Rheumatoid Arthritis

PHILADELPHIA — Risk of ischemic heart disease but not heart failure has declined recently among patients with rheumatoid arthritis, according to data presented at the annual meeting of the American College of Rheumatology.

The data involved two cohorts of patients with rheumatoid arthritis (RA)—349 who were diagnosed during 1980–1994 and 469 diagnosed in 1995–2007. All were residents of Olmstead County, Minn., Cynthia S. Crowson of the Mayo Clinic in Rochester, Minn., said in a poster session at the meeting.

The patients were followed for a mean of 9.6 years, during which 89 patients developed coronary heart disease (excluding 83 patients with CHD prior to RA incidence) and 82 patients developed heart failure (HF) (excluding 20 patients with HF prior to RA incidence). This translated into a 5-year CHD risk of 7.5% in the 1980–1994 cohort and 4.5% in the 1995–2007 cohort. The 5-year risk for HF was 5.8% in the 1980–1994 cohort and 5.1% in the 1995–2007 cohort.

The 1980–1994 and 1995–2007 cohorts were similar in demographics and disease characteristics: Mean age was 56.2 years and 55.5 years, respectively; 68% and 69% were female; length of follow-up was 15.3 years and 5.6 years; 66% of both groups had ever been positive for rheumatoid factor. Maximum erythrocyte sedimentation rate in the first year after diagnosis was 36.2 mm/hr and 29.9 mm/hr. There were radiologically evident changes or erosions within the first year after diagnosis in 24% and 29%, respectively.

A total of 61% and 50% of each group reported having ever smoked and 28% and 17% were current smokers. The decline in smoking is one piece of good news in the study, Ms. Crowson said in an interview.

On the downside is the increase in obesity: In all, 33% of the members of the 1980–1994 cohort had a body mass index greater than or equal to 30 kg/m

Past or current methotrexate use was reported by 48% and 64% of the cohorts. Hydroxychloroquine use was reported by 52% and 64%. Biologic use was reported by 12% and 21%, respectively, and steroid use was reported by 72% and 81%.

Because ischemic heart disease involves diastolic failure and HF involves systolic dysfunction, strategies need to address both disease mechanisms in order to lower the rate of heart failure in RA patients, Ms. Crowson said during an interview. Patients with RA may be benefiting from earlier diagnosis and treatment, which is translating into less ischemic heart disease, although it seems unlikely that biologic use is contributing to the beneficial effect, given how few patients used them in this study, she said.

According to the American Heart Association, the prevalence of ischemic heart disease in 2007 was 3.7% and the prevalence of heart failure was 2.4% in 2004 (www.americanheart.org/downloadable/heart/1166712318459HS_StatsInsideText.pdf

Ms. Crowson said she had no financial conflicts of interest to disclose.

This CT image of the lungs of a 45-year-old patient with left heart failure show perihilar distribution of airspace pulmonary edema (bat's wing edema), and consolidation and ground-glass opacities in lower lobes. Also noted are mild interlobular septal thickening (arrows) and small pleural effusions.

Source ©Elsevier

PHILADELPHIA — Risk of ischemic heart disease but not heart failure has declined recently among patients with rheumatoid arthritis, according to data presented at the annual meeting of the American College of Rheumatology.

The data involved two cohorts of patients with rheumatoid arthritis (RA)—349 who were diagnosed during 1980–1994 and 469 diagnosed in 1995–2007. All were residents of Olmstead County, Minn., Cynthia S. Crowson of the Mayo Clinic in Rochester, Minn., said in a poster session at the meeting.

The patients were followed for a mean of 9.6 years, during which 89 patients developed coronary heart disease (excluding 83 patients with CHD prior to RA incidence) and 82 patients developed heart failure (HF) (excluding 20 patients with HF prior to RA incidence). This translated into a 5-year CHD risk of 7.5% in the 1980–1994 cohort and 4.5% in the 1995–2007 cohort. The 5-year risk for HF was 5.8% in the 1980–1994 cohort and 5.1% in the 1995–2007 cohort.

The 1980–1994 and 1995–2007 cohorts were similar in demographics and disease characteristics: Mean age was 56.2 years and 55.5 years, respectively; 68% and 69% were female; length of follow-up was 15.3 years and 5.6 years; 66% of both groups had ever been positive for rheumatoid factor. Maximum erythrocyte sedimentation rate in the first year after diagnosis was 36.2 mm/hr and 29.9 mm/hr. There were radiologically evident changes or erosions within the first year after diagnosis in 24% and 29%, respectively.

A total of 61% and 50% of each group reported having ever smoked and 28% and 17% were current smokers. The decline in smoking is one piece of good news in the study, Ms. Crowson said in an interview.

On the downside is the increase in obesity: In all, 33% of the members of the 1980–1994 cohort had a body mass index greater than or equal to 30 kg/m

Past or current methotrexate use was reported by 48% and 64% of the cohorts. Hydroxychloroquine use was reported by 52% and 64%. Biologic use was reported by 12% and 21%, respectively, and steroid use was reported by 72% and 81%.

Because ischemic heart disease involves diastolic failure and HF involves systolic dysfunction, strategies need to address both disease mechanisms in order to lower the rate of heart failure in RA patients, Ms. Crowson said during an interview. Patients with RA may be benefiting from earlier diagnosis and treatment, which is translating into less ischemic heart disease, although it seems unlikely that biologic use is contributing to the beneficial effect, given how few patients used them in this study, she said.

According to the American Heart Association, the prevalence of ischemic heart disease in 2007 was 3.7% and the prevalence of heart failure was 2.4% in 2004 (www.americanheart.org/downloadable/heart/1166712318459HS_StatsInsideText.pdf

Ms. Crowson said she had no financial conflicts of interest to disclose.

This CT image of the lungs of a 45-year-old patient with left heart failure show perihilar distribution of airspace pulmonary edema (bat's wing edema), and consolidation and ground-glass opacities in lower lobes. Also noted are mild interlobular septal thickening (arrows) and small pleural effusions.

Source ©Elsevier

PHILADELPHIA — Risk of ischemic heart disease but not heart failure has declined recently among patients with rheumatoid arthritis, according to data presented at the annual meeting of the American College of Rheumatology.

The data involved two cohorts of patients with rheumatoid arthritis (RA)—349 who were diagnosed during 1980–1994 and 469 diagnosed in 1995–2007. All were residents of Olmstead County, Minn., Cynthia S. Crowson of the Mayo Clinic in Rochester, Minn., said in a poster session at the meeting.

The patients were followed for a mean of 9.6 years, during which 89 patients developed coronary heart disease (excluding 83 patients with CHD prior to RA incidence) and 82 patients developed heart failure (HF) (excluding 20 patients with HF prior to RA incidence). This translated into a 5-year CHD risk of 7.5% in the 1980–1994 cohort and 4.5% in the 1995–2007 cohort. The 5-year risk for HF was 5.8% in the 1980–1994 cohort and 5.1% in the 1995–2007 cohort.

The 1980–1994 and 1995–2007 cohorts were similar in demographics and disease characteristics: Mean age was 56.2 years and 55.5 years, respectively; 68% and 69% were female; length of follow-up was 15.3 years and 5.6 years; 66% of both groups had ever been positive for rheumatoid factor. Maximum erythrocyte sedimentation rate in the first year after diagnosis was 36.2 mm/hr and 29.9 mm/hr. There were radiologically evident changes or erosions within the first year after diagnosis in 24% and 29%, respectively.

A total of 61% and 50% of each group reported having ever smoked and 28% and 17% were current smokers. The decline in smoking is one piece of good news in the study, Ms. Crowson said in an interview.

On the downside is the increase in obesity: In all, 33% of the members of the 1980–1994 cohort had a body mass index greater than or equal to 30 kg/m

Past or current methotrexate use was reported by 48% and 64% of the cohorts. Hydroxychloroquine use was reported by 52% and 64%. Biologic use was reported by 12% and 21%, respectively, and steroid use was reported by 72% and 81%.

Because ischemic heart disease involves diastolic failure and HF involves systolic dysfunction, strategies need to address both disease mechanisms in order to lower the rate of heart failure in RA patients, Ms. Crowson said during an interview. Patients with RA may be benefiting from earlier diagnosis and treatment, which is translating into less ischemic heart disease, although it seems unlikely that biologic use is contributing to the beneficial effect, given how few patients used them in this study, she said.

According to the American Heart Association, the prevalence of ischemic heart disease in 2007 was 3.7% and the prevalence of heart failure was 2.4% in 2004 (www.americanheart.org/downloadable/heart/1166712318459HS_StatsInsideText.pdf

Ms. Crowson said she had no financial conflicts of interest to disclose.

This CT image of the lungs of a 45-year-old patient with left heart failure show perihilar distribution of airspace pulmonary edema (bat's wing edema), and consolidation and ground-glass opacities in lower lobes. Also noted are mild interlobular septal thickening (arrows) and small pleural effusions.

Source ©Elsevier

A worldwide team of spondyloarthritis experts published a new set of criteria for classifying the axial form of the disease, an action expected to dramatically expand the number of patients identified with axial spondyloarthritis and enable physicians to flag affected patients sooner and start them on treatment. A major hope is that earlier treatment, either with NSAIDs) or tumor necrosis factor (TNF) inhibitors, will help patients by slowing progression of axial spondyloarthritis (SpA). But this anticipated benefit has yet to be supported by study results.

With the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria now published (Ann. Rheum. Dis. 2009;68:770–6; 778–83), it remains unclear whether most U.S. rheumatologists and primary care physicians will buy into the criteria and apply them.

The report showed that the new classification criteria (see box) identified people with axial SpA with a sensitivity of 83% and a specificity of 84% when tested on 649 patients. The new classification criteria were compared against identification by expert rheumatologists.

If implemented, the new criteria would “increase the frequency of diagnosing [axial SpA] by probably threefold, to as high as 1.5%” of the adult U.S. population,” said Dr. John D. Reveille, professor of medicine and director of the division of rheumatology and clinical immunogenetics at the University of Texas at Houston. He based his estimate on the application of the new axial SpA criteria to a representative sample of the U.S. population collected in the National Health and Nutrition Examination Survey (NHANES).

“The new criteria will be helpful in identifying more patients with the disease, and also for recognizing the disease very early,” agreed Dr. Muhammad A. Khan, professor of medicine at Case Western Reserve University in Cleveland. “The new criteria are much better than older criteria, which require x-ray evidence of abnormalities in the sacroiliac joints. With the new criteria, you can make the diagnosis [even] when the x-ray is normal, provided you have MRI evidence,” he said in an interview. Dr. Khan was the sole U.S.-based member of ASAS to serve on the expert panel that devised the new classification criteria.

Axial SpA has typically gone undetected until much later in the course of the disease, when it has progressed to ankylosing spondylitis with its characteristic spinal-bone changes that are visible on plain x-ray films.

“The old classification criteria required patients to have x-ray changes of sacroiliitis, which take 6–10 years to develop after patients have other symptoms,” said Dr. Atul Deodhar, medical director of the rheumatology clinics at the Oregon Health and Science University in Portland. “We definitely need new criteria; we can't call it ankylosing spondylitis if the patient doesn't have x-ray changes. The diagnosis of axial spondyloarthritis is completely new,” he said in an interview.

Identification of inflammation in axial joints using MRI is a key element in the new axial SpA classification. Axial joint inflammation is often hard to diagnose without MRI because the affected joints are in locations that are impossible to palpate, Dr. Deodhar said.

Early diagnosis is vital for timely treatment. Without it, physicians wait to see x-ray evidence of ankylosing spondylitis. A wait of up to 10 years “is a long period of time to deny patients access to medications that have been shown to work in this disease,” Dr. Reveille said.

“We think that if we intervene sooner, we can prevent some of the significant morbidity and disability associated with this condition,” said Dr. John A. Flynn, professor of medicine at Johns Hopkins University in Baltimore. Some rheumatologists “have been doing this [using MRI to help make an early diagnosis of axial SpA] for 5–10 years,” according to Dr. Flynn. “Now clinical science is catching up with that experience, saying we realize that the time from symptom onset to diagnosis has been very long” when the diagnosis relies on x-ray changes. “If the [patient's clinical presentation] sounds good for the condition but the x-rays don't show anything, we should push to get the MRI.”

But Dr. Flynn and Dr. Deodhar stressed that the appearance of axial joint inflammation on MRI is not enough to make the diagnosis, as this can occur in people without axial SpA. Other key factors include age younger than 45 years, slow onset of symptoms, reduced spine mobility, stiffness and pain that worsens with rest but improves with exercise (unlike mechanical back pain that improves with rest and worsens with exercise), and exacerbation of pain and stiffness while sleeping that takes several hours to improve on awakening. “I'm not getting an MRI on the majority of my patients [with back pain] because the back pain that I see is usually not inflammatory; it's mechanical,” said Dr. Flynn.

U.S. experts share concern about how widely the criteria will be applied by other rheumatologists and, perhaps more importantly, by U.S. primary care physicians who see the bulk of these patients initially. “There clearly is a difference of opinion [in the United States and in Europe],” said Dr. Flynn. “I was amazed when I looked at the centers” that participated in the ASAS study. None was in the United States.

The validation study used patients from 25 centers in 16 countries, with 14 of the centers in Europe, 5 in Asia, 4 in Turkey, 1 in Canada, and 1 in Columbia (Ann. Rheum. Dis. 2009;68:777–83).

One possible reason why European rheumatologists have been more active in developing the new criteria is that their population contains a higher proportion of people with the HLA B27 genotype, who are most susceptible to developing axial SpA. “The question is, Are the Europeans not only seeing more, but do they see different patients?” Dr. Flynn noted. “I think you've got to validate [the new criteria] with U.S. patients too.”

“American rheumatologists are still not as well versed in spondyloarthritis as our European colleagues,” Dr. Khan said. But if the new classification criteria were followed, it would result in better patient care, Dr. Reveille said.

Treatment today for axial SpA starts with an NSAID, followed by a course with a second NSAID of a different type if the first fails. If both NSAID regimens fail to produce satisfactory results within 3 months, current standards say the next step is treatment with a TNF inhibitor.

In the United States, those include adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), and golimumab (Simponi). Although none has Food and Drug Administration approval for use in axial SpA, all four are approved for treating ankylosing spondylitis.

Ideal treatments for axial SpA don't include nonbiological disease-modifying drugs, such as methotrexate and sulfasalazine.

No study results have yet documented that early treatment with an NSAID or with a TNF inhibitor slows or stops progression of axial SpA, but specialists are optimistic that such is the case, and that these data will eventually exist.

“We suspect early treatment might have better outcomes; there is the precedent with rheumatoid arthritis,” Dr. Khan said.

In addition, even without evidence of slowed progression, early treatment “clearly improves quality of life and function and reduces time lost from work,” Dr. Flynn said.

The importance of early identification and treatment of spondylitis has been recognized by the leadership of the Spondylitis Association of America (SAA). Researchers working with SAA sponsorship developed a screening tool aimed at helping people with chronic back pain self-identify whether they have indications of an inflammatory process that needs medical evaluation.

A report on the development of the SAA screening tool for ankylosing spondylitis is scheduled to appear in the January issue of Arthritis Care and Research, and then the SAA will publicize it as an Internet-based tool, said SAA executive director Laurie Savage.

Patients with back pain for at least 3 months and with an age of onset younger than 45 years are classified as having spondyloarthritis if they have sacroiliitis on imaging plus at least one spondyloarthritis feature (see below), or if they are HLA B27 positive and have at least two other spondyloarthritis features.

Sacroiliitis on imaging is defined as one of the following:

▸ Active acute inflammation on MRI highly suggestive of sacroiliitis associated with spondyloarthritis.

▸ Definite radiographic sacroiliitis, according to the modified New York criteria.

Spondyloarthritis features include the following:

▸ Inflammatory back pain

▸ Arthritis

▸ Enthesitis

▸ Uveitis

▸ Dactylitis

▸ Psoriasis

▸ Crohn's disease/ulcerative colitis

▸ Good response to NSAIDs

▸ Family history for spondyloarthritis

▸ HLA B27 positive

▸ Elevated C-reactive protein (in the context of chronic back pain)

In these MRI images of a patient with spondyloarthritis, black arrowheads show erosions, a black arrow indicates accentuated sclerosis, white arrows show active osteitis, and white arrowheads show active enthesitis.

Source ©Elsevier, European Journal of Radiology, Mager et al, 71, 2, Elsevier Ireland Ltd, 182–8, 2009

A worldwide team of spondyloarthritis experts published a new set of criteria for classifying the axial form of the disease, an action expected to dramatically expand the number of patients identified with axial spondyloarthritis and enable physicians to flag affected patients sooner and start them on treatment. A major hope is that earlier treatment, either with NSAIDs) or tumor necrosis factor (TNF) inhibitors, will help patients by slowing progression of axial spondyloarthritis (SpA). But this anticipated benefit has yet to be supported by study results.

With the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria now published (Ann. Rheum. Dis. 2009;68:770–6; 778–83), it remains unclear whether most U.S. rheumatologists and primary care physicians will buy into the criteria and apply them.

The report showed that the new classification criteria (see box) identified people with axial SpA with a sensitivity of 83% and a specificity of 84% when tested on 649 patients. The new classification criteria were compared against identification by expert rheumatologists.

If implemented, the new criteria would “increase the frequency of diagnosing [axial SpA] by probably threefold, to as high as 1.5%” of the adult U.S. population,” said Dr. John D. Reveille, professor of medicine and director of the division of rheumatology and clinical immunogenetics at the University of Texas at Houston. He based his estimate on the application of the new axial SpA criteria to a representative sample of the U.S. population collected in the National Health and Nutrition Examination Survey (NHANES).

“The new criteria will be helpful in identifying more patients with the disease, and also for recognizing the disease very early,” agreed Dr. Muhammad A. Khan, professor of medicine at Case Western Reserve University in Cleveland. “The new criteria are much better than older criteria, which require x-ray evidence of abnormalities in the sacroiliac joints. With the new criteria, you can make the diagnosis [even] when the x-ray is normal, provided you have MRI evidence,” he said in an interview. Dr. Khan was the sole U.S.-based member of ASAS to serve on the expert panel that devised the new classification criteria.

Axial SpA has typically gone undetected until much later in the course of the disease, when it has progressed to ankylosing spondylitis with its characteristic spinal-bone changes that are visible on plain x-ray films.

“The old classification criteria required patients to have x-ray changes of sacroiliitis, which take 6–10 years to develop after patients have other symptoms,” said Dr. Atul Deodhar, medical director of the rheumatology clinics at the Oregon Health and Science University in Portland. “We definitely need new criteria; we can't call it ankylosing spondylitis if the patient doesn't have x-ray changes. The diagnosis of axial spondyloarthritis is completely new,” he said in an interview.

Identification of inflammation in axial joints using MRI is a key element in the new axial SpA classification. Axial joint inflammation is often hard to diagnose without MRI because the affected joints are in locations that are impossible to palpate, Dr. Deodhar said.

Early diagnosis is vital for timely treatment. Without it, physicians wait to see x-ray evidence of ankylosing spondylitis. A wait of up to 10 years “is a long period of time to deny patients access to medications that have been shown to work in this disease,” Dr. Reveille said.

“We think that if we intervene sooner, we can prevent some of the significant morbidity and disability associated with this condition,” said Dr. John A. Flynn, professor of medicine at Johns Hopkins University in Baltimore. Some rheumatologists “have been doing this [using MRI to help make an early diagnosis of axial SpA] for 5–10 years,” according to Dr. Flynn. “Now clinical science is catching up with that experience, saying we realize that the time from symptom onset to diagnosis has been very long” when the diagnosis relies on x-ray changes. “If the [patient's clinical presentation] sounds good for the condition but the x-rays don't show anything, we should push to get the MRI.”

But Dr. Flynn and Dr. Deodhar stressed that the appearance of axial joint inflammation on MRI is not enough to make the diagnosis, as this can occur in people without axial SpA. Other key factors include age younger than 45 years, slow onset of symptoms, reduced spine mobility, stiffness and pain that worsens with rest but improves with exercise (unlike mechanical back pain that improves with rest and worsens with exercise), and exacerbation of pain and stiffness while sleeping that takes several hours to improve on awakening. “I'm not getting an MRI on the majority of my patients [with back pain] because the back pain that I see is usually not inflammatory; it's mechanical,” said Dr. Flynn.

U.S. experts share concern about how widely the criteria will be applied by other rheumatologists and, perhaps more importantly, by U.S. primary care physicians who see the bulk of these patients initially. “There clearly is a difference of opinion [in the United States and in Europe],” said Dr. Flynn. “I was amazed when I looked at the centers” that participated in the ASAS study. None was in the United States.

The validation study used patients from 25 centers in 16 countries, with 14 of the centers in Europe, 5 in Asia, 4 in Turkey, 1 in Canada, and 1 in Columbia (Ann. Rheum. Dis. 2009;68:777–83).

One possible reason why European rheumatologists have been more active in developing the new criteria is that their population contains a higher proportion of people with the HLA B27 genotype, who are most susceptible to developing axial SpA. “The question is, Are the Europeans not only seeing more, but do they see different patients?” Dr. Flynn noted. “I think you've got to validate [the new criteria] with U.S. patients too.”

“American rheumatologists are still not as well versed in spondyloarthritis as our European colleagues,” Dr. Khan said. But if the new classification criteria were followed, it would result in better patient care, Dr. Reveille said.

Treatment today for axial SpA starts with an NSAID, followed by a course with a second NSAID of a different type if the first fails. If both NSAID regimens fail to produce satisfactory results within 3 months, current standards say the next step is treatment with a TNF inhibitor.

In the United States, those include adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), and golimumab (Simponi). Although none has Food and Drug Administration approval for use in axial SpA, all four are approved for treating ankylosing spondylitis.

Ideal treatments for axial SpA don't include nonbiological disease-modifying drugs, such as methotrexate and sulfasalazine.

No study results have yet documented that early treatment with an NSAID or with a TNF inhibitor slows or stops progression of axial SpA, but specialists are optimistic that such is the case, and that these data will eventually exist.

“We suspect early treatment might have better outcomes; there is the precedent with rheumatoid arthritis,” Dr. Khan said.

In addition, even without evidence of slowed progression, early treatment “clearly improves quality of life and function and reduces time lost from work,” Dr. Flynn said.

The importance of early identification and treatment of spondylitis has been recognized by the leadership of the Spondylitis Association of America (SAA). Researchers working with SAA sponsorship developed a screening tool aimed at helping people with chronic back pain self-identify whether they have indications of an inflammatory process that needs medical evaluation.

A report on the development of the SAA screening tool for ankylosing spondylitis is scheduled to appear in the January issue of Arthritis Care and Research, and then the SAA will publicize it as an Internet-based tool, said SAA executive director Laurie Savage.

Patients with back pain for at least 3 months and with an age of onset younger than 45 years are classified as having spondyloarthritis if they have sacroiliitis on imaging plus at least one spondyloarthritis feature (see below), or if they are HLA B27 positive and have at least two other spondyloarthritis features.

Sacroiliitis on imaging is defined as one of the following:

▸ Active acute inflammation on MRI highly suggestive of sacroiliitis associated with spondyloarthritis.

▸ Definite radiographic sacroiliitis, according to the modified New York criteria.

Spondyloarthritis features include the following:

▸ Inflammatory back pain

▸ Arthritis

▸ Enthesitis

▸ Uveitis

▸ Dactylitis

▸ Psoriasis

▸ Crohn's disease/ulcerative colitis

▸ Good response to NSAIDs

▸ Family history for spondyloarthritis

▸ HLA B27 positive

▸ Elevated C-reactive protein (in the context of chronic back pain)

In these MRI images of a patient with spondyloarthritis, black arrowheads show erosions, a black arrow indicates accentuated sclerosis, white arrows show active osteitis, and white arrowheads show active enthesitis.

Source ©Elsevier, European Journal of Radiology, Mager et al, 71, 2, Elsevier Ireland Ltd, 182–8, 2009

A worldwide team of spondyloarthritis experts published a new set of criteria for classifying the axial form of the disease, an action expected to dramatically expand the number of patients identified with axial spondyloarthritis and enable physicians to flag affected patients sooner and start them on treatment. A major hope is that earlier treatment, either with NSAIDs) or tumor necrosis factor (TNF) inhibitors, will help patients by slowing progression of axial spondyloarthritis (SpA). But this anticipated benefit has yet to be supported by study results.

With the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria now published (Ann. Rheum. Dis. 2009;68:770–6; 778–83), it remains unclear whether most U.S. rheumatologists and primary care physicians will buy into the criteria and apply them.

The report showed that the new classification criteria (see box) identified people with axial SpA with a sensitivity of 83% and a specificity of 84% when tested on 649 patients. The new classification criteria were compared against identification by expert rheumatologists.

If implemented, the new criteria would “increase the frequency of diagnosing [axial SpA] by probably threefold, to as high as 1.5%” of the adult U.S. population,” said Dr. John D. Reveille, professor of medicine and director of the division of rheumatology and clinical immunogenetics at the University of Texas at Houston. He based his estimate on the application of the new axial SpA criteria to a representative sample of the U.S. population collected in the National Health and Nutrition Examination Survey (NHANES).

“The new criteria will be helpful in identifying more patients with the disease, and also for recognizing the disease very early,” agreed Dr. Muhammad A. Khan, professor of medicine at Case Western Reserve University in Cleveland. “The new criteria are much better than older criteria, which require x-ray evidence of abnormalities in the sacroiliac joints. With the new criteria, you can make the diagnosis [even] when the x-ray is normal, provided you have MRI evidence,” he said in an interview. Dr. Khan was the sole U.S.-based member of ASAS to serve on the expert panel that devised the new classification criteria.

Axial SpA has typically gone undetected until much later in the course of the disease, when it has progressed to ankylosing spondylitis with its characteristic spinal-bone changes that are visible on plain x-ray films.

“The old classification criteria required patients to have x-ray changes of sacroiliitis, which take 6–10 years to develop after patients have other symptoms,” said Dr. Atul Deodhar, medical director of the rheumatology clinics at the Oregon Health and Science University in Portland. “We definitely need new criteria; we can't call it ankylosing spondylitis if the patient doesn't have x-ray changes. The diagnosis of axial spondyloarthritis is completely new,” he said in an interview.

Identification of inflammation in axial joints using MRI is a key element in the new axial SpA classification. Axial joint inflammation is often hard to diagnose without MRI because the affected joints are in locations that are impossible to palpate, Dr. Deodhar said.

Early diagnosis is vital for timely treatment. Without it, physicians wait to see x-ray evidence of ankylosing spondylitis. A wait of up to 10 years “is a long period of time to deny patients access to medications that have been shown to work in this disease,” Dr. Reveille said.

“We think that if we intervene sooner, we can prevent some of the significant morbidity and disability associated with this condition,” said Dr. John A. Flynn, professor of medicine at Johns Hopkins University in Baltimore. Some rheumatologists “have been doing this [using MRI to help make an early diagnosis of axial SpA] for 5–10 years,” according to Dr. Flynn. “Now clinical science is catching up with that experience, saying we realize that the time from symptom onset to diagnosis has been very long” when the diagnosis relies on x-ray changes. “If the [patient's clinical presentation] sounds good for the condition but the x-rays don't show anything, we should push to get the MRI.”

But Dr. Flynn and Dr. Deodhar stressed that the appearance of axial joint inflammation on MRI is not enough to make the diagnosis, as this can occur in people without axial SpA. Other key factors include age younger than 45 years, slow onset of symptoms, reduced spine mobility, stiffness and pain that worsens with rest but improves with exercise (unlike mechanical back pain that improves with rest and worsens with exercise), and exacerbation of pain and stiffness while sleeping that takes several hours to improve on awakening. “I'm not getting an MRI on the majority of my patients [with back pain] because the back pain that I see is usually not inflammatory; it's mechanical,” said Dr. Flynn.

U.S. experts share concern about how widely the criteria will be applied by other rheumatologists and, perhaps more importantly, by U.S. primary care physicians who see the bulk of these patients initially. “There clearly is a difference of opinion [in the United States and in Europe],” said Dr. Flynn. “I was amazed when I looked at the centers” that participated in the ASAS study. None was in the United States.

The validation study used patients from 25 centers in 16 countries, with 14 of the centers in Europe, 5 in Asia, 4 in Turkey, 1 in Canada, and 1 in Columbia (Ann. Rheum. Dis. 2009;68:777–83).

One possible reason why European rheumatologists have been more active in developing the new criteria is that their population contains a higher proportion of people with the HLA B27 genotype, who are most susceptible to developing axial SpA. “The question is, Are the Europeans not only seeing more, but do they see different patients?” Dr. Flynn noted. “I think you've got to validate [the new criteria] with U.S. patients too.”

“American rheumatologists are still not as well versed in spondyloarthritis as our European colleagues,” Dr. Khan said. But if the new classification criteria were followed, it would result in better patient care, Dr. Reveille said.

Treatment today for axial SpA starts with an NSAID, followed by a course with a second NSAID of a different type if the first fails. If both NSAID regimens fail to produce satisfactory results within 3 months, current standards say the next step is treatment with a TNF inhibitor.

In the United States, those include adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), and golimumab (Simponi). Although none has Food and Drug Administration approval for use in axial SpA, all four are approved for treating ankylosing spondylitis.

Ideal treatments for axial SpA don't include nonbiological disease-modifying drugs, such as methotrexate and sulfasalazine.

No study results have yet documented that early treatment with an NSAID or with a TNF inhibitor slows or stops progression of axial SpA, but specialists are optimistic that such is the case, and that these data will eventually exist.

“We suspect early treatment might have better outcomes; there is the precedent with rheumatoid arthritis,” Dr. Khan said.

In addition, even without evidence of slowed progression, early treatment “clearly improves quality of life and function and reduces time lost from work,” Dr. Flynn said.

The importance of early identification and treatment of spondylitis has been recognized by the leadership of the Spondylitis Association of America (SAA). Researchers working with SAA sponsorship developed a screening tool aimed at helping people with chronic back pain self-identify whether they have indications of an inflammatory process that needs medical evaluation.

A report on the development of the SAA screening tool for ankylosing spondylitis is scheduled to appear in the January issue of Arthritis Care and Research, and then the SAA will publicize it as an Internet-based tool, said SAA executive director Laurie Savage.

Patients with back pain for at least 3 months and with an age of onset younger than 45 years are classified as having spondyloarthritis if they have sacroiliitis on imaging plus at least one spondyloarthritis feature (see below), or if they are HLA B27 positive and have at least two other spondyloarthritis features.

Sacroiliitis on imaging is defined as one of the following:

▸ Active acute inflammation on MRI highly suggestive of sacroiliitis associated with spondyloarthritis.

▸ Definite radiographic sacroiliitis, according to the modified New York criteria.

Spondyloarthritis features include the following:

▸ Inflammatory back pain

▸ Arthritis

▸ Enthesitis

▸ Uveitis

▸ Dactylitis

▸ Psoriasis

▸ Crohn's disease/ulcerative colitis

▸ Good response to NSAIDs

▸ Family history for spondyloarthritis

▸ HLA B27 positive

▸ Elevated C-reactive protein (in the context of chronic back pain)

In these MRI images of a patient with spondyloarthritis, black arrowheads show erosions, a black arrow indicates accentuated sclerosis, white arrows show active osteitis, and white arrowheads show active enthesitis.

Source ©Elsevier, European Journal of Radiology, Mager et al, 71, 2, Elsevier Ireland Ltd, 182–8, 2009

COPENHAGEN — Etanercept was better than sulfasalazine for improving clinical symptoms in patients with ankylosing spondylitis, regardless of whether they had peripheral joint involvement.

“These findings support the role of etanercept as a key therapy for the management of subjects with AS [ankylosing spondylitis] regardless of peripheral joint involvement,” Dr. Jürgen Braun and his associates reported in a poster at the annual European Congress of Rheumatology.

The results help further solidify the role of tumor necrosis factor (TNF) inhibitors as the standard of care for treating AS, Dr. Braun said in an interview. Until recently, when TNF inhibitors became established as prime agents for treating AS, sulfasalazine had been the most widely used drug in this disorder, said Dr. Braun, director of the regional rheumatology center at St. Josefs Hospital in Herne, Germany.

The new analysis used data collected from 566 patients with active AS who had failed treatment with a NSAID. The study randomized them to either etanercept (Enbrel) 50 mg subcutaneously once weekly or up to 3 g sulfasalazine daily. The study's primary end point was the percentage of patients having a 20% or better improvement from baseline in their disease state, as measured by ASAS (Assessment of AS International Society) 20 criteria, after 16 weeks of treatment. The study was done at several centers in 15 European countries and in China.

The study was sponsored by Wyeth, the company that markets etanercept. Dr. Braun said that he was on the speakers bureau of and received grants from “all companies that sell biologics in the field of SpA.” His coauthors all served as speakers for, received grants from, or were employees of Wyeth.

Dr. Braun and his associates reported results for the entire group of 566 patients last October at the annual meeting of the American College of Rheumatology.

An ASAS 20 response occurred in 76% of 379 patients treated with etanercept and in 51% of 187 patients treated with sulfasalazine, a statistically significant difference (Arthritis Rheum. 2008;58:S415).

In their most recent report on these data at the EULAR Congress, the researchers updated the ASAS 20 response in sulfasalazine-treated patients to 53%, still significantly less than the 76% rate in those treated with etanercept.

Further assessment in a post hoc analysis divided the patients into a group of 374 without swollen peripheral joints, and a group of 181 with at least one swollen peripheral joint. (Joint status wasn't available for the other 11 patients in the study.)

Among the patients with peripheral joint swelling, an ASAS 20 response was still significantly more common in those treated with etanercept (69%) than in those treated with sulfasalazine (50%), they reported in their poster. A significant difference in favor of etanercept also appeared in the subgroup of patients without peripheral joint swelling.

Etanercept was significantly better than sulfasalazine among both subgroups for all of the other efficacy measures reported, including achievement of partial remission, and improvement of several of the Bath AS clinical measures, including the Bath AS Disease Severity Index.

The emergence of etanercept and other TNF inhibitors as substantially more effective than sulfasalazine for treating AS has been a major advance in AS treatment. Although sulfasalazine has been, until recently, the most commonly used drug, it never achieved an anchor role for AS, as methotrexate has for treating rheumatoid arthritis, Dr. Braun said in the interview. The ASAS is now in the process of updating its AS treatment recommendations, which the group last issued in 2005. The updated recommendations should be released by the end of this year, Dr. Braun said.

Figures reported at the EULAR Congress show 76% of patients responded to etanercept, 53% to sulfasalazine.

Source Dr. Braun

COPENHAGEN — Etanercept was better than sulfasalazine for improving clinical symptoms in patients with ankylosing spondylitis, regardless of whether they had peripheral joint involvement.

“These findings support the role of etanercept as a key therapy for the management of subjects with AS [ankylosing spondylitis] regardless of peripheral joint involvement,” Dr. Jürgen Braun and his associates reported in a poster at the annual European Congress of Rheumatology.

The results help further solidify the role of tumor necrosis factor (TNF) inhibitors as the standard of care for treating AS, Dr. Braun said in an interview. Until recently, when TNF inhibitors became established as prime agents for treating AS, sulfasalazine had been the most widely used drug in this disorder, said Dr. Braun, director of the regional rheumatology center at St. Josefs Hospital in Herne, Germany.

The new analysis used data collected from 566 patients with active AS who had failed treatment with a NSAID. The study randomized them to either etanercept (Enbrel) 50 mg subcutaneously once weekly or up to 3 g sulfasalazine daily. The study's primary end point was the percentage of patients having a 20% or better improvement from baseline in their disease state, as measured by ASAS (Assessment of AS International Society) 20 criteria, after 16 weeks of treatment. The study was done at several centers in 15 European countries and in China.

The study was sponsored by Wyeth, the company that markets etanercept. Dr. Braun said that he was on the speakers bureau of and received grants from “all companies that sell biologics in the field of SpA.” His coauthors all served as speakers for, received grants from, or were employees of Wyeth.

Dr. Braun and his associates reported results for the entire group of 566 patients last October at the annual meeting of the American College of Rheumatology.

An ASAS 20 response occurred in 76% of 379 patients treated with etanercept and in 51% of 187 patients treated with sulfasalazine, a statistically significant difference (Arthritis Rheum. 2008;58:S415).

In their most recent report on these data at the EULAR Congress, the researchers updated the ASAS 20 response in sulfasalazine-treated patients to 53%, still significantly less than the 76% rate in those treated with etanercept.

Further assessment in a post hoc analysis divided the patients into a group of 374 without swollen peripheral joints, and a group of 181 with at least one swollen peripheral joint. (Joint status wasn't available for the other 11 patients in the study.)

Among the patients with peripheral joint swelling, an ASAS 20 response was still significantly more common in those treated with etanercept (69%) than in those treated with sulfasalazine (50%), they reported in their poster. A significant difference in favor of etanercept also appeared in the subgroup of patients without peripheral joint swelling.

Etanercept was significantly better than sulfasalazine among both subgroups for all of the other efficacy measures reported, including achievement of partial remission, and improvement of several of the Bath AS clinical measures, including the Bath AS Disease Severity Index.

The emergence of etanercept and other TNF inhibitors as substantially more effective than sulfasalazine for treating AS has been a major advance in AS treatment. Although sulfasalazine has been, until recently, the most commonly used drug, it never achieved an anchor role for AS, as methotrexate has for treating rheumatoid arthritis, Dr. Braun said in the interview. The ASAS is now in the process of updating its AS treatment recommendations, which the group last issued in 2005. The updated recommendations should be released by the end of this year, Dr. Braun said.

Figures reported at the EULAR Congress show 76% of patients responded to etanercept, 53% to sulfasalazine.

Source Dr. Braun

COPENHAGEN — Etanercept was better than sulfasalazine for improving clinical symptoms in patients with ankylosing spondylitis, regardless of whether they had peripheral joint involvement.

“These findings support the role of etanercept as a key therapy for the management of subjects with AS [ankylosing spondylitis] regardless of peripheral joint involvement,” Dr. Jürgen Braun and his associates reported in a poster at the annual European Congress of Rheumatology.

The results help further solidify the role of tumor necrosis factor (TNF) inhibitors as the standard of care for treating AS, Dr. Braun said in an interview. Until recently, when TNF inhibitors became established as prime agents for treating AS, sulfasalazine had been the most widely used drug in this disorder, said Dr. Braun, director of the regional rheumatology center at St. Josefs Hospital in Herne, Germany.

The new analysis used data collected from 566 patients with active AS who had failed treatment with a NSAID. The study randomized them to either etanercept (Enbrel) 50 mg subcutaneously once weekly or up to 3 g sulfasalazine daily. The study's primary end point was the percentage of patients having a 20% or better improvement from baseline in their disease state, as measured by ASAS (Assessment of AS International Society) 20 criteria, after 16 weeks of treatment. The study was done at several centers in 15 European countries and in China.

The study was sponsored by Wyeth, the company that markets etanercept. Dr. Braun said that he was on the speakers bureau of and received grants from “all companies that sell biologics in the field of SpA.” His coauthors all served as speakers for, received grants from, or were employees of Wyeth.

Dr. Braun and his associates reported results for the entire group of 566 patients last October at the annual meeting of the American College of Rheumatology.

An ASAS 20 response occurred in 76% of 379 patients treated with etanercept and in 51% of 187 patients treated with sulfasalazine, a statistically significant difference (Arthritis Rheum. 2008;58:S415).

In their most recent report on these data at the EULAR Congress, the researchers updated the ASAS 20 response in sulfasalazine-treated patients to 53%, still significantly less than the 76% rate in those treated with etanercept.

Further assessment in a post hoc analysis divided the patients into a group of 374 without swollen peripheral joints, and a group of 181 with at least one swollen peripheral joint. (Joint status wasn't available for the other 11 patients in the study.)

Among the patients with peripheral joint swelling, an ASAS 20 response was still significantly more common in those treated with etanercept (69%) than in those treated with sulfasalazine (50%), they reported in their poster. A significant difference in favor of etanercept also appeared in the subgroup of patients without peripheral joint swelling.

Etanercept was significantly better than sulfasalazine among both subgroups for all of the other efficacy measures reported, including achievement of partial remission, and improvement of several of the Bath AS clinical measures, including the Bath AS Disease Severity Index.

The emergence of etanercept and other TNF inhibitors as substantially more effective than sulfasalazine for treating AS has been a major advance in AS treatment. Although sulfasalazine has been, until recently, the most commonly used drug, it never achieved an anchor role for AS, as methotrexate has for treating rheumatoid arthritis, Dr. Braun said in the interview. The ASAS is now in the process of updating its AS treatment recommendations, which the group last issued in 2005. The updated recommendations should be released by the end of this year, Dr. Braun said.

Figures reported at the EULAR Congress show 76% of patients responded to etanercept, 53% to sulfasalazine.

Source Dr. Braun

Estimates of how many patients with gout should be treated with febuxostat range from just 5% to millions, according to experts interviewed for this article.

What is not debatable 6 months after febuxostat went on the U.S. market is that it's clearly the second-line agent behind allopurinol, the experts agreed. Allopurinol retains the top spot because of its substantially larger and longer track record and its dramatically lower cost.

Febuxostat (Uloric) received a warm welcome from gout specialists following its approval by the Food and Drug Administration. It was the first new gout drug in decades, and early U.S. sales numbersfwere in line with expectations of its marketer, Takeda Pharmaceuticals North America Inc., said Heather Dean, Takeda's marketing director for the drug. Several gout experts interviewed for this article said that they had no special concerns about febuxostat's safety, aside from the usual uncertainties that surround any drug when it first enters the market.

Despite that, the type of gout patient who is a good candidates for febuxostat treatment remains controversial. At one end are some experts who concede a scant few percent of gout patients—those who are truly intolerant of or unresponsive to maximum allopurinol treatment—as appropriate candidates. At the other end are specialists who say that febuxostat is the preferred drug for any gout patient who has moderate renal failure or who fails to respond to 300 mg/day of allopurinol, categories that encompass a sizeable fraction, perhaps even a majority, of symptomatic gout patients.

Some of the following facts that play into the decision to treat with allopurinol or febuxostat are undisputable:

▸ Allopurinol (or more accurately, its active form in blood, oxypurinol) is excreted by the kidney, so patients with impaired renal function have higher blood levels of oxypurinol than do patients with normal kidneys, a situation that demands dose adjustment.

▸ Allopurinol is ineffective at the standard dosage of 300 mg/day for perhaps half of gout patients, but in the vast majority of these cases it's effective when the dose is raised. Some specialists will prescribe the labeled maximum (800 mg/day) but many physicians are not comfortable prescribing such high doses.

▸ Febuxostat does not require any dosage adjustment in patients with renal impairment, and is labeled for use only at either 40 mg or 80 mg/day.

▸ Internet-based drug stores sell febuxostat for more than $5 a day vs. 0.10/day for allopurinol.

But much of the split on how gout patients will do on allopurinol compared with febuxostat depends on opinion.

Patients With Renal Insufficiency

Impaired renal function is an issue in gout because uric acid crystals form in kidneys as well as in joints Hyperuricemia itself may cause kidney damage. As a result, “about half the patients with chronic gout have significant impairment of renal function,” said Dr. Peter A. Simkin, a rheumatologist at the University of Washington in Seattle. Some experts, like Dr. Simkin, on't see impaired renal function as a barrier to allopurinol use. “It's both safe and appropriate to use allopurinol in patients with renal insufficiency,” hehe id in an interview. “The main thing [renal insufficiency] means is that patients can often be properly controlled with a low dose of allopurinol. Renal dysfunction is not a reason to not use allopurinol. You start with a low dose and escalate slowly, but that's what we do with allopurinol for any patient. Rengh blood levels of oxypurinol that can occur in patients with renal impairment must be avoided because they boost the risk of a hypersensitivity reaction, milder allergic reactions, or other forms of intolerance. Dr. Simkin said he had no disclosures relevant to febuxostat and allopurinol.

Other specialists say that now that febuxostat is an option, they'll avoid potential problems by immediately jumping to the new drug for patients with impaired renal function. “Allopurinol should be first-line therapy in treating patients with hyperuricemia and gout unless their renal function prohibits use of allopurinol,” said Dr. Robin K. Dore, a rheumatologist at the University of California, Los Angeles. Dr. Dore said she has been a consultant to and has been on the speakers bureau of Takeda, and she participated in some febuxostat studies.

The strategy of avoiding allopurinol entirely in patients with renal dysfunction and going straight to febuxostat was also endorsed by Dr. Naomi Schlesinger, a rheumatologist at the University of Medicine and Dentistry of New Jersey, in New Brunswick. Dr. Schlesinger said that she has served on an advisory board and the speakers bureau of Takeda, and that she has also received research funds from the company.

But febuxostat should not be considered completely free from renal concerns, said Dr. Ted R. Mikuls, a rheumatologist at the University of Nebraska in Omaha. “Studies of febuxostat have not included patients with a serum creatinine level of more than 2.0 mg/dL that I'm aware of,” he said in an interview. “The medical community must demand a lot more data before using [febuxostat] widely in patients with renal failure.” In addition, “I'm not aware of data that allopurinol damages kidneys. What most rheumatologists do is dose it very judiciously in patients with renal dysfunction, gradually increasing it to get the uric acid level where it needs to be.” Dr. Mikuls said he had no disclosures relevant to febuxostat and allopurinol.

“I am not convinced that careful allopurinol dose titration cannot achieve successful management of patients with impaired renal function,” said Dr. Michael A. Becker, a rheumatologist at the University of Chicago. But febuxostatimay already be the “standard of care” for renal dysfunction patients, he said in an interview. Dr. Becker said he has been a consultant to Takeda, and he was a coinvestigator on several of the febuxostat pivotal trials.

Allopurinol Intolerance

A small percentage of gout patients (perhaps fewer than 10%) are intolerant of allopurinol. Intolerance can range from a serious hypersensitivity reaction to a milder allergic reaction or another form of adverse reaction, such as gastrointestinal distress. A patient with hypersensitivity to allopurinol is someone for whom “febuxostat could be really helpful,” but this is “pretty rare, far less than a few percent,” Dr. Mikuls said. “More common are other problems [with allopurinol], such as stomach upset. These reactions may occur in 5%–10% of patients, and this is another group of patients for whom “febuxostat can be really important.” Dr. Simkin differed slightly, estimating the total percentage of allopurinol-intolerant patients to be fewer than 5%.

Lack of Allopurinol Efficacy

In treating symptomatic gout, the guiding number rheumatologists look at is the serum level of uric acid. When the level drops below 6.0 mg/dL, existing uric acid crystals disappear by dissolving into the blood, thereby alleviating symptoms.

Although many patients respond to an allopurinol dosage of less than or up to 300 mg/day (especially if they have renal dysfunction such that their blood level of oxypurinol is unusually high relative to their allopurinol dose), the majority of patients needs more than 300 mg/day, Dr. Simkin said. “It's appropriate to use up to 800 mg/day,” and dosages of 300–800 mg/day are usually effective, he added. But doses this high are also not often prescribed by physicians. “The main reason [why patients have uncontrolled gout] is misuse of allopurinol. Patients don't get treated with adequate doses.”

Patients who don't respond to high allopurinol doses are “very rare,” Dr. Simkin noted. He currently has “two such patients, and they're doing better on febuxostat. There is no reason to think that febuxostat won't be effective in patients who had issues with allopurinol, he said.

“It is clear that a majority of the current gout patient population does not achieve a goal serum urate range of less than 6.0 mg/dL on 300 mg allopurinol,” said Dr. Becker. “Many physicians do not like to go to a higher allopurinol dose.” One reason is that “there is little evidence for allopurinol safety and efficacy [in dosages] greater than 300 mg/day,” he said. Despite the lack of data, “I suspect that very few patients fail treatment with an allopurinol dosage of 600 mg or 800 mg/day,” Dr. Becker said. Patients who do fail at these higher dosages are “probably not likely” to do any better on febuxostat, he added.

When patients don't respond adequately to 300 mg/day of allopurinol, Dr. Mikuls pushes the dosage as high as 800 mg/day, although he's not comfortable treating patients at this level. Patients who are still not at the serum uric acid goal at 800 mg/day should be switched to febuxostat, although it remains unclear how these patients respond following the switch. “I think we'd all like to see a data-driven answer to that question,” he said. But some experts are cautious about any allopurinol dosage above 300 mg/day. No safety data exist for dosages over 300 mg/day of allopurinol, said Dr. Schlesinger. “Now that we have an option, these patients should probably be on febuxostat.”

“In the rheumatology community, most of us routinely use [dosages of] allopurinol greater than 300 mg/day, but data collected by Takeda demonstrate that in the general medical community, 300 mg/day or less” is the dosage typically prescribed, said Dr. Dore. “Personally, I will increase the dose up to 400–500 mg of allopurinol per day before switching to febuxostat.”

The Bottom Line

What does all this mean for the number of gout patients who should get febuxostat? On the low end, estimates range down to fewer than 5%, according to Dr. Simkin, whose total is mostly patients who are intolerant of allopurinol. On the high end, Dr. Schlesinger estimated that “millions” of U.S. gout patients need febuxostat, includinged all gout patients with chronic kidney disease, those who don't respond to a 300 mg/day allopurinol dosage, and those who are allopurinol intolerant.

'Millions' of U.S. gout patients, including those with renal problems, could benefit from febuxostat.

Source Dr. Schlesinger

Estimates of how many patients with gout should be treated with febuxostat range from just 5% to millions, according to experts interviewed for this article.

What is not debatable 6 months after febuxostat went on the U.S. market is that it's clearly the second-line agent behind allopurinol, the experts agreed. Allopurinol retains the top spot because of its substantially larger and longer track record and its dramatically lower cost.

Febuxostat (Uloric) received a warm welcome from gout specialists following its approval by the Food and Drug Administration. It was the first new gout drug in decades, and early U.S. sales numbersfwere in line with expectations of its marketer, Takeda Pharmaceuticals North America Inc., said Heather Dean, Takeda's marketing director for the drug. Several gout experts interviewed for this article said that they had no special concerns about febuxostat's safety, aside from the usual uncertainties that surround any drug when it first enters the market.

Despite that, the type of gout patient who is a good candidates for febuxostat treatment remains controversial. At one end are some experts who concede a scant few percent of gout patients—those who are truly intolerant of or unresponsive to maximum allopurinol treatment—as appropriate candidates. At the other end are specialists who say that febuxostat is the preferred drug for any gout patient who has moderate renal failure or who fails to respond to 300 mg/day of allopurinol, categories that encompass a sizeable fraction, perhaps even a majority, of symptomatic gout patients.

Some of the following facts that play into the decision to treat with allopurinol or febuxostat are undisputable:

▸ Allopurinol (or more accurately, its active form in blood, oxypurinol) is excreted by the kidney, so patients with impaired renal function have higher blood levels of oxypurinol than do patients with normal kidneys, a situation that demands dose adjustment.

▸ Allopurinol is ineffective at the standard dosage of 300 mg/day for perhaps half of gout patients, but in the vast majority of these cases it's effective when the dose is raised. Some specialists will prescribe the labeled maximum (800 mg/day) but many physicians are not comfortable prescribing such high doses.

▸ Febuxostat does not require any dosage adjustment in patients with renal impairment, and is labeled for use only at either 40 mg or 80 mg/day.

▸ Internet-based drug stores sell febuxostat for more than $5 a day vs. 0.10/day for allopurinol.

But much of the split on how gout patients will do on allopurinol compared with febuxostat depends on opinion.

Patients With Renal Insufficiency

Impaired renal function is an issue in gout because uric acid crystals form in kidneys as well as in joints Hyperuricemia itself may cause kidney damage. As a result, “about half the patients with chronic gout have significant impairment of renal function,” said Dr. Peter A. Simkin, a rheumatologist at the University of Washington in Seattle. Some experts, like Dr. Simkin, on't see impaired renal function as a barrier to allopurinol use. “It's both safe and appropriate to use allopurinol in patients with renal insufficiency,” hehe id in an interview. “The main thing [renal insufficiency] means is that patients can often be properly controlled with a low dose of allopurinol. Renal dysfunction is not a reason to not use allopurinol. You start with a low dose and escalate slowly, but that's what we do with allopurinol for any patient. Rengh blood levels of oxypurinol that can occur in patients with renal impairment must be avoided because they boost the risk of a hypersensitivity reaction, milder allergic reactions, or other forms of intolerance. Dr. Simkin said he had no disclosures relevant to febuxostat and allopurinol.

Other specialists say that now that febuxostat is an option, they'll avoid potential problems by immediately jumping to the new drug for patients with impaired renal function. “Allopurinol should be first-line therapy in treating patients with hyperuricemia and gout unless their renal function prohibits use of allopurinol,” said Dr. Robin K. Dore, a rheumatologist at the University of California, Los Angeles. Dr. Dore said she has been a consultant to and has been on the speakers bureau of Takeda, and she participated in some febuxostat studies.

The strategy of avoiding allopurinol entirely in patients with renal dysfunction and going straight to febuxostat was also endorsed by Dr. Naomi Schlesinger, a rheumatologist at the University of Medicine and Dentistry of New Jersey, in New Brunswick. Dr. Schlesinger said that she has served on an advisory board and the speakers bureau of Takeda, and that she has also received research funds from the company.

But febuxostat should not be considered completely free from renal concerns, said Dr. Ted R. Mikuls, a rheumatologist at the University of Nebraska in Omaha. “Studies of febuxostat have not included patients with a serum creatinine level of more than 2.0 mg/dL that I'm aware of,” he said in an interview. “The medical community must demand a lot more data before using [febuxostat] widely in patients with renal failure.” In addition, “I'm not aware of data that allopurinol damages kidneys. What most rheumatologists do is dose it very judiciously in patients with renal dysfunction, gradually increasing it to get the uric acid level where it needs to be.” Dr. Mikuls said he had no disclosures relevant to febuxostat and allopurinol.

“I am not convinced that careful allopurinol dose titration cannot achieve successful management of patients with impaired renal function,” said Dr. Michael A. Becker, a rheumatologist at the University of Chicago. But febuxostatimay already be the “standard of care” for renal dysfunction patients, he said in an interview. Dr. Becker said he has been a consultant to Takeda, and he was a coinvestigator on several of the febuxostat pivotal trials.

Allopurinol Intolerance

A small percentage of gout patients (perhaps fewer than 10%) are intolerant of allopurinol. Intolerance can range from a serious hypersensitivity reaction to a milder allergic reaction or another form of adverse reaction, such as gastrointestinal distress. A patient with hypersensitivity to allopurinol is someone for whom “febuxostat could be really helpful,” but this is “pretty rare, far less than a few percent,” Dr. Mikuls said. “More common are other problems [with allopurinol], such as stomach upset. These reactions may occur in 5%–10% of patients, and this is another group of patients for whom “febuxostat can be really important.” Dr. Simkin differed slightly, estimating the total percentage of allopurinol-intolerant patients to be fewer than 5%.

Lack of Allopurinol Efficacy

In treating symptomatic gout, the guiding number rheumatologists look at is the serum level of uric acid. When the level drops below 6.0 mg/dL, existing uric acid crystals disappear by dissolving into the blood, thereby alleviating symptoms.

Although many patients respond to an allopurinol dosage of less than or up to 300 mg/day (especially if they have renal dysfunction such that their blood level of oxypurinol is unusually high relative to their allopurinol dose), the majority of patients needs more than 300 mg/day, Dr. Simkin said. “It's appropriate to use up to 800 mg/day,” and dosages of 300–800 mg/day are usually effective, he added. But doses this high are also not often prescribed by physicians. “The main reason [why patients have uncontrolled gout] is misuse of allopurinol. Patients don't get treated with adequate doses.”

Patients who don't respond to high allopurinol doses are “very rare,” Dr. Simkin noted. He currently has “two such patients, and they're doing better on febuxostat. There is no reason to think that febuxostat won't be effective in patients who had issues with allopurinol, he said.

“It is clear that a majority of the current gout patient population does not achieve a goal serum urate range of less than 6.0 mg/dL on 300 mg allopurinol,” said Dr. Becker. “Many physicians do not like to go to a higher allopurinol dose.” One reason is that “there is little evidence for allopurinol safety and efficacy [in dosages] greater than 300 mg/day,” he said. Despite the lack of data, “I suspect that very few patients fail treatment with an allopurinol dosage of 600 mg or 800 mg/day,” Dr. Becker said. Patients who do fail at these higher dosages are “probably not likely” to do any better on febuxostat, he added.

When patients don't respond adequately to 300 mg/day of allopurinol, Dr. Mikuls pushes the dosage as high as 800 mg/day, although he's not comfortable treating patients at this level. Patients who are still not at the serum uric acid goal at 800 mg/day should be switched to febuxostat, although it remains unclear how these patients respond following the switch. “I think we'd all like to see a data-driven answer to that question,” he said. But some experts are cautious about any allopurinol dosage above 300 mg/day. No safety data exist for dosages over 300 mg/day of allopurinol, said Dr. Schlesinger. “Now that we have an option, these patients should probably be on febuxostat.”

“In the rheumatology community, most of us routinely use [dosages of] allopurinol greater than 300 mg/day, but data collected by Takeda demonstrate that in the general medical community, 300 mg/day or less” is the dosage typically prescribed, said Dr. Dore. “Personally, I will increase the dose up to 400–500 mg of allopurinol per day before switching to febuxostat.”

The Bottom Line

What does all this mean for the number of gout patients who should get febuxostat? On the low end, estimates range down to fewer than 5%, according to Dr. Simkin, whose total is mostly patients who are intolerant of allopurinol. On the high end, Dr. Schlesinger estimated that “millions” of U.S. gout patients need febuxostat, includinged all gout patients with chronic kidney disease, those who don't respond to a 300 mg/day allopurinol dosage, and those who are allopurinol intolerant.

'Millions' of U.S. gout patients, including those with renal problems, could benefit from febuxostat.

Source Dr. Schlesinger

Estimates of how many patients with gout should be treated with febuxostat range from just 5% to millions, according to experts interviewed for this article.

What is not debatable 6 months after febuxostat went on the U.S. market is that it's clearly the second-line agent behind allopurinol, the experts agreed. Allopurinol retains the top spot because of its substantially larger and longer track record and its dramatically lower cost.

Febuxostat (Uloric) received a warm welcome from gout specialists following its approval by the Food and Drug Administration. It was the first new gout drug in decades, and early U.S. sales numbersfwere in line with expectations of its marketer, Takeda Pharmaceuticals North America Inc., said Heather Dean, Takeda's marketing director for the drug. Several gout experts interviewed for this article said that they had no special concerns about febuxostat's safety, aside from the usual uncertainties that surround any drug when it first enters the market.

Despite that, the type of gout patient who is a good candidates for febuxostat treatment remains controversial. At one end are some experts who concede a scant few percent of gout patients—those who are truly intolerant of or unresponsive to maximum allopurinol treatment—as appropriate candidates. At the other end are specialists who say that febuxostat is the preferred drug for any gout patient who has moderate renal failure or who fails to respond to 300 mg/day of allopurinol, categories that encompass a sizeable fraction, perhaps even a majority, of symptomatic gout patients.

Some of the following facts that play into the decision to treat with allopurinol or febuxostat are undisputable:

▸ Allopurinol (or more accurately, its active form in blood, oxypurinol) is excreted by the kidney, so patients with impaired renal function have higher blood levels of oxypurinol than do patients with normal kidneys, a situation that demands dose adjustment.

▸ Allopurinol is ineffective at the standard dosage of 300 mg/day for perhaps half of gout patients, but in the vast majority of these cases it's effective when the dose is raised. Some specialists will prescribe the labeled maximum (800 mg/day) but many physicians are not comfortable prescribing such high doses.

▸ Febuxostat does not require any dosage adjustment in patients with renal impairment, and is labeled for use only at either 40 mg or 80 mg/day.

▸ Internet-based drug stores sell febuxostat for more than $5 a day vs. 0.10/day for allopurinol.

But much of the split on how gout patients will do on allopurinol compared with febuxostat depends on opinion.

Patients With Renal Insufficiency

Impaired renal function is an issue in gout because uric acid crystals form in kidneys as well as in joints Hyperuricemia itself may cause kidney damage. As a result, “about half the patients with chronic gout have significant impairment of renal function,” said Dr. Peter A. Simkin, a rheumatologist at the University of Washington in Seattle. Some experts, like Dr. Simkin, on't see impaired renal function as a barrier to allopurinol use. “It's both safe and appropriate to use allopurinol in patients with renal insufficiency,” hehe id in an interview. “The main thing [renal insufficiency] means is that patients can often be properly controlled with a low dose of allopurinol. Renal dysfunction is not a reason to not use allopurinol. You start with a low dose and escalate slowly, but that's what we do with allopurinol for any patient. Rengh blood levels of oxypurinol that can occur in patients with renal impairment must be avoided because they boost the risk of a hypersensitivity reaction, milder allergic reactions, or other forms of intolerance. Dr. Simkin said he had no disclosures relevant to febuxostat and allopurinol.

Other specialists say that now that febuxostat is an option, they'll avoid potential problems by immediately jumping to the new drug for patients with impaired renal function. “Allopurinol should be first-line therapy in treating patients with hyperuricemia and gout unless their renal function prohibits use of allopurinol,” said Dr. Robin K. Dore, a rheumatologist at the University of California, Los Angeles. Dr. Dore said she has been a consultant to and has been on the speakers bureau of Takeda, and she participated in some febuxostat studies.

The strategy of avoiding allopurinol entirely in patients with renal dysfunction and going straight to febuxostat was also endorsed by Dr. Naomi Schlesinger, a rheumatologist at the University of Medicine and Dentistry of New Jersey, in New Brunswick. Dr. Schlesinger said that she has served on an advisory board and the speakers bureau of Takeda, and that she has also received research funds from the company.

But febuxostat should not be considered completely free from renal concerns, said Dr. Ted R. Mikuls, a rheumatologist at the University of Nebraska in Omaha. “Studies of febuxostat have not included patients with a serum creatinine level of more than 2.0 mg/dL that I'm aware of,” he said in an interview. “The medical community must demand a lot more data before using [febuxostat] widely in patients with renal failure.” In addition, “I'm not aware of data that allopurinol damages kidneys. What most rheumatologists do is dose it very judiciously in patients with renal dysfunction, gradually increasing it to get the uric acid level where it needs to be.” Dr. Mikuls said he had no disclosures relevant to febuxostat and allopurinol.

“I am not convinced that careful allopurinol dose titration cannot achieve successful management of patients with impaired renal function,” said Dr. Michael A. Becker, a rheumatologist at the University of Chicago. But febuxostatimay already be the “standard of care” for renal dysfunction patients, he said in an interview. Dr. Becker said he has been a consultant to Takeda, and he was a coinvestigator on several of the febuxostat pivotal trials.

Allopurinol Intolerance

A small percentage of gout patients (perhaps fewer than 10%) are intolerant of allopurinol. Intolerance can range from a serious hypersensitivity reaction to a milder allergic reaction or another form of adverse reaction, such as gastrointestinal distress. A patient with hypersensitivity to allopurinol is someone for whom “febuxostat could be really helpful,” but this is “pretty rare, far less than a few percent,” Dr. Mikuls said. “More common are other problems [with allopurinol], such as stomach upset. These reactions may occur in 5%–10% of patients, and this is another group of patients for whom “febuxostat can be really important.” Dr. Simkin differed slightly, estimating the total percentage of allopurinol-intolerant patients to be fewer than 5%.

Lack of Allopurinol Efficacy

In treating symptomatic gout, the guiding number rheumatologists look at is the serum level of uric acid. When the level drops below 6.0 mg/dL, existing uric acid crystals disappear by dissolving into the blood, thereby alleviating symptoms.

Although many patients respond to an allopurinol dosage of less than or up to 300 mg/day (especially if they have renal dysfunction such that their blood level of oxypurinol is unusually high relative to their allopurinol dose), the majority of patients needs more than 300 mg/day, Dr. Simkin said. “It's appropriate to use up to 800 mg/day,” and dosages of 300–800 mg/day are usually effective, he added. But doses this high are also not often prescribed by physicians. “The main reason [why patients have uncontrolled gout] is misuse of allopurinol. Patients don't get treated with adequate doses.”

Patients who don't respond to high allopurinol doses are “very rare,” Dr. Simkin noted. He currently has “two such patients, and they're doing better on febuxostat. There is no reason to think that febuxostat won't be effective in patients who had issues with allopurinol, he said.

“It is clear that a majority of the current gout patient population does not achieve a goal serum urate range of less than 6.0 mg/dL on 300 mg allopurinol,” said Dr. Becker. “Many physicians do not like to go to a higher allopurinol dose.” One reason is that “there is little evidence for allopurinol safety and efficacy [in dosages] greater than 300 mg/day,” he said. Despite the lack of data, “I suspect that very few patients fail treatment with an allopurinol dosage of 600 mg or 800 mg/day,” Dr. Becker said. Patients who do fail at these higher dosages are “probably not likely” to do any better on febuxostat, he added.

When patients don't respond adequately to 300 mg/day of allopurinol, Dr. Mikuls pushes the dosage as high as 800 mg/day, although he's not comfortable treating patients at this level. Patients who are still not at the serum uric acid goal at 800 mg/day should be switched to febuxostat, although it remains unclear how these patients respond following the switch. “I think we'd all like to see a data-driven answer to that question,” he said. But some experts are cautious about any allopurinol dosage above 300 mg/day. No safety data exist for dosages over 300 mg/day of allopurinol, said Dr. Schlesinger. “Now that we have an option, these patients should probably be on febuxostat.”

“In the rheumatology community, most of us routinely use [dosages of] allopurinol greater than 300 mg/day, but data collected by Takeda demonstrate that in the general medical community, 300 mg/day or less” is the dosage typically prescribed, said Dr. Dore. “Personally, I will increase the dose up to 400–500 mg of allopurinol per day before switching to febuxostat.”

The Bottom Line

What does all this mean for the number of gout patients who should get febuxostat? On the low end, estimates range down to fewer than 5%, according to Dr. Simkin, whose total is mostly patients who are intolerant of allopurinol. On the high end, Dr. Schlesinger estimated that “millions” of U.S. gout patients need febuxostat, includinged all gout patients with chronic kidney disease, those who don't respond to a 300 mg/day allopurinol dosage, and those who are allopurinol intolerant.

'Millions' of U.S. gout patients, including those with renal problems, could benefit from febuxostat.

Source Dr. Schlesinger

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati

Patients with osteoarthritis of the knee who undergo arthroscopic meniscectomy have better outcomes at 6 weeks' follow-up if they receive a steroid injection in the knee joint after surgery, according to the results of a randomized, controlled trial.

The meniscectomy patients who received an intra-articular steroid/lidocaine injection reported significantly less pain and better function at 6 weeks' follow-up than did patients who received a saline/lidocaine injection, sinvestigators reported.

The difference between groups disappeared by 6 months after the operation, however.

The study cohort consisted of 58 patients (59 knees) with a meniscal tear who were treated with arthroscopic surgery at Rush University Medical Center, Chicago, between December 2004 and January 2007. All patients had confirmed chondromalacia (modified Outerbridge grade 2 or higher) in the ipsilateral knee. Exclusion criteria included a steroid injection in the 2 months prior to surgery and inadequate follow-up data. A single surgeon performed all the operations.

Before surgery, patients were randomized in a double-blinded manner to receive a postoperative injection of lidocaine plus either 1 mL (40 mg) of methylprednisolone (Depo-Medrol) or 1 mL of 0.9% normal saline. The injection was administered into the knee after the arthroscopic portals were closed.

The steroid group (19 men, 10 women) had a mean age of 49 years, and the saline group (22 men, 8 women) had a mean age of 52 years.

Before surgery and at follow-up times of 6 weeks and 6, 9, and 12 months, patients had an exam and completed a subjective function survey. The investigators calculated function scores using several systems, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, International Knee Documentation Committee (IKDC) score, and Short Form-12. There were no significant differences in preoperative scores between groups.

At 6 weeks' follow-up, the steroid group had significantly better scores than did the saline group on the KOOS sport scale, KOOS qQuality of life scale, and IKDC and treatment satisfaction scales, according to the investigators, led by Dr. Loukas Koyonos (Am. J. Sports Med. 2009;37:1077–82).

At 6, 9, and 12 months, “score differences between the steroid and saline groups had disappeared,” the investigators wrote. At these time points, both groups showed significant improvements over their preoperative scores on all scales except the SF-12. By 12 months' follow-up, 86% of the steroid group and 69% of the saline group were “completely or mostly satisfied” with the surgery.

“The addition of a postoperative corticosteroid injection resulted in improved pain and function at an early time point; however, it provided no lasting difference compared with only local anesthetic injection,” the researchers concluded. Additional trials “are necessary to further characterize the benefits, indications, and durability of intra-articular corticosteroid injections” in the setting of OA.

Limitations included the fact that “the study was underpowered to detect a significant difference in the distribution of chondromalacia and meniscectomies,” they wrote.

In addition, “the saline group had a higher prevalence of tricompartmental arthritis and bilateral meniscectomies, suggestive of a more advanced disease state, which may contribute to the lower scores observed in these patients.”

The authors reported that this research was supported by a grant from Pfizer Inc.

Patients with osteoarthritis of the knee who undergo arthroscopic meniscectomy have better outcomes at 6 weeks' follow-up if they receive a steroid injection in the knee joint after surgery, according to the results of a randomized, controlled trial.

The meniscectomy patients who received an intra-articular steroid/lidocaine injection reported significantly less pain and better function at 6 weeks' follow-up than did patients who received a saline/lidocaine injection, sinvestigators reported.

The difference between groups disappeared by 6 months after the operation, however.

The study cohort consisted of 58 patients (59 knees) with a meniscal tear who were treated with arthroscopic surgery at Rush University Medical Center, Chicago, between December 2004 and January 2007. All patients had confirmed chondromalacia (modified Outerbridge grade 2 or higher) in the ipsilateral knee. Exclusion criteria included a steroid injection in the 2 months prior to surgery and inadequate follow-up data. A single surgeon performed all the operations.

Before surgery, patients were randomized in a double-blinded manner to receive a postoperative injection of lidocaine plus either 1 mL (40 mg) of methylprednisolone (Depo-Medrol) or 1 mL of 0.9% normal saline. The injection was administered into the knee after the arthroscopic portals were closed.

The steroid group (19 men, 10 women) had a mean age of 49 years, and the saline group (22 men, 8 women) had a mean age of 52 years.

Before surgery and at follow-up times of 6 weeks and 6, 9, and 12 months, patients had an exam and completed a subjective function survey. The investigators calculated function scores using several systems, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, International Knee Documentation Committee (IKDC) score, and Short Form-12. There were no significant differences in preoperative scores between groups.

At 6 weeks' follow-up, the steroid group had significantly better scores than did the saline group on the KOOS sport scale, KOOS qQuality of life scale, and IKDC and treatment satisfaction scales, according to the investigators, led by Dr. Loukas Koyonos (Am. J. Sports Med. 2009;37:1077–82).

At 6, 9, and 12 months, “score differences between the steroid and saline groups had disappeared,” the investigators wrote. At these time points, both groups showed significant improvements over their preoperative scores on all scales except the SF-12. By 12 months' follow-up, 86% of the steroid group and 69% of the saline group were “completely or mostly satisfied” with the surgery.

“The addition of a postoperative corticosteroid injection resulted in improved pain and function at an early time point; however, it provided no lasting difference compared with only local anesthetic injection,” the researchers concluded. Additional trials “are necessary to further characterize the benefits, indications, and durability of intra-articular corticosteroid injections” in the setting of OA.

Limitations included the fact that “the study was underpowered to detect a significant difference in the distribution of chondromalacia and meniscectomies,” they wrote.

In addition, “the saline group had a higher prevalence of tricompartmental arthritis and bilateral meniscectomies, suggestive of a more advanced disease state, which may contribute to the lower scores observed in these patients.”

The authors reported that this research was supported by a grant from Pfizer Inc.

Patients with osteoarthritis of the knee who undergo arthroscopic meniscectomy have better outcomes at 6 weeks' follow-up if they receive a steroid injection in the knee joint after surgery, according to the results of a randomized, controlled trial.

The meniscectomy patients who received an intra-articular steroid/lidocaine injection reported significantly less pain and better function at 6 weeks' follow-up than did patients who received a saline/lidocaine injection, sinvestigators reported.

The difference between groups disappeared by 6 months after the operation, however.

The study cohort consisted of 58 patients (59 knees) with a meniscal tear who were treated with arthroscopic surgery at Rush University Medical Center, Chicago, between December 2004 and January 2007. All patients had confirmed chondromalacia (modified Outerbridge grade 2 or higher) in the ipsilateral knee. Exclusion criteria included a steroid injection in the 2 months prior to surgery and inadequate follow-up data. A single surgeon performed all the operations.

Before surgery, patients were randomized in a double-blinded manner to receive a postoperative injection of lidocaine plus either 1 mL (40 mg) of methylprednisolone (Depo-Medrol) or 1 mL of 0.9% normal saline. The injection was administered into the knee after the arthroscopic portals were closed.

The steroid group (19 men, 10 women) had a mean age of 49 years, and the saline group (22 men, 8 women) had a mean age of 52 years.

Before surgery and at follow-up times of 6 weeks and 6, 9, and 12 months, patients had an exam and completed a subjective function survey. The investigators calculated function scores using several systems, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm score, International Knee Documentation Committee (IKDC) score, and Short Form-12. There were no significant differences in preoperative scores between groups.

At 6 weeks' follow-up, the steroid group had significantly better scores than did the saline group on the KOOS sport scale, KOOS qQuality of life scale, and IKDC and treatment satisfaction scales, according to the investigators, led by Dr. Loukas Koyonos (Am. J. Sports Med. 2009;37:1077–82).

At 6, 9, and 12 months, “score differences between the steroid and saline groups had disappeared,” the investigators wrote. At these time points, both groups showed significant improvements over their preoperative scores on all scales except the SF-12. By 12 months' follow-up, 86% of the steroid group and 69% of the saline group were “completely or mostly satisfied” with the surgery.

“The addition of a postoperative corticosteroid injection resulted in improved pain and function at an early time point; however, it provided no lasting difference compared with only local anesthetic injection,” the researchers concluded. Additional trials “are necessary to further characterize the benefits, indications, and durability of intra-articular corticosteroid injections” in the setting of OA.

Limitations included the fact that “the study was underpowered to detect a significant difference in the distribution of chondromalacia and meniscectomies,” they wrote.

In addition, “the saline group had a higher prevalence of tricompartmental arthritis and bilateral meniscectomies, suggestive of a more advanced disease state, which may contribute to the lower scores observed in these patients.”

The authors reported that this research was supported by a grant from Pfizer Inc.

COPENHAGEN — New criteria for diagnosing peripheral spondylarthritis from the Assessment of Spondyloarthritis International Society had a higher sensitivity and specificity than did either of the diagnostic schemes currently used.

The new criteria “performed well in patients with predominantly peripheral manifestations [of spondyloarthritis (SpA)], and appeared to be better balanced in [this] study” than were the two diagnostic formulas most often used today: the system of the European Spondylarthropathy Study Group (ESSG), and the system developed by Dr. Bernard Amor, said Dr. Martin Rudwaleit at the annual European Congress of Rheumatology. Both the ESSG and the Amor criteria were first introduced nearly 20 years ago.

“I assume that, in the past, many patients who were thought to have undifferentiated arthritis had, in fact, SpA. These patients will be better captured with the new criteria. The new criteria were designed to help rheumatologists [who are] less experienced with SpA,” said Dr. Rudwaleit, a rheumatologist at Charité University Hospital Berlin and a member of the Assessment of Spondyloarthritis International Society (ASAS).

The new peripheral SpA criteria complement the new ASAS criteria, published in June, for diagnosing predominantly axial SpA (Ann. Rheum. Dis. 2009;68:770-6;777-83).

The major difference between the new peripheral SpA criteria and the ESSG and Amor criteria is the addition of positivity for HLA B27 as a strong determinant of SpA, along with peripheral arthritis, enthesitis, or dactylitis, Dr. Rudwaleit said in an interview. “HLA B27 is an important marker for SpA.”

Many rheumatologists who specialize in SpA “would say that if a patient has peripheral arthritis and has HLA B27, and if you rule out other possibilities such as peripheral rheumatoid arthritis, then they have SpA, and this is really new for the criteria. It's probably why the sensitivity was better. The ESSG misses these patients because in them HLA B27 has no role. In the Amor criteria, peripheral arthritis and HLA B27 without additional SpA features do not suffice for classifying a patient with SpA.”

Among the patients who were used to test the criteria, HLA B27 occurred in 46% of those diagnosed with SpA by the experts, compared with 6% of patients who were not diagnosed with SpA.

To develop the new peripheral SpA diagnostic criteria, the ASAS invited its membership of about 100 rheumatologists to participate; 28 members were actively involved. They developed two slightly different sets of criteria that they then tested using a multicenter series of 266 patients with predominantly peripheral arthritis of the SpA type.

Each participating ASAS rheumatologist carefully examined each peripheral arthritis patient at his or her institution, and determined a “gold standard” diagnosis of either SpA or not-SpA, based on experience and judgment. They diagnosed 176 patients (66%) with SpA; the remaining 90 patients didn't have SpA, the experts said. Each patient was then assessed by both of the new, draft ASAS criteria sets, as well as by the ESSG and Amor criteria.

The ASAS criteria set that performed best is useful in diagnosing peripheral SpA in patients who present with peripheral arthritis of the SpA type (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus at least one additional feature from list 1, or at least two additional features from list 2. (See box.)

When applied to the 266 test patients and compared with the diagnosis of each patient by the consulting ASAS experts, the ASAS criteria had a sensitivity of 75% and specificity of 82%. In contrast, the ESSG criteria had a sensitivity of 55% and a specificity of 81%, the Amor criteria had a sensitivity of 35% and a specificity of 98%, and the alternative ASAS criteria had a sensitivity of 63% and a specificity of 90%, Dr. Rudwaleit reported.

The new ASAS criteria will be published toward the end of the year.

Dr. Rudwaleit said that he and his associates had no relevant conflicts of interest to disclose.

ASAS Criteria for Peripheral SpA

Patients need to have peripheral arthritis (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus either:

At least one of these features:

Crohn's disease

HLA B27

Preceding infection

Psoriasis

Sacroiliitis on MRI/x-ray imaging

Uveitis

Or at least two of these features:

Arthritis

Dactylitis

Enthesitis

Family history of spondyloarthritis

Inflammatory back pain

Source: Dr. Rudwaleit

COPENHAGEN — New criteria for diagnosing peripheral spondylarthritis from the Assessment of Spondyloarthritis International Society had a higher sensitivity and specificity than did either of the diagnostic schemes currently used.

The new criteria “performed well in patients with predominantly peripheral manifestations [of spondyloarthritis (SpA)], and appeared to be better balanced in [this] study” than were the two diagnostic formulas most often used today: the system of the European Spondylarthropathy Study Group (ESSG), and the system developed by Dr. Bernard Amor, said Dr. Martin Rudwaleit at the annual European Congress of Rheumatology. Both the ESSG and the Amor criteria were first introduced nearly 20 years ago.

“I assume that, in the past, many patients who were thought to have undifferentiated arthritis had, in fact, SpA. These patients will be better captured with the new criteria. The new criteria were designed to help rheumatologists [who are] less experienced with SpA,” said Dr. Rudwaleit, a rheumatologist at Charité University Hospital Berlin and a member of the Assessment of Spondyloarthritis International Society (ASAS).

The new peripheral SpA criteria complement the new ASAS criteria, published in June, for diagnosing predominantly axial SpA (Ann. Rheum. Dis. 2009;68:770-6;777-83).

The major difference between the new peripheral SpA criteria and the ESSG and Amor criteria is the addition of positivity for HLA B27 as a strong determinant of SpA, along with peripheral arthritis, enthesitis, or dactylitis, Dr. Rudwaleit said in an interview. “HLA B27 is an important marker for SpA.”

Many rheumatologists who specialize in SpA “would say that if a patient has peripheral arthritis and has HLA B27, and if you rule out other possibilities such as peripheral rheumatoid arthritis, then they have SpA, and this is really new for the criteria. It's probably why the sensitivity was better. The ESSG misses these patients because in them HLA B27 has no role. In the Amor criteria, peripheral arthritis and HLA B27 without additional SpA features do not suffice for classifying a patient with SpA.”

Among the patients who were used to test the criteria, HLA B27 occurred in 46% of those diagnosed with SpA by the experts, compared with 6% of patients who were not diagnosed with SpA.

To develop the new peripheral SpA diagnostic criteria, the ASAS invited its membership of about 100 rheumatologists to participate; 28 members were actively involved. They developed two slightly different sets of criteria that they then tested using a multicenter series of 266 patients with predominantly peripheral arthritis of the SpA type.

Each participating ASAS rheumatologist carefully examined each peripheral arthritis patient at his or her institution, and determined a “gold standard” diagnosis of either SpA or not-SpA, based on experience and judgment. They diagnosed 176 patients (66%) with SpA; the remaining 90 patients didn't have SpA, the experts said. Each patient was then assessed by both of the new, draft ASAS criteria sets, as well as by the ESSG and Amor criteria.

The ASAS criteria set that performed best is useful in diagnosing peripheral SpA in patients who present with peripheral arthritis of the SpA type (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus at least one additional feature from list 1, or at least two additional features from list 2. (See box.)

When applied to the 266 test patients and compared with the diagnosis of each patient by the consulting ASAS experts, the ASAS criteria had a sensitivity of 75% and specificity of 82%. In contrast, the ESSG criteria had a sensitivity of 55% and a specificity of 81%, the Amor criteria had a sensitivity of 35% and a specificity of 98%, and the alternative ASAS criteria had a sensitivity of 63% and a specificity of 90%, Dr. Rudwaleit reported.

The new ASAS criteria will be published toward the end of the year.

Dr. Rudwaleit said that he and his associates had no relevant conflicts of interest to disclose.

ASAS Criteria for Peripheral SpA

Patients need to have peripheral arthritis (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus either:

At least one of these features:

Crohn's disease

HLA B27

Preceding infection

Psoriasis

Sacroiliitis on MRI/x-ray imaging

Uveitis

Or at least two of these features:

Arthritis

Dactylitis

Enthesitis

Family history of spondyloarthritis

Inflammatory back pain

Source: Dr. Rudwaleit

COPENHAGEN — New criteria for diagnosing peripheral spondylarthritis from the Assessment of Spondyloarthritis International Society had a higher sensitivity and specificity than did either of the diagnostic schemes currently used.

The new criteria “performed well in patients with predominantly peripheral manifestations [of spondyloarthritis (SpA)], and appeared to be better balanced in [this] study” than were the two diagnostic formulas most often used today: the system of the European Spondylarthropathy Study Group (ESSG), and the system developed by Dr. Bernard Amor, said Dr. Martin Rudwaleit at the annual European Congress of Rheumatology. Both the ESSG and the Amor criteria were first introduced nearly 20 years ago.

“I assume that, in the past, many patients who were thought to have undifferentiated arthritis had, in fact, SpA. These patients will be better captured with the new criteria. The new criteria were designed to help rheumatologists [who are] less experienced with SpA,” said Dr. Rudwaleit, a rheumatologist at Charité University Hospital Berlin and a member of the Assessment of Spondyloarthritis International Society (ASAS).

The new peripheral SpA criteria complement the new ASAS criteria, published in June, for diagnosing predominantly axial SpA (Ann. Rheum. Dis. 2009;68:770-6;777-83).

The major difference between the new peripheral SpA criteria and the ESSG and Amor criteria is the addition of positivity for HLA B27 as a strong determinant of SpA, along with peripheral arthritis, enthesitis, or dactylitis, Dr. Rudwaleit said in an interview. “HLA B27 is an important marker for SpA.”

Many rheumatologists who specialize in SpA “would say that if a patient has peripheral arthritis and has HLA B27, and if you rule out other possibilities such as peripheral rheumatoid arthritis, then they have SpA, and this is really new for the criteria. It's probably why the sensitivity was better. The ESSG misses these patients because in them HLA B27 has no role. In the Amor criteria, peripheral arthritis and HLA B27 without additional SpA features do not suffice for classifying a patient with SpA.”

Among the patients who were used to test the criteria, HLA B27 occurred in 46% of those diagnosed with SpA by the experts, compared with 6% of patients who were not diagnosed with SpA.

To develop the new peripheral SpA diagnostic criteria, the ASAS invited its membership of about 100 rheumatologists to participate; 28 members were actively involved. They developed two slightly different sets of criteria that they then tested using a multicenter series of 266 patients with predominantly peripheral arthritis of the SpA type.

Each participating ASAS rheumatologist carefully examined each peripheral arthritis patient at his or her institution, and determined a “gold standard” diagnosis of either SpA or not-SpA, based on experience and judgment. They diagnosed 176 patients (66%) with SpA; the remaining 90 patients didn't have SpA, the experts said. Each patient was then assessed by both of the new, draft ASAS criteria sets, as well as by the ESSG and Amor criteria.

The ASAS criteria set that performed best is useful in diagnosing peripheral SpA in patients who present with peripheral arthritis of the SpA type (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus at least one additional feature from list 1, or at least two additional features from list 2. (See box.)

When applied to the 266 test patients and compared with the diagnosis of each patient by the consulting ASAS experts, the ASAS criteria had a sensitivity of 75% and specificity of 82%. In contrast, the ESSG criteria had a sensitivity of 55% and a specificity of 81%, the Amor criteria had a sensitivity of 35% and a specificity of 98%, and the alternative ASAS criteria had a sensitivity of 63% and a specificity of 90%, Dr. Rudwaleit reported.

The new ASAS criteria will be published toward the end of the year.

Dr. Rudwaleit said that he and his associates had no relevant conflicts of interest to disclose.

ASAS Criteria for Peripheral SpA

Patients need to have peripheral arthritis (asymmetric, lower limb, or both), enthesitis, or dactylitis, plus either:

At least one of these features:

Crohn's disease

HLA B27

Preceding infection

Psoriasis

Sacroiliitis on MRI/x-ray imaging

Uveitis

Or at least two of these features:

Arthritis

Dactylitis

Enthesitis

Family history of spondyloarthritis

Inflammatory back pain

Source: Dr. Rudwaleit

COPENHAGEN — Patients with refractory chronic gout who were put on pegloticase had statistically significant and clinically meaningful improvements in their health-related quality of life after 25 weeks of treatment in two placebo-controlled studies with a total of 157 patients.

Refractory chronic gout accounts for a small subset of patients with gout (about 1%-2%) who have significantly lower health-related quality of life scores than do age- and sex-matched norms. Combined results from two similar studies of the investigational drug pegloticase showed that, in addition to significantly cutting disease activity and pain, the pegloticase regimen improved other physical and mental domains and resulted in normal or near-normal values in more than half the domains measured on the SF-36 (Medical Outcomes Study 36-Item Short Form Health Survey), Dr. Vibeke Strand said at the annual European Congress of Rheumatology. About 50,000 Americans have treatment-resistant gout, she estimated.

“We never before had gout patients report feeling better by function, global assessment, pain, and health-related quality of life, so it's a very clinically meaningful result,” Dr. Strand said in an interview. “Treatment-failure gout affects not just the physical domains, but the mental domains, too.”

Savient Pharmaceuticals Inc. announced on Aug. 2 that the Food and Drug Administration had notified the company that its intravenous drug pegloticase, under review for treating chronic gout in refractory patients, could not be approved at this time, partly because of manufacturing issues. The company plans to meet with the agency to address these issues, according to the statement.

Without pegloticase treatment, patients with refractory chronic gout have an average health-related quality of life (QOL) that's worse than that of patients with osteoarthritis and hypertension, and worse than that of patients with angina and hypertension, said Dr. Strand, a rheumatologist at Stanford (Calif.) University. The severity of their health-related quality of life is comparable to that of patients with long-standing rheumatoid arthritis and patients with active systemic lupus erythematosus, she added.

Dr. Strand and her associates measured improvements in quality of life in 157 of the 212 total patients enrolled in two similar trials, the GOUT (Gout Outcomes and Uric Acid Treatment) 1 and GOUT 2 studies. Both studies randomized patients with treatment-resistant gout to treatment with 8 mg pegloticase administered by a 2-hour IV infusion every 2 weeks, 8 mg pegloticase infused once every 4 weeks, or placebo. Treatment continued for 25 weeks.

Pegloticase is a pegylated form of a modified, mammalian urate oxidase. The study was funded by Savient Pharmaceuticals, which is developing pegloticase (Krystexxa). Dr. Strand reported receiving research support from and serving as a consultant to Savient.

The primary outcome of the pivotal GOUT 1 and GOUT 2 studies was the proportion of patients with normalization of their plasma uric acid level during the final 3 months on treatment. Data in prior reports showed that this was significantly boosted by pegloticase treatment in these two studies.

The new analysis examined data collected at baseline and after 25 weeks on treatment from the SF-36 (with eight domains) and the HAQ-DI (Health Assessment Questionnaire–Disability Index). Baseline levels showed SF-36 domain scores that were 15-30 points (on a 0-100 scale) below U.S. normative levels. The HAQ-DI scores reflected moderate to severe levels of disability, Dr. N. Lawrence Edwards, Dr. Strand, and their associates reported in a poster presented at the congress.

For example, scores in the physical function domain averaged 45 in the 212 patients with refractory chronic gout, compared with 60 in age- and sex-matched norms. Average mental health domain scores were 68 in patients vs. 79 in age- and sex-matched norms.

The average domain scores in the gout patients who were enrolled in the two pegloticase studies were similar to the average SF-36 domain scores in a longitudinal study of 110 patients with refractory chronic gout, and in a third study of about 1,500 Veterans Affairs patients with gout, according to a second report at the meeting by Dr. Strand.

The 85 patients in GOUT 1 and GOUT 2 who received pegloticase every 2 weeks had “clinically-meaningful” improvements in their average SF-36 scores for all eight domains, reported Dr. Edwards, professor of rheumatology at the University of Florida in Gainesville, and his associates in their poster. Improvements, compared with baseline, were greatest for bodily pain, physical functioning, physical role, and social functioning. Pegloticase every 2 weeks for 25 weeks led to normal or near-normal average scores for five domains: bodily pain, mental health, emotional role, social functioning, and vitality. Pegloticase also produced significant improvements in HAQ-disability index scores.

Dr. Edwards said that he received research support from Savient.

COPENHAGEN — Patients with refractory chronic gout who were put on pegloticase had statistically significant and clinically meaningful improvements in their health-related quality of life after 25 weeks of treatment in two placebo-controlled studies with a total of 157 patients.

Refractory chronic gout accounts for a small subset of patients with gout (about 1%-2%) who have significantly lower health-related quality of life scores than do age- and sex-matched norms. Combined results from two similar studies of the investigational drug pegloticase showed that, in addition to significantly cutting disease activity and pain, the pegloticase regimen improved other physical and mental domains and resulted in normal or near-normal values in more than half the domains measured on the SF-36 (Medical Outcomes Study 36-Item Short Form Health Survey), Dr. Vibeke Strand said at the annual European Congress of Rheumatology. About 50,000 Americans have treatment-resistant gout, she estimated.

“We never before had gout patients report feeling better by function, global assessment, pain, and health-related quality of life, so it's a very clinically meaningful result,” Dr. Strand said in an interview. “Treatment-failure gout affects not just the physical domains, but the mental domains, too.”

Savient Pharmaceuticals Inc. announced on Aug. 2 that the Food and Drug Administration had notified the company that its intravenous drug pegloticase, under review for treating chronic gout in refractory patients, could not be approved at this time, partly because of manufacturing issues. The company plans to meet with the agency to address these issues, according to the statement.

Without pegloticase treatment, patients with refractory chronic gout have an average health-related quality of life (QOL) that's worse than that of patients with osteoarthritis and hypertension, and worse than that of patients with angina and hypertension, said Dr. Strand, a rheumatologist at Stanford (Calif.) University. The severity of their health-related quality of life is comparable to that of patients with long-standing rheumatoid arthritis and patients with active systemic lupus erythematosus, she added.

Dr. Strand and her associates measured improvements in quality of life in 157 of the 212 total patients enrolled in two similar trials, the GOUT (Gout Outcomes and Uric Acid Treatment) 1 and GOUT 2 studies. Both studies randomized patients with treatment-resistant gout to treatment with 8 mg pegloticase administered by a 2-hour IV infusion every 2 weeks, 8 mg pegloticase infused once every 4 weeks, or placebo. Treatment continued for 25 weeks.

Pegloticase is a pegylated form of a modified, mammalian urate oxidase. The study was funded by Savient Pharmaceuticals, which is developing pegloticase (Krystexxa). Dr. Strand reported receiving research support from and serving as a consultant to Savient.

The primary outcome of the pivotal GOUT 1 and GOUT 2 studies was the proportion of patients with normalization of their plasma uric acid level during the final 3 months on treatment. Data in prior reports showed that this was significantly boosted by pegloticase treatment in these two studies.

The new analysis examined data collected at baseline and after 25 weeks on treatment from the SF-36 (with eight domains) and the HAQ-DI (Health Assessment Questionnaire–Disability Index). Baseline levels showed SF-36 domain scores that were 15-30 points (on a 0-100 scale) below U.S. normative levels. The HAQ-DI scores reflected moderate to severe levels of disability, Dr. N. Lawrence Edwards, Dr. Strand, and their associates reported in a poster presented at the congress.

For example, scores in the physical function domain averaged 45 in the 212 patients with refractory chronic gout, compared with 60 in age- and sex-matched norms. Average mental health domain scores were 68 in patients vs. 79 in age- and sex-matched norms.

The average domain scores in the gout patients who were enrolled in the two pegloticase studies were similar to the average SF-36 domain scores in a longitudinal study of 110 patients with refractory chronic gout, and in a third study of about 1,500 Veterans Affairs patients with gout, according to a second report at the meeting by Dr. Strand.

The 85 patients in GOUT 1 and GOUT 2 who received pegloticase every 2 weeks had “clinically-meaningful” improvements in their average SF-36 scores for all eight domains, reported Dr. Edwards, professor of rheumatology at the University of Florida in Gainesville, and his associates in their poster. Improvements, compared with baseline, were greatest for bodily pain, physical functioning, physical role, and social functioning. Pegloticase every 2 weeks for 25 weeks led to normal or near-normal average scores for five domains: bodily pain, mental health, emotional role, social functioning, and vitality. Pegloticase also produced significant improvements in HAQ-disability index scores.

Dr. Edwards said that he received research support from Savient.

COPENHAGEN — Patients with refractory chronic gout who were put on pegloticase had statistically significant and clinically meaningful improvements in their health-related quality of life after 25 weeks of treatment in two placebo-controlled studies with a total of 157 patients.

Refractory chronic gout accounts for a small subset of patients with gout (about 1%-2%) who have significantly lower health-related quality of life scores than do age- and sex-matched norms. Combined results from two similar studies of the investigational drug pegloticase showed that, in addition to significantly cutting disease activity and pain, the pegloticase regimen improved other physical and mental domains and resulted in normal or near-normal values in more than half the domains measured on the SF-36 (Medical Outcomes Study 36-Item Short Form Health Survey), Dr. Vibeke Strand said at the annual European Congress of Rheumatology. About 50,000 Americans have treatment-resistant gout, she estimated.

“We never before had gout patients report feeling better by function, global assessment, pain, and health-related quality of life, so it's a very clinically meaningful result,” Dr. Strand said in an interview. “Treatment-failure gout affects not just the physical domains, but the mental domains, too.”

Savient Pharmaceuticals Inc. announced on Aug. 2 that the Food and Drug Administration had notified the company that its intravenous drug pegloticase, under review for treating chronic gout in refractory patients, could not be approved at this time, partly because of manufacturing issues. The company plans to meet with the agency to address these issues, according to the statement.

Without pegloticase treatment, patients with refractory chronic gout have an average health-related quality of life (QOL) that's worse than that of patients with osteoarthritis and hypertension, and worse than that of patients with angina and hypertension, said Dr. Strand, a rheumatologist at Stanford (Calif.) University. The severity of their health-related quality of life is comparable to that of patients with long-standing rheumatoid arthritis and patients with active systemic lupus erythematosus, she added.

Dr. Strand and her associates measured improvements in quality of life in 157 of the 212 total patients enrolled in two similar trials, the GOUT (Gout Outcomes and Uric Acid Treatment) 1 and GOUT 2 studies. Both studies randomized patients with treatment-resistant gout to treatment with 8 mg pegloticase administered by a 2-hour IV infusion every 2 weeks, 8 mg pegloticase infused once every 4 weeks, or placebo. Treatment continued for 25 weeks.

Pegloticase is a pegylated form of a modified, mammalian urate oxidase. The study was funded by Savient Pharmaceuticals, which is developing pegloticase (Krystexxa). Dr. Strand reported receiving research support from and serving as a consultant to Savient.

The primary outcome of the pivotal GOUT 1 and GOUT 2 studies was the proportion of patients with normalization of their plasma uric acid level during the final 3 months on treatment. Data in prior reports showed that this was significantly boosted by pegloticase treatment in these two studies.

The new analysis examined data collected at baseline and after 25 weeks on treatment from the SF-36 (with eight domains) and the HAQ-DI (Health Assessment Questionnaire–Disability Index). Baseline levels showed SF-36 domain scores that were 15-30 points (on a 0-100 scale) below U.S. normative levels. The HAQ-DI scores reflected moderate to severe levels of disability, Dr. N. Lawrence Edwards, Dr. Strand, and their associates reported in a poster presented at the congress.

For example, scores in the physical function domain averaged 45 in the 212 patients with refractory chronic gout, compared with 60 in age- and sex-matched norms. Average mental health domain scores were 68 in patients vs. 79 in age- and sex-matched norms.

The average domain scores in the gout patients who were enrolled in the two pegloticase studies were similar to the average SF-36 domain scores in a longitudinal study of 110 patients with refractory chronic gout, and in a third study of about 1,500 Veterans Affairs patients with gout, according to a second report at the meeting by Dr. Strand.

The 85 patients in GOUT 1 and GOUT 2 who received pegloticase every 2 weeks had “clinically-meaningful” improvements in their average SF-36 scores for all eight domains, reported Dr. Edwards, professor of rheumatology at the University of Florida in Gainesville, and his associates in their poster. Improvements, compared with baseline, were greatest for bodily pain, physical functioning, physical role, and social functioning. Pegloticase every 2 weeks for 25 weeks led to normal or near-normal average scores for five domains: bodily pain, mental health, emotional role, social functioning, and vitality. Pegloticase also produced significant improvements in HAQ-disability index scores.

Dr. Edwards said that he received research support from Savient.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

COPENHAGEN — Prednisone in initial dosages lower than 5 mg/day is as effective as higher doses in rheumatoid arthritis patients, a study has shown.

Although the use of glucocorticoids in RA remains controversial, the drugs continue to play a major role in the treatment of the disease, Dr. Theodore Pincus said at the annual European Congress of Rheumatology. “Textbooks suggest that glucocorticoids should be used in rheumatoid arthritis only for patients with life-threatening complications, or as a bridge therapy until [disease modifying antirheumatic drug] treatment begins to work, yet estimates suggest that they are used by 20%-80% of patients in usual clinical practice.” Therefore, he noted, determining the lowest effective dosage is important.

Toward this end, Dr. Pincus, clinical professor of medicine at New York University and the Hospital for Joint Diseases, New York, and his colleagues retrospectively analyzed the efficacy of prednisone in the usual care of 308 RA patients treated over a 25-year period. Using a database of all patient visits to a weekly academic clinic during 1980-2004, the investigators analyzed all initial prednisone prescriptions and classified patients into those treated with an initial prednisone dosage of 5 mg/day or higher and those treated with an initial dose lower than 5 mg/day. The 5-mg threshold was used because the efficacy of prednisone at 5 mg daily in RA has been documented, according to Dr. Pincus.

Of the 308 patients, 195 were treated with an initial prednisone dose of 5 mg or higher and 113 were treated with an initial dose less than 5 mg. Nearly all of the patients taking prednisone also took DMARDs, primarily methotrexate.

All of the patients in the study completed the MDHAQ-FN (Multidimensional Health Assessment Questionnaire including physical function measures), and a VAS (Visual Analog Scale) pain measure at each visit. The investigators compared the baseline, 12-month, and 24-month follow-up scores of patients in both dosage groups and used the change in scores from baseline to 12 and 24 months as outcome measures. They also analyzed the data based on 5-year subgroups to account for changes in prescribing practices over time. At baseline, patients in the higher-dose group had higher function and pain scores than did those in the lower-dose group, Dr. Pincus noted in a poster presentation.

The mean improvements in MDHAQ-FN scores were statistically similar between both groups, said Dr. Pincus. At 12 and 24 months, the mean MDHAQ-FN improvement from baseline was 40% and 31% in patients in the higher-dose group vs. 34% and 24% in patients in the lower-dose group. The mean improvements in pain scores were also similar between both groups. At 12 and 24 months, the mean improvement in pain from baseline was 37% and 42% in the higher-dose group, and 37% and 35% in the lower-dose group, he said.

When analyzed by 5-year periods, the initial prednisone dose fell from a mean of 10.3 mg in 1980-1984 to 6.5 mg (in 1985-89), 5.1 mg (in 1990-1994), 4.1 mg (in 1995-1999), and 3.6 mg (in 2000-2004). From 1980 to 2004, the median dosage fell from 5 mg/day to 3 mg/day. Before 1990, there were some differences in the pain and function scores between the lower- and higher-dose groups, but the differences were not maintained in the analysis of the 25-year period, he said.

“The findings suggest that many [RA] patients can be treated effectively with initial prednisone doses of less than 5 mg/day, achieving pain and function improvements comparable to those seen at higher doses,” said Dr. Pincus.

Dr. Pincus reported having no financial conflicts of interest to disclose.

COPENHAGEN — Prednisone in initial dosages lower than 5 mg/day is as effective as higher doses in rheumatoid arthritis patients, a study has shown.

Although the use of glucocorticoids in RA remains controversial, the drugs continue to play a major role in the treatment of the disease, Dr. Theodore Pincus said at the annual European Congress of Rheumatology. “Textbooks suggest that glucocorticoids should be used in rheumatoid arthritis only for patients with life-threatening complications, or as a bridge therapy until [disease modifying antirheumatic drug] treatment begins to work, yet estimates suggest that they are used by 20%-80% of patients in usual clinical practice.” Therefore, he noted, determining the lowest effective dosage is important.

Toward this end, Dr. Pincus, clinical professor of medicine at New York University and the Hospital for Joint Diseases, New York, and his colleagues retrospectively analyzed the efficacy of prednisone in the usual care of 308 RA patients treated over a 25-year period. Using a database of all patient visits to a weekly academic clinic during 1980-2004, the investigators analyzed all initial prednisone prescriptions and classified patients into those treated with an initial prednisone dosage of 5 mg/day or higher and those treated with an initial dose lower than 5 mg/day. The 5-mg threshold was used because the efficacy of prednisone at 5 mg daily in RA has been documented, according to Dr. Pincus.

Of the 308 patients, 195 were treated with an initial prednisone dose of 5 mg or higher and 113 were treated with an initial dose less than 5 mg. Nearly all of the patients taking prednisone also took DMARDs, primarily methotrexate.

All of the patients in the study completed the MDHAQ-FN (Multidimensional Health Assessment Questionnaire including physical function measures), and a VAS (Visual Analog Scale) pain measure at each visit. The investigators compared the baseline, 12-month, and 24-month follow-up scores of patients in both dosage groups and used the change in scores from baseline to 12 and 24 months as outcome measures. They also analyzed the data based on 5-year subgroups to account for changes in prescribing practices over time. At baseline, patients in the higher-dose group had higher function and pain scores than did those in the lower-dose group, Dr. Pincus noted in a poster presentation.

The mean improvements in MDHAQ-FN scores were statistically similar between both groups, said Dr. Pincus. At 12 and 24 months, the mean MDHAQ-FN improvement from baseline was 40% and 31% in patients in the higher-dose group vs. 34% and 24% in patients in the lower-dose group. The mean improvements in pain scores were also similar between both groups. At 12 and 24 months, the mean improvement in pain from baseline was 37% and 42% in the higher-dose group, and 37% and 35% in the lower-dose group, he said.

When analyzed by 5-year periods, the initial prednisone dose fell from a mean of 10.3 mg in 1980-1984 to 6.5 mg (in 1985-89), 5.1 mg (in 1990-1994), 4.1 mg (in 1995-1999), and 3.6 mg (in 2000-2004). From 1980 to 2004, the median dosage fell from 5 mg/day to 3 mg/day. Before 1990, there were some differences in the pain and function scores between the lower- and higher-dose groups, but the differences were not maintained in the analysis of the 25-year period, he said.

“The findings suggest that many [RA] patients can be treated effectively with initial prednisone doses of less than 5 mg/day, achieving pain and function improvements comparable to those seen at higher doses,” said Dr. Pincus.

Dr. Pincus reported having no financial conflicts of interest to disclose.

COPENHAGEN — Prednisone in initial dosages lower than 5 mg/day is as effective as higher doses in rheumatoid arthritis patients, a study has shown.

Although the use of glucocorticoids in RA remains controversial, the drugs continue to play a major role in the treatment of the disease, Dr. Theodore Pincus said at the annual European Congress of Rheumatology. “Textbooks suggest that glucocorticoids should be used in rheumatoid arthritis only for patients with life-threatening complications, or as a bridge therapy until [disease modifying antirheumatic drug] treatment begins to work, yet estimates suggest that they are used by 20%-80% of patients in usual clinical practice.” Therefore, he noted, determining the lowest effective dosage is important.

Toward this end, Dr. Pincus, clinical professor of medicine at New York University and the Hospital for Joint Diseases, New York, and his colleagues retrospectively analyzed the efficacy of prednisone in the usual care of 308 RA patients treated over a 25-year period. Using a database of all patient visits to a weekly academic clinic during 1980-2004, the investigators analyzed all initial prednisone prescriptions and classified patients into those treated with an initial prednisone dosage of 5 mg/day or higher and those treated with an initial dose lower than 5 mg/day. The 5-mg threshold was used because the efficacy of prednisone at 5 mg daily in RA has been documented, according to Dr. Pincus.

Of the 308 patients, 195 were treated with an initial prednisone dose of 5 mg or higher and 113 were treated with an initial dose less than 5 mg. Nearly all of the patients taking prednisone also took DMARDs, primarily methotrexate.

All of the patients in the study completed the MDHAQ-FN (Multidimensional Health Assessment Questionnaire including physical function measures), and a VAS (Visual Analog Scale) pain measure at each visit. The investigators compared the baseline, 12-month, and 24-month follow-up scores of patients in both dosage groups and used the change in scores from baseline to 12 and 24 months as outcome measures. They also analyzed the data based on 5-year subgroups to account for changes in prescribing practices over time. At baseline, patients in the higher-dose group had higher function and pain scores than did those in the lower-dose group, Dr. Pincus noted in a poster presentation.

The mean improvements in MDHAQ-FN scores were statistically similar between both groups, said Dr. Pincus. At 12 and 24 months, the mean MDHAQ-FN improvement from baseline was 40% and 31% in patients in the higher-dose group vs. 34% and 24% in patients in the lower-dose group. The mean improvements in pain scores were also similar between both groups. At 12 and 24 months, the mean improvement in pain from baseline was 37% and 42% in the higher-dose group, and 37% and 35% in the lower-dose group, he said.

When analyzed by 5-year periods, the initial prednisone dose fell from a mean of 10.3 mg in 1980-1984 to 6.5 mg (in 1985-89), 5.1 mg (in 1990-1994), 4.1 mg (in 1995-1999), and 3.6 mg (in 2000-2004). From 1980 to 2004, the median dosage fell from 5 mg/day to 3 mg/day. Before 1990, there were some differences in the pain and function scores between the lower- and higher-dose groups, but the differences were not maintained in the analysis of the 25-year period, he said.

“The findings suggest that many [RA] patients can be treated effectively with initial prednisone doses of less than 5 mg/day, achieving pain and function improvements comparable to those seen at higher doses,” said Dr. Pincus.

Dr. Pincus reported having no financial conflicts of interest to disclose.