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.

The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.

Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.

“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.

“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.

Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.

An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.

“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.

The prevalence of HERV-K113 and HERV-K115 varies widely across countries. The top number is the prevalence of HERV-K113 in each country. Underneath is the prevalence of HERV-K115. Courtesy Dr. David Moyes

BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.

Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.

The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.

Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.

“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.

“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.

Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.

An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.

“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.

The prevalence of HERV-K113 and HERV-K115 varies widely across countries. The top number is the prevalence of HERV-K113 in each country. Underneath is the prevalence of HERV-K115. Courtesy Dr. David Moyes

Tumor necrosis factor agents do not increase the overall risk of cancer in patients with rheumatoid arthritis but may be associated with an increased risk of lymphomas, an analysis of data from the South Swedish Arthritis Treatment Group register suggests.

The study is the first to question whether use of anti-TNF-α agents increases the risk of lymphoma independently of disease severity.

Pierre Geborek, M.D., and colleagues at Lund (Sweden) University Hospital, identified 757 patients treated with etanercept (Enbrel) or infliximab (Remicade) from the register and 800 conservatively treated patients recruited from an outpatient clinic and private practices (Ann. Rheum. Dis. 2005;64:699–703).

Patients were followed from initiation of anti-TNF treatment (or July 1, 1997, for the comparison group) until death or Dec. 31, 2002.

In the anti-TNF group, there were 16 tumors (5 lymphomas) in 1,603 person-years at risk, compared with 69 tumors (2 lymphomas) in 3,948 person-years in the control group.

The standardized incidence ratios in the anti-TNF group and the control group were 1.1 and 1.4 for all tumors and 11.5 and 1.3 for lymphomas, respectively.

The increased overall tumor incidence in the control group was mainly due to smoking-related lesions, according to the investigators.

The total cancer risk excluding lymphomas was 0.79 among patients treated with anti-TNF agents and 1.39 in the comparison group.

The unadjusted hazard ratio for lymphoma was 4.9 in anti-TNF-treated patients relative to the conventionally treated patients. The hazard ratio was 5.0 after adjusting for differences in baseline Health Assessment Questionnaire scores, which were used as a marker of severity.

The results for overall tumor standardized incidence ratios in the anti-TNF-treated patients, compared with controls, must be interpreted with caution because of the limited number of observations and the relatively short follow-up period, the investigators wrote.

The withholding of anti-TNF treatment in patients with a known previous cancer also may have contributed to the lower incidence of cancer in this group.

In an accompanying editorial, Jarrod Franklin and colleagues at Manchester (England) University noted the study failed to detect a raised incidence of lymphoma in the control group, despite detecting an increased risk of all-site cancers in this population.

This is surprising, they said; given that the results of several studies would suggest such patients would be at an increased risk of lymphoma.

They welcomed the investigation but agreed it is difficult to reach a “robust conclusion” on the question of anti-TNF-α agents, disease severity, and lymphoma risk.

“With increasing recruitment and follow-up of such cohorts, a more definitive answer should be available in the not too distant future,” they wrote.

Eric Ruderman, M.D., a rheumatologist with Northwestern University, Chicago, concurred. “It's important information, but the issue you have to take into consideration is that their denominators were fairly small to look at such a rare event,” he said in an interview. “One or two patients one way or the other may have made a significant difference.”

Tumor necrosis factor agents do not increase the overall risk of cancer in patients with rheumatoid arthritis but may be associated with an increased risk of lymphomas, an analysis of data from the South Swedish Arthritis Treatment Group register suggests.

The study is the first to question whether use of anti-TNF-α agents increases the risk of lymphoma independently of disease severity.

Pierre Geborek, M.D., and colleagues at Lund (Sweden) University Hospital, identified 757 patients treated with etanercept (Enbrel) or infliximab (Remicade) from the register and 800 conservatively treated patients recruited from an outpatient clinic and private practices (Ann. Rheum. Dis. 2005;64:699–703).

Patients were followed from initiation of anti-TNF treatment (or July 1, 1997, for the comparison group) until death or Dec. 31, 2002.

In the anti-TNF group, there were 16 tumors (5 lymphomas) in 1,603 person-years at risk, compared with 69 tumors (2 lymphomas) in 3,948 person-years in the control group.

The standardized incidence ratios in the anti-TNF group and the control group were 1.1 and 1.4 for all tumors and 11.5 and 1.3 for lymphomas, respectively.

The increased overall tumor incidence in the control group was mainly due to smoking-related lesions, according to the investigators.

The total cancer risk excluding lymphomas was 0.79 among patients treated with anti-TNF agents and 1.39 in the comparison group.

The unadjusted hazard ratio for lymphoma was 4.9 in anti-TNF-treated patients relative to the conventionally treated patients. The hazard ratio was 5.0 after adjusting for differences in baseline Health Assessment Questionnaire scores, which were used as a marker of severity.

The results for overall tumor standardized incidence ratios in the anti-TNF-treated patients, compared with controls, must be interpreted with caution because of the limited number of observations and the relatively short follow-up period, the investigators wrote.

The withholding of anti-TNF treatment in patients with a known previous cancer also may have contributed to the lower incidence of cancer in this group.

In an accompanying editorial, Jarrod Franklin and colleagues at Manchester (England) University noted the study failed to detect a raised incidence of lymphoma in the control group, despite detecting an increased risk of all-site cancers in this population.

This is surprising, they said; given that the results of several studies would suggest such patients would be at an increased risk of lymphoma.

They welcomed the investigation but agreed it is difficult to reach a “robust conclusion” on the question of anti-TNF-α agents, disease severity, and lymphoma risk.

“With increasing recruitment and follow-up of such cohorts, a more definitive answer should be available in the not too distant future,” they wrote.

Eric Ruderman, M.D., a rheumatologist with Northwestern University, Chicago, concurred. “It's important information, but the issue you have to take into consideration is that their denominators were fairly small to look at such a rare event,” he said in an interview. “One or two patients one way or the other may have made a significant difference.”

Tumor necrosis factor agents do not increase the overall risk of cancer in patients with rheumatoid arthritis but may be associated with an increased risk of lymphomas, an analysis of data from the South Swedish Arthritis Treatment Group register suggests.

The study is the first to question whether use of anti-TNF-α agents increases the risk of lymphoma independently of disease severity.

Pierre Geborek, M.D., and colleagues at Lund (Sweden) University Hospital, identified 757 patients treated with etanercept (Enbrel) or infliximab (Remicade) from the register and 800 conservatively treated patients recruited from an outpatient clinic and private practices (Ann. Rheum. Dis. 2005;64:699–703).

Patients were followed from initiation of anti-TNF treatment (or July 1, 1997, for the comparison group) until death or Dec. 31, 2002.

In the anti-TNF group, there were 16 tumors (5 lymphomas) in 1,603 person-years at risk, compared with 69 tumors (2 lymphomas) in 3,948 person-years in the control group.

The standardized incidence ratios in the anti-TNF group and the control group were 1.1 and 1.4 for all tumors and 11.5 and 1.3 for lymphomas, respectively.

The increased overall tumor incidence in the control group was mainly due to smoking-related lesions, according to the investigators.

The total cancer risk excluding lymphomas was 0.79 among patients treated with anti-TNF agents and 1.39 in the comparison group.

The unadjusted hazard ratio for lymphoma was 4.9 in anti-TNF-treated patients relative to the conventionally treated patients. The hazard ratio was 5.0 after adjusting for differences in baseline Health Assessment Questionnaire scores, which were used as a marker of severity.

The results for overall tumor standardized incidence ratios in the anti-TNF-treated patients, compared with controls, must be interpreted with caution because of the limited number of observations and the relatively short follow-up period, the investigators wrote.

The withholding of anti-TNF treatment in patients with a known previous cancer also may have contributed to the lower incidence of cancer in this group.

In an accompanying editorial, Jarrod Franklin and colleagues at Manchester (England) University noted the study failed to detect a raised incidence of lymphoma in the control group, despite detecting an increased risk of all-site cancers in this population.

This is surprising, they said; given that the results of several studies would suggest such patients would be at an increased risk of lymphoma.

They welcomed the investigation but agreed it is difficult to reach a “robust conclusion” on the question of anti-TNF-α agents, disease severity, and lymphoma risk.

“With increasing recruitment and follow-up of such cohorts, a more definitive answer should be available in the not too distant future,” they wrote.

Eric Ruderman, M.D., a rheumatologist with Northwestern University, Chicago, concurred. “It's important information, but the issue you have to take into consideration is that their denominators were fairly small to look at such a rare event,” he said in an interview. “One or two patients one way or the other may have made a significant difference.”

DESTIN, FLA. — The advent of disease-modifying drugs has made magnetic resonance imaging an indispensable tool for diagnosing and monitoring patients with rheumatoid arthritis, Charles G. Peterfy, M.D., said at a rheumatology meeting sponsored by Virginia Commonwealth University.

MRI already is the tool of choice for use in clinical trials. Now it's time for clinical practice to incorporate this superior technology, said Dr. Peterfy, a radiologist specializing in musculoskeletal imaging, and chief medical officer of Synarc Inc., which specializes in radiology services for clinical trials. Radiographs have a number of shortcomings. Not only are they relatively insensitive for predicting disease progression and bone erosion, they are not accurate for measuring cartilage loss or for visualizing the synovium.

MRI can provide information on synovitis, tendonitis, and bone edema (or osteitis), all of which improve the predictive accuracy, particularly the negative predictive value. “The absence of these findings on MRI is a very powerful predictor that this patient is not going to progress,” Dr. Peterfy said at the meeting, also sponsored by the International Society for Clinical Densitometry.

MRI of synovitis correlates with histopathology, Doppler ultrasound, PET imaging and “has been found to be more sensitive than clinical examination for swelling and tenderness,” he said.

There are MRI techniques that allow the visualization of preerosive osteitis, which is key because osteitis can progress very rapidly, said Dr. Peterfy, who also is on the advisory board for MagneVu, the maker of portable MRI units. According to one study, baseline osteitis can predict functional disability at 6 years. A number of studies have demonstrated that MRI detects erosions earlier than x-rays, said Dr. Peterfy. In fact, one study demonstrated the ability of baseline MRI to predict bone erosions as much as 2 years later.

The development of a semiquantitative scoring system—such as the Rheumatoid Arthritis MRI Score (RAMRIS) developed by the European League Against Rheumatism-Outcome Measures in Rheumatoid Arthritis Clinical Trials (EULAR-OMERACT)—should help standardize the use of MRI to monitor the progression of RA. This system incorporates erosions, osteitis, and synovitis to assess disease changes. The group recently published an MRI atlas intended to improve the performance and generalizability of the MRI scoring system (Ann. Rheum. Dis. 2005;64 [suppl. 1]:i3-i55).

DESTIN, FLA. — The advent of disease-modifying drugs has made magnetic resonance imaging an indispensable tool for diagnosing and monitoring patients with rheumatoid arthritis, Charles G. Peterfy, M.D., said at a rheumatology meeting sponsored by Virginia Commonwealth University.

MRI already is the tool of choice for use in clinical trials. Now it's time for clinical practice to incorporate this superior technology, said Dr. Peterfy, a radiologist specializing in musculoskeletal imaging, and chief medical officer of Synarc Inc., which specializes in radiology services for clinical trials. Radiographs have a number of shortcomings. Not only are they relatively insensitive for predicting disease progression and bone erosion, they are not accurate for measuring cartilage loss or for visualizing the synovium.

MRI can provide information on synovitis, tendonitis, and bone edema (or osteitis), all of which improve the predictive accuracy, particularly the negative predictive value. “The absence of these findings on MRI is a very powerful predictor that this patient is not going to progress,” Dr. Peterfy said at the meeting, also sponsored by the International Society for Clinical Densitometry.

MRI of synovitis correlates with histopathology, Doppler ultrasound, PET imaging and “has been found to be more sensitive than clinical examination for swelling and tenderness,” he said.

There are MRI techniques that allow the visualization of preerosive osteitis, which is key because osteitis can progress very rapidly, said Dr. Peterfy, who also is on the advisory board for MagneVu, the maker of portable MRI units. According to one study, baseline osteitis can predict functional disability at 6 years. A number of studies have demonstrated that MRI detects erosions earlier than x-rays, said Dr. Peterfy. In fact, one study demonstrated the ability of baseline MRI to predict bone erosions as much as 2 years later.

The development of a semiquantitative scoring system—such as the Rheumatoid Arthritis MRI Score (RAMRIS) developed by the European League Against Rheumatism-Outcome Measures in Rheumatoid Arthritis Clinical Trials (EULAR-OMERACT)—should help standardize the use of MRI to monitor the progression of RA. This system incorporates erosions, osteitis, and synovitis to assess disease changes. The group recently published an MRI atlas intended to improve the performance and generalizability of the MRI scoring system (Ann. Rheum. Dis. 2005;64 [suppl. 1]:i3-i55).

DESTIN, FLA. — The advent of disease-modifying drugs has made magnetic resonance imaging an indispensable tool for diagnosing and monitoring patients with rheumatoid arthritis, Charles G. Peterfy, M.D., said at a rheumatology meeting sponsored by Virginia Commonwealth University.

MRI already is the tool of choice for use in clinical trials. Now it's time for clinical practice to incorporate this superior technology, said Dr. Peterfy, a radiologist specializing in musculoskeletal imaging, and chief medical officer of Synarc Inc., which specializes in radiology services for clinical trials. Radiographs have a number of shortcomings. Not only are they relatively insensitive for predicting disease progression and bone erosion, they are not accurate for measuring cartilage loss or for visualizing the synovium.

MRI can provide information on synovitis, tendonitis, and bone edema (or osteitis), all of which improve the predictive accuracy, particularly the negative predictive value. “The absence of these findings on MRI is a very powerful predictor that this patient is not going to progress,” Dr. Peterfy said at the meeting, also sponsored by the International Society for Clinical Densitometry.

MRI of synovitis correlates with histopathology, Doppler ultrasound, PET imaging and “has been found to be more sensitive than clinical examination for swelling and tenderness,” he said.

There are MRI techniques that allow the visualization of preerosive osteitis, which is key because osteitis can progress very rapidly, said Dr. Peterfy, who also is on the advisory board for MagneVu, the maker of portable MRI units. According to one study, baseline osteitis can predict functional disability at 6 years. A number of studies have demonstrated that MRI detects erosions earlier than x-rays, said Dr. Peterfy. In fact, one study demonstrated the ability of baseline MRI to predict bone erosions as much as 2 years later.

The development of a semiquantitative scoring system—such as the Rheumatoid Arthritis MRI Score (RAMRIS) developed by the European League Against Rheumatism-Outcome Measures in Rheumatoid Arthritis Clinical Trials (EULAR-OMERACT)—should help standardize the use of MRI to monitor the progression of RA. This system incorporates erosions, osteitis, and synovitis to assess disease changes. The group recently published an MRI atlas intended to improve the performance and generalizability of the MRI scoring system (Ann. Rheum. Dis. 2005;64 [suppl. 1]:i3-i55).

DESTIN, FLA. — Oral desensitization appears to be a safe and effective alternative for patients who are allergic to allopurinol and who cannot take other urate-lowering drugs for gout, Adel G. Fam, M.D., reported at a rheumatology meeting sponsored by Virginia Commonwealth University.

While 1%-3% of patients experience a pruritic maculopapular rash in response to allopurinol, severe allopurinol hypersensitivity syndrome (AHS) occurs in only about 0.4% of patients, said Dr. Fam, a professor of rheumatology at the University of Toronto.

Dr. Fam suggested that allopurinol desensitization be considered in gout patients with any of the following circumstances:

▸ Renal impairment, which renders uricosuric drugs ineffective.

▸ Underexcretion hyperuricemia; and allergy, intolerance, or contraindications to both probenecid and sulfinpyrazone.

▸ Overproduction/overexcretion hyperuricemia, which coupled with uricosurics can increase the risk of renal stones.

▸ History of transplantation, renal insufficiency, and severe and debilitating gout.

▸ The patient requires prevention of malignancy-associated hyperuricemia and tumor lysis syndrome due to cytolytic therapy for hematologic malignancies; the resulting massive uricosuria precludes the use of uricosuric drugs.

The standard allopurinol desensitization protocol starts patients at a 50-mcg dose of allopurinol in suspension. The dose is gradually increased at 3-day intervals up to a target dose of 50-100 mg/day (in tablet form). The dosage can be adjusted if a rash occurs, Dr. Fam said at the meeting, also sponsored by the International Society for Clinical Densitometry.

For high-risk patients, a modified protocol is recommended. This protocol begins with allopurinol, 10 mcg or 25 mcg, in suspension. The dosage is titrated every 5-10 days.

In a retrospective study of 32 patients, 78% were able to tolerate long-term allopurinol therapy following desensitization (Arthritis Rheum. 2001;44:231-8).

The diagnostic criteria for AHS includes a definite history of exposure to allopurinol, lack of exposure to another drug that may have caused similar symptoms, and the fulfillment of either two major criteria or one major and one minor criterion. Major criteria include: worsening renal function, acute hepatocellular injury, and rash (toxic epidermal necrosis, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis). Minor criteria include: fever, eosinophilia, and leukocytosis.

DESTIN, FLA. — Oral desensitization appears to be a safe and effective alternative for patients who are allergic to allopurinol and who cannot take other urate-lowering drugs for gout, Adel G. Fam, M.D., reported at a rheumatology meeting sponsored by Virginia Commonwealth University.

While 1%-3% of patients experience a pruritic maculopapular rash in response to allopurinol, severe allopurinol hypersensitivity syndrome (AHS) occurs in only about 0.4% of patients, said Dr. Fam, a professor of rheumatology at the University of Toronto.

Dr. Fam suggested that allopurinol desensitization be considered in gout patients with any of the following circumstances:

▸ Renal impairment, which renders uricosuric drugs ineffective.

▸ Underexcretion hyperuricemia; and allergy, intolerance, or contraindications to both probenecid and sulfinpyrazone.

▸ Overproduction/overexcretion hyperuricemia, which coupled with uricosurics can increase the risk of renal stones.

▸ History of transplantation, renal insufficiency, and severe and debilitating gout.

▸ The patient requires prevention of malignancy-associated hyperuricemia and tumor lysis syndrome due to cytolytic therapy for hematologic malignancies; the resulting massive uricosuria precludes the use of uricosuric drugs.

The standard allopurinol desensitization protocol starts patients at a 50-mcg dose of allopurinol in suspension. The dose is gradually increased at 3-day intervals up to a target dose of 50-100 mg/day (in tablet form). The dosage can be adjusted if a rash occurs, Dr. Fam said at the meeting, also sponsored by the International Society for Clinical Densitometry.

For high-risk patients, a modified protocol is recommended. This protocol begins with allopurinol, 10 mcg or 25 mcg, in suspension. The dosage is titrated every 5-10 days.

In a retrospective study of 32 patients, 78% were able to tolerate long-term allopurinol therapy following desensitization (Arthritis Rheum. 2001;44:231-8).

The diagnostic criteria for AHS includes a definite history of exposure to allopurinol, lack of exposure to another drug that may have caused similar symptoms, and the fulfillment of either two major criteria or one major and one minor criterion. Major criteria include: worsening renal function, acute hepatocellular injury, and rash (toxic epidermal necrosis, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis). Minor criteria include: fever, eosinophilia, and leukocytosis.

DESTIN, FLA. — Oral desensitization appears to be a safe and effective alternative for patients who are allergic to allopurinol and who cannot take other urate-lowering drugs for gout, Adel G. Fam, M.D., reported at a rheumatology meeting sponsored by Virginia Commonwealth University.

While 1%-3% of patients experience a pruritic maculopapular rash in response to allopurinol, severe allopurinol hypersensitivity syndrome (AHS) occurs in only about 0.4% of patients, said Dr. Fam, a professor of rheumatology at the University of Toronto.

Dr. Fam suggested that allopurinol desensitization be considered in gout patients with any of the following circumstances:

▸ Renal impairment, which renders uricosuric drugs ineffective.

▸ Underexcretion hyperuricemia; and allergy, intolerance, or contraindications to both probenecid and sulfinpyrazone.

▸ Overproduction/overexcretion hyperuricemia, which coupled with uricosurics can increase the risk of renal stones.

▸ History of transplantation, renal insufficiency, and severe and debilitating gout.

▸ The patient requires prevention of malignancy-associated hyperuricemia and tumor lysis syndrome due to cytolytic therapy for hematologic malignancies; the resulting massive uricosuria precludes the use of uricosuric drugs.

The standard allopurinol desensitization protocol starts patients at a 50-mcg dose of allopurinol in suspension. The dose is gradually increased at 3-day intervals up to a target dose of 50-100 mg/day (in tablet form). The dosage can be adjusted if a rash occurs, Dr. Fam said at the meeting, also sponsored by the International Society for Clinical Densitometry.

For high-risk patients, a modified protocol is recommended. This protocol begins with allopurinol, 10 mcg or 25 mcg, in suspension. The dosage is titrated every 5-10 days.

In a retrospective study of 32 patients, 78% were able to tolerate long-term allopurinol therapy following desensitization (Arthritis Rheum. 2001;44:231-8).

The diagnostic criteria for AHS includes a definite history of exposure to allopurinol, lack of exposure to another drug that may have caused similar symptoms, and the fulfillment of either two major criteria or one major and one minor criterion. Major criteria include: worsening renal function, acute hepatocellular injury, and rash (toxic epidermal necrosis, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis). Minor criteria include: fever, eosinophilia, and leukocytosis.

CHICAGO — Recent events surrounding selective cyclooxygenase-2 inhibitors will have far-reaching implications for future drug trials, Gary S. Hoffman, M.D., said at a symposium sponsored by the American College of Rheumatology.

Drugs under investigation for chronic diseases such as arthritis will require longer trials and follow-up than in the past, in part because of their likely long-term use among the patients who need them.

“We can no longer endorse or not endorse these drugs based upon short-term studies, some of which have been as short as 6 weeks or 12 weeks and usually, certainly, less than a year,” said Dr. Hoffman, a member of the Food and Drug Administration's arthritis advisory committee.

NSAID trials now will include cardiovascular and thrombotic events among the adverse events they monitor.

But this raises questions as to whether there are other adverse events (AEs) such as cancer, autoimmune effects, or neurocognitive dysfunction that are beyond our current knowledge, said Dr. Hoffman, professor of medicine and chair of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.

“Are we looking at this with blinders on because of recent events or are there other important AEs that we should also be casting a broader net for?” Dr. Hoffman asked.

“Perhaps there are increases in malignancies if you follow patients who take drug x, y, or z long enough. How long should those patients be studied in the context of randomized trials?” he said.

Although answers to these questions are lacking, it's obvious that closer premarket drug scrutiny will come at a greater cost, he said.

Forces such as the market, consumers, and the medical community will need to determine how cost-effectiveness will be measured, and ultimately who will pay.

New strategies need to be developed to make new drug studies cost effective, he said.

Ironically, it was adverse events associated with nonselective NSAIDs that drove the COX-2 market in the first place, he noted. Research suggests that as much as one-third of every dollar spent on NSAIDs goes to managing adverse events.

CHICAGO — Recent events surrounding selective cyclooxygenase-2 inhibitors will have far-reaching implications for future drug trials, Gary S. Hoffman, M.D., said at a symposium sponsored by the American College of Rheumatology.

Drugs under investigation for chronic diseases such as arthritis will require longer trials and follow-up than in the past, in part because of their likely long-term use among the patients who need them.

“We can no longer endorse or not endorse these drugs based upon short-term studies, some of which have been as short as 6 weeks or 12 weeks and usually, certainly, less than a year,” said Dr. Hoffman, a member of the Food and Drug Administration's arthritis advisory committee.

NSAID trials now will include cardiovascular and thrombotic events among the adverse events they monitor.

But this raises questions as to whether there are other adverse events (AEs) such as cancer, autoimmune effects, or neurocognitive dysfunction that are beyond our current knowledge, said Dr. Hoffman, professor of medicine and chair of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.

“Are we looking at this with blinders on because of recent events or are there other important AEs that we should also be casting a broader net for?” Dr. Hoffman asked.

“Perhaps there are increases in malignancies if you follow patients who take drug x, y, or z long enough. How long should those patients be studied in the context of randomized trials?” he said.

Although answers to these questions are lacking, it's obvious that closer premarket drug scrutiny will come at a greater cost, he said.

Forces such as the market, consumers, and the medical community will need to determine how cost-effectiveness will be measured, and ultimately who will pay.

New strategies need to be developed to make new drug studies cost effective, he said.

Ironically, it was adverse events associated with nonselective NSAIDs that drove the COX-2 market in the first place, he noted. Research suggests that as much as one-third of every dollar spent on NSAIDs goes to managing adverse events.

CHICAGO — Recent events surrounding selective cyclooxygenase-2 inhibitors will have far-reaching implications for future drug trials, Gary S. Hoffman, M.D., said at a symposium sponsored by the American College of Rheumatology.

Drugs under investigation for chronic diseases such as arthritis will require longer trials and follow-up than in the past, in part because of their likely long-term use among the patients who need them.

“We can no longer endorse or not endorse these drugs based upon short-term studies, some of which have been as short as 6 weeks or 12 weeks and usually, certainly, less than a year,” said Dr. Hoffman, a member of the Food and Drug Administration's arthritis advisory committee.

NSAID trials now will include cardiovascular and thrombotic events among the adverse events they monitor.

But this raises questions as to whether there are other adverse events (AEs) such as cancer, autoimmune effects, or neurocognitive dysfunction that are beyond our current knowledge, said Dr. Hoffman, professor of medicine and chair of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.

“Are we looking at this with blinders on because of recent events or are there other important AEs that we should also be casting a broader net for?” Dr. Hoffman asked.

“Perhaps there are increases in malignancies if you follow patients who take drug x, y, or z long enough. How long should those patients be studied in the context of randomized trials?” he said.

Although answers to these questions are lacking, it's obvious that closer premarket drug scrutiny will come at a greater cost, he said.

Forces such as the market, consumers, and the medical community will need to determine how cost-effectiveness will be measured, and ultimately who will pay.

New strategies need to be developed to make new drug studies cost effective, he said.

Ironically, it was adverse events associated with nonselective NSAIDs that drove the COX-2 market in the first place, he noted. Research suggests that as much as one-third of every dollar spent on NSAIDs goes to managing adverse events.

KEVIN FOLEY, RESEARCH/ANGIE RIES, DESIGN

KEVIN FOLEY, RESEARCH/ANGIE RIES, DESIGN

KEVIN FOLEY, RESEARCH/ANGIE RIES, DESIGN

CHICAGO — Agility and perturbation exercises may enhance knee stability and function in patients with knee osteoarthritis, G. Kelley Fitzgerald, Ph.D., reported at a symposium sponsored by the American College of Rheumatology.

Knee instability is a common problem in knee osteoarthritis (OA) and affects physical function beyond what can be explained by knee pain and muscle weakness, said Dr. Fitzgerald, a physical therapist at the University of Pittsburgh.

In an study of 105 patients with knee OA, Dr. Fitzgerald found that 67 patients (64%) reported knee instability during daily living activities, and 47 (45%) reported that instability affects their physical function (Arthritis Rheum. 2004;51:941-6).

A gait analysis of 48 patients, led by colleague John D. Childs, Ph.D., found that those with knee OA had reduced knee flexion and extension movements and significant increases in muscle co-contractions during walking. The vastus lateralis, medial hamstrings, tibialis anterior, and medial gastrocnemius were activated about 1.5 times longer than the same muscles in controls (Clin. Biomech. [Bristol, Avon]2004;19:44-9).

To keep their knee stable, patients will often freeze their range of motion and simplify the steps necessary to perform a movement. The instability encourages them to resort to “primitive movement steps that limit their ability to perform higher level movements,” he said.

The combination of restricted knee movement and increased co-contractions puts additional stress on the joint, which in turn can accelerate OA disease progression.

The same interventions used to promote knee stability in athletes with knee ligament injuries can be modified to improve knee stability and function in people with knee OA, said Dr. Fitzgerald, who recommended adding agility and perturbation exercises twice a week to a traditional strengthening and stretching program.

Such modifications mean that agility drills with quick starts and stops are done at a walk rather than while running.

Perturbation techniques that for athletes involve a therapist rocking a roller or tilt board while the patient stands on it are done with the OA patient sitting down or while standing on both legs, rather than just one leg.

Exposing the patient's knee to such unpredictable and varied stresses can help expand movement patterns and boost the patient's confidence to perform more complex movements, making the patient more likely to stay active, he said.

The exercises have been tried in a handful of knee OA patients, who were then able to return to higher levels of physical activity with less pain and instability following rehabilitation.

In one case report, a 73-year-old woman with bilateral knee OA who complained of partial “giving away” at the knee during walking, was able to resume playing golf and tennis, in addition to feeling more confident while walking and going up and down stairs following rehabilitation. Her program consisted of a dozen sessions, held twice a week, of agility and perturbation exercises in addition to stretching, strengthening, and endurance exercises (Phys. Ther. 2002;82:372-82).

The results are “promising,” Dr. Fitzgerald said. The role of agility and perturbation training will be further evaluated in a forthcoming randomized trial of 160 patients with knee OA.

CHICAGO — Agility and perturbation exercises may enhance knee stability and function in patients with knee osteoarthritis, G. Kelley Fitzgerald, Ph.D., reported at a symposium sponsored by the American College of Rheumatology.

Knee instability is a common problem in knee osteoarthritis (OA) and affects physical function beyond what can be explained by knee pain and muscle weakness, said Dr. Fitzgerald, a physical therapist at the University of Pittsburgh.

In an study of 105 patients with knee OA, Dr. Fitzgerald found that 67 patients (64%) reported knee instability during daily living activities, and 47 (45%) reported that instability affects their physical function (Arthritis Rheum. 2004;51:941-6).

A gait analysis of 48 patients, led by colleague John D. Childs, Ph.D., found that those with knee OA had reduced knee flexion and extension movements and significant increases in muscle co-contractions during walking. The vastus lateralis, medial hamstrings, tibialis anterior, and medial gastrocnemius were activated about 1.5 times longer than the same muscles in controls (Clin. Biomech. [Bristol, Avon]2004;19:44-9).

To keep their knee stable, patients will often freeze their range of motion and simplify the steps necessary to perform a movement. The instability encourages them to resort to “primitive movement steps that limit their ability to perform higher level movements,” he said.

The combination of restricted knee movement and increased co-contractions puts additional stress on the joint, which in turn can accelerate OA disease progression.

The same interventions used to promote knee stability in athletes with knee ligament injuries can be modified to improve knee stability and function in people with knee OA, said Dr. Fitzgerald, who recommended adding agility and perturbation exercises twice a week to a traditional strengthening and stretching program.

Such modifications mean that agility drills with quick starts and stops are done at a walk rather than while running.

Perturbation techniques that for athletes involve a therapist rocking a roller or tilt board while the patient stands on it are done with the OA patient sitting down or while standing on both legs, rather than just one leg.

Exposing the patient's knee to such unpredictable and varied stresses can help expand movement patterns and boost the patient's confidence to perform more complex movements, making the patient more likely to stay active, he said.

The exercises have been tried in a handful of knee OA patients, who were then able to return to higher levels of physical activity with less pain and instability following rehabilitation.

In one case report, a 73-year-old woman with bilateral knee OA who complained of partial “giving away” at the knee during walking, was able to resume playing golf and tennis, in addition to feeling more confident while walking and going up and down stairs following rehabilitation. Her program consisted of a dozen sessions, held twice a week, of agility and perturbation exercises in addition to stretching, strengthening, and endurance exercises (Phys. Ther. 2002;82:372-82).

The results are “promising,” Dr. Fitzgerald said. The role of agility and perturbation training will be further evaluated in a forthcoming randomized trial of 160 patients with knee OA.

CHICAGO — Agility and perturbation exercises may enhance knee stability and function in patients with knee osteoarthritis, G. Kelley Fitzgerald, Ph.D., reported at a symposium sponsored by the American College of Rheumatology.

Knee instability is a common problem in knee osteoarthritis (OA) and affects physical function beyond what can be explained by knee pain and muscle weakness, said Dr. Fitzgerald, a physical therapist at the University of Pittsburgh.

In an study of 105 patients with knee OA, Dr. Fitzgerald found that 67 patients (64%) reported knee instability during daily living activities, and 47 (45%) reported that instability affects their physical function (Arthritis Rheum. 2004;51:941-6).

A gait analysis of 48 patients, led by colleague John D. Childs, Ph.D., found that those with knee OA had reduced knee flexion and extension movements and significant increases in muscle co-contractions during walking. The vastus lateralis, medial hamstrings, tibialis anterior, and medial gastrocnemius were activated about 1.5 times longer than the same muscles in controls (Clin. Biomech. [Bristol, Avon]2004;19:44-9).

To keep their knee stable, patients will often freeze their range of motion and simplify the steps necessary to perform a movement. The instability encourages them to resort to “primitive movement steps that limit their ability to perform higher level movements,” he said.

The combination of restricted knee movement and increased co-contractions puts additional stress on the joint, which in turn can accelerate OA disease progression.

The same interventions used to promote knee stability in athletes with knee ligament injuries can be modified to improve knee stability and function in people with knee OA, said Dr. Fitzgerald, who recommended adding agility and perturbation exercises twice a week to a traditional strengthening and stretching program.

Such modifications mean that agility drills with quick starts and stops are done at a walk rather than while running.

Perturbation techniques that for athletes involve a therapist rocking a roller or tilt board while the patient stands on it are done with the OA patient sitting down or while standing on both legs, rather than just one leg.

Exposing the patient's knee to such unpredictable and varied stresses can help expand movement patterns and boost the patient's confidence to perform more complex movements, making the patient more likely to stay active, he said.

The exercises have been tried in a handful of knee OA patients, who were then able to return to higher levels of physical activity with less pain and instability following rehabilitation.

In one case report, a 73-year-old woman with bilateral knee OA who complained of partial “giving away” at the knee during walking, was able to resume playing golf and tennis, in addition to feeling more confident while walking and going up and down stairs following rehabilitation. Her program consisted of a dozen sessions, held twice a week, of agility and perturbation exercises in addition to stretching, strengthening, and endurance exercises (Phys. Ther. 2002;82:372-82).

The results are “promising,” Dr. Fitzgerald said. The role of agility and perturbation training will be further evaluated in a forthcoming randomized trial of 160 patients with knee OA.