Nancy Walsh

NEW YORK — The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial was flawed from its inception and should have been stopped because of its multiple shortcomings, according to Dr. Anthony J. Comerota.

Instead, the Food and Drug Administration used data from the SAPPHIRE trial in its decision to approve carotid stents in high-risk patients, and the results of the study were published in the New England Journal of Medicine (2004; 351:1493-501), “arguably the most influential medical journal in the world,” said Dr. Comerota, who served on the FDA panel that reviewed the data.

SAPPHIRE was based on an improperly designed and executed feasibility study, which was undertaken to determine if carotid angioplasty and stenting (CAS) could be performed with less than two times the 6.7% stroke and death rate of carotid endarterectomy found in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), Dr. Comerota argued.

However, only truly high-risk patients with symptomatic atherosclerosis were enrolled in NASCET, whereas the majority of patients in the SAPPHIRE feasibility study were asymptomatic, Dr. Comerota said at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic. Fewer than 20% of CAS patients had more than 80% stenosis, 72% were asymptomatic, and 26% had recurrent stenosis. “These are low-risk patients,” said Dr. Comerota, director of the Jobst Vascular Center, Toledo (Ohio) Hospital.

Furthermore, SAPPHIRE was designed as a randomized trial, yet a majority of patients were not randomized, but instead were entered into registries, and enrollment was terminated after only 334 of the target 2,900 had entered the study. “Termination was due to poor enrollment because of 'competing registries'—yet it was the sponsoring company's own registry that led to termination,” Dr. Comerota said.

Another flaw in the study design was the inclusion of troponin-based MI as part of the primary end point, which also included stroke and death. The reason for this inclusion, according to the authors, was that patients with non-Q-wave MI have a 27-fold increased risk of an MI in the next 6 months. This was not borne out in the investigators' report of long-term outcomes, when there was no signal of an increased rate of MI, Dr. Comerota said.

“Furthermore, the statistical analysis was not done according to protocol, but rather was a unique triangular analysis I have not seen before or since SAPPHIRE,” he added.

The FDA panel that reviewed the data for approval of the device included six cardiologists, two interventional radiologists, two vascular surgeons, and one neurologist. “There was no statistician on the panel, and the vote to recommend was 6–5. You can draw your own conclusions,” said Dr. Comerota.

SAPPHIRE was supported by Cordis Corp., the manufacturer of the stent used in the study.

Some consider carotid stenting to be the ideal solution (right) to stenosis (left) in high-risk patients, but the patients in the SAPPHIREregistry were not high risk, said Dr. Anthony J. Comerota. Fewer than 20% of CAS patients had more than 80% stenosis. ©Elsevier, Textbook of Clinical Neurology, Goetz, Christopher G., M.D., 3rd Ed., 2007

NEW YORK — The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial was flawed from its inception and should have been stopped because of its multiple shortcomings, according to Dr. Anthony J. Comerota.

Instead, the Food and Drug Administration used data from the SAPPHIRE trial in its decision to approve carotid stents in high-risk patients, and the results of the study were published in the New England Journal of Medicine (2004; 351:1493-501), “arguably the most influential medical journal in the world,” said Dr. Comerota, who served on the FDA panel that reviewed the data.

SAPPHIRE was based on an improperly designed and executed feasibility study, which was undertaken to determine if carotid angioplasty and stenting (CAS) could be performed with less than two times the 6.7% stroke and death rate of carotid endarterectomy found in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), Dr. Comerota argued.

However, only truly high-risk patients with symptomatic atherosclerosis were enrolled in NASCET, whereas the majority of patients in the SAPPHIRE feasibility study were asymptomatic, Dr. Comerota said at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic. Fewer than 20% of CAS patients had more than 80% stenosis, 72% were asymptomatic, and 26% had recurrent stenosis. “These are low-risk patients,” said Dr. Comerota, director of the Jobst Vascular Center, Toledo (Ohio) Hospital.

Furthermore, SAPPHIRE was designed as a randomized trial, yet a majority of patients were not randomized, but instead were entered into registries, and enrollment was terminated after only 334 of the target 2,900 had entered the study. “Termination was due to poor enrollment because of 'competing registries'—yet it was the sponsoring company's own registry that led to termination,” Dr. Comerota said.

Another flaw in the study design was the inclusion of troponin-based MI as part of the primary end point, which also included stroke and death. The reason for this inclusion, according to the authors, was that patients with non-Q-wave MI have a 27-fold increased risk of an MI in the next 6 months. This was not borne out in the investigators' report of long-term outcomes, when there was no signal of an increased rate of MI, Dr. Comerota said.

“Furthermore, the statistical analysis was not done according to protocol, but rather was a unique triangular analysis I have not seen before or since SAPPHIRE,” he added.

The FDA panel that reviewed the data for approval of the device included six cardiologists, two interventional radiologists, two vascular surgeons, and one neurologist. “There was no statistician on the panel, and the vote to recommend was 6–5. You can draw your own conclusions,” said Dr. Comerota.

SAPPHIRE was supported by Cordis Corp., the manufacturer of the stent used in the study.

Some consider carotid stenting to be the ideal solution (right) to stenosis (left) in high-risk patients, but the patients in the SAPPHIREregistry were not high risk, said Dr. Anthony J. Comerota. Fewer than 20% of CAS patients had more than 80% stenosis. ©Elsevier, Textbook of Clinical Neurology, Goetz, Christopher G., M.D., 3rd Ed., 2007

NEW YORK — The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial was flawed from its inception and should have been stopped because of its multiple shortcomings, according to Dr. Anthony J. Comerota.

Instead, the Food and Drug Administration used data from the SAPPHIRE trial in its decision to approve carotid stents in high-risk patients, and the results of the study were published in the New England Journal of Medicine (2004; 351:1493-501), “arguably the most influential medical journal in the world,” said Dr. Comerota, who served on the FDA panel that reviewed the data.

SAPPHIRE was based on an improperly designed and executed feasibility study, which was undertaken to determine if carotid angioplasty and stenting (CAS) could be performed with less than two times the 6.7% stroke and death rate of carotid endarterectomy found in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), Dr. Comerota argued.

However, only truly high-risk patients with symptomatic atherosclerosis were enrolled in NASCET, whereas the majority of patients in the SAPPHIRE feasibility study were asymptomatic, Dr. Comerota said at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic. Fewer than 20% of CAS patients had more than 80% stenosis, 72% were asymptomatic, and 26% had recurrent stenosis. “These are low-risk patients,” said Dr. Comerota, director of the Jobst Vascular Center, Toledo (Ohio) Hospital.

Furthermore, SAPPHIRE was designed as a randomized trial, yet a majority of patients were not randomized, but instead were entered into registries, and enrollment was terminated after only 334 of the target 2,900 had entered the study. “Termination was due to poor enrollment because of 'competing registries'—yet it was the sponsoring company's own registry that led to termination,” Dr. Comerota said.

Another flaw in the study design was the inclusion of troponin-based MI as part of the primary end point, which also included stroke and death. The reason for this inclusion, according to the authors, was that patients with non-Q-wave MI have a 27-fold increased risk of an MI in the next 6 months. This was not borne out in the investigators' report of long-term outcomes, when there was no signal of an increased rate of MI, Dr. Comerota said.

“Furthermore, the statistical analysis was not done according to protocol, but rather was a unique triangular analysis I have not seen before or since SAPPHIRE,” he added.

The FDA panel that reviewed the data for approval of the device included six cardiologists, two interventional radiologists, two vascular surgeons, and one neurologist. “There was no statistician on the panel, and the vote to recommend was 6–5. You can draw your own conclusions,” said Dr. Comerota.

SAPPHIRE was supported by Cordis Corp., the manufacturer of the stent used in the study.

Some consider carotid stenting to be the ideal solution (right) to stenosis (left) in high-risk patients, but the patients in the SAPPHIREregistry were not high risk, said Dr. Anthony J. Comerota. Fewer than 20% of CAS patients had more than 80% stenosis. ©Elsevier, Textbook of Clinical Neurology, Goetz, Christopher G., M.D., 3rd Ed., 2007

PHILADELPHIA — Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, accelerate recovery of renal function, or alter the rate of nonrenal organ failure in the randomized Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study.

Results of previous smaller studies evaluating different strategies of renal support have been inconsistent, and while some studies favored more intensive, higher-dose approaches, such a strategy has not been adopted widely in the United States.

To address the uncertainty as to the optimal approach for acute kidney injury, a large trial was undertaken comparing conventional with intensive renal support. An integrative approach was used, in which hemodynamically stable patients were on standard intermittent therapy and hemodynamically unstable patients were on continuous therapy or sustained low-efficiency dialysis, according to the lead investigator, Dr. Paul M. Palevsky.

“Patients could move between modalities of therapy as their hemodynamic status changed, but they remained within a dosing schedule which was five to six times per week for a total effluent flow rate of 35 mL/kg per hour in the intensive group, and three times per week for a total effluent flow rate of 20 mL/kg per hour in the less-intensive group,” said Dr. Palevsky of the renal section, VA Pittsburgh Healthcare System, and the department of medicine at the University of Pittsburgh.

To be eligible, patients had to be 18 years or older, critically ill, have acute kidney injury consistent with acute tubular necrosis, and have failure of one or more nonrenal organs, or sepsis.

A total of 563 patients were randomized to the intensive group; 561 were randomized to the conventional group.

The populations were well matched at baseline in terms of age, at a mean of 60 years, as well as in race, sex, and ethnicity and in baseline severity of illness and renal function, Dr. Palevsky said at the annual meeting of the American Society of Nephrology.

Mean serum creatinine was 1.1 mg/dL in both groups at baseline. A total of 88% of patients had an estimated glomerular filtration rate of at least 45 mL/min per 1.73 m

Therapy continued for 28 days or until the patient regained renal function, was withdrawn from life-sustaining care, was discharged from the acute care hospital, or died.

Patients in the intensive therapy group received an average of 5.4 sessions per week, with an interval between treatments of 1.1 days, while those in the less-intensive group averaged 3 sessions per week with an interval of 2 days between treatments.

Prescribed and delivered flow rates of venovenous hemodiafiltration were approximately 36 mL/kg per hour for the intensive group and just over 20 mL/kg per hour for the less-intensive group (N. Engl. J. Med. 2008;359:7–20).

“We observed no difference between the two groups on our primary outcome measure of 60-day all-cause mortality, with 53.6% in the intensive arm and 51.5% in the less-intensive arm,” he said.

Complete recovery of kidney function by day 28 was seen in 15% of the intensive therapy group, and in 18% of those in the less-intensive group; there was no difference between the groups in number of days free of organ failure.

“We then looked at 1-year mortality and again there was no difference, with a total mortality of 34% in each group. Among patients who survived to day 60 there was an additional 20% mortality at 1 year,” he said. Not only was mortality not decreased with the intensive therapy, but a greater percentage of patients undergoing intensive therapy experienced treatment-related hypotension and had more hypocalcemia and hypophosphatemia, he noted.

Dr. Palevsky disclosed no conflicts of interest.

PHILADELPHIA — Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, accelerate recovery of renal function, or alter the rate of nonrenal organ failure in the randomized Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study.

Results of previous smaller studies evaluating different strategies of renal support have been inconsistent, and while some studies favored more intensive, higher-dose approaches, such a strategy has not been adopted widely in the United States.

To address the uncertainty as to the optimal approach for acute kidney injury, a large trial was undertaken comparing conventional with intensive renal support. An integrative approach was used, in which hemodynamically stable patients were on standard intermittent therapy and hemodynamically unstable patients were on continuous therapy or sustained low-efficiency dialysis, according to the lead investigator, Dr. Paul M. Palevsky.

“Patients could move between modalities of therapy as their hemodynamic status changed, but they remained within a dosing schedule which was five to six times per week for a total effluent flow rate of 35 mL/kg per hour in the intensive group, and three times per week for a total effluent flow rate of 20 mL/kg per hour in the less-intensive group,” said Dr. Palevsky of the renal section, VA Pittsburgh Healthcare System, and the department of medicine at the University of Pittsburgh.

To be eligible, patients had to be 18 years or older, critically ill, have acute kidney injury consistent with acute tubular necrosis, and have failure of one or more nonrenal organs, or sepsis.

A total of 563 patients were randomized to the intensive group; 561 were randomized to the conventional group.

The populations were well matched at baseline in terms of age, at a mean of 60 years, as well as in race, sex, and ethnicity and in baseline severity of illness and renal function, Dr. Palevsky said at the annual meeting of the American Society of Nephrology.

Mean serum creatinine was 1.1 mg/dL in both groups at baseline. A total of 88% of patients had an estimated glomerular filtration rate of at least 45 mL/min per 1.73 m

Therapy continued for 28 days or until the patient regained renal function, was withdrawn from life-sustaining care, was discharged from the acute care hospital, or died.

Patients in the intensive therapy group received an average of 5.4 sessions per week, with an interval between treatments of 1.1 days, while those in the less-intensive group averaged 3 sessions per week with an interval of 2 days between treatments.

Prescribed and delivered flow rates of venovenous hemodiafiltration were approximately 36 mL/kg per hour for the intensive group and just over 20 mL/kg per hour for the less-intensive group (N. Engl. J. Med. 2008;359:7–20).

“We observed no difference between the two groups on our primary outcome measure of 60-day all-cause mortality, with 53.6% in the intensive arm and 51.5% in the less-intensive arm,” he said.

Complete recovery of kidney function by day 28 was seen in 15% of the intensive therapy group, and in 18% of those in the less-intensive group; there was no difference between the groups in number of days free of organ failure.

“We then looked at 1-year mortality and again there was no difference, with a total mortality of 34% in each group. Among patients who survived to day 60 there was an additional 20% mortality at 1 year,” he said. Not only was mortality not decreased with the intensive therapy, but a greater percentage of patients undergoing intensive therapy experienced treatment-related hypotension and had more hypocalcemia and hypophosphatemia, he noted.

Dr. Palevsky disclosed no conflicts of interest.

PHILADELPHIA — Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, accelerate recovery of renal function, or alter the rate of nonrenal organ failure in the randomized Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study.

Results of previous smaller studies evaluating different strategies of renal support have been inconsistent, and while some studies favored more intensive, higher-dose approaches, such a strategy has not been adopted widely in the United States.

To address the uncertainty as to the optimal approach for acute kidney injury, a large trial was undertaken comparing conventional with intensive renal support. An integrative approach was used, in which hemodynamically stable patients were on standard intermittent therapy and hemodynamically unstable patients were on continuous therapy or sustained low-efficiency dialysis, according to the lead investigator, Dr. Paul M. Palevsky.

“Patients could move between modalities of therapy as their hemodynamic status changed, but they remained within a dosing schedule which was five to six times per week for a total effluent flow rate of 35 mL/kg per hour in the intensive group, and three times per week for a total effluent flow rate of 20 mL/kg per hour in the less-intensive group,” said Dr. Palevsky of the renal section, VA Pittsburgh Healthcare System, and the department of medicine at the University of Pittsburgh.

To be eligible, patients had to be 18 years or older, critically ill, have acute kidney injury consistent with acute tubular necrosis, and have failure of one or more nonrenal organs, or sepsis.

A total of 563 patients were randomized to the intensive group; 561 were randomized to the conventional group.

The populations were well matched at baseline in terms of age, at a mean of 60 years, as well as in race, sex, and ethnicity and in baseline severity of illness and renal function, Dr. Palevsky said at the annual meeting of the American Society of Nephrology.

Mean serum creatinine was 1.1 mg/dL in both groups at baseline. A total of 88% of patients had an estimated glomerular filtration rate of at least 45 mL/min per 1.73 m

Therapy continued for 28 days or until the patient regained renal function, was withdrawn from life-sustaining care, was discharged from the acute care hospital, or died.

Patients in the intensive therapy group received an average of 5.4 sessions per week, with an interval between treatments of 1.1 days, while those in the less-intensive group averaged 3 sessions per week with an interval of 2 days between treatments.

Prescribed and delivered flow rates of venovenous hemodiafiltration were approximately 36 mL/kg per hour for the intensive group and just over 20 mL/kg per hour for the less-intensive group (N. Engl. J. Med. 2008;359:7–20).

“We observed no difference between the two groups on our primary outcome measure of 60-day all-cause mortality, with 53.6% in the intensive arm and 51.5% in the less-intensive arm,” he said.

Complete recovery of kidney function by day 28 was seen in 15% of the intensive therapy group, and in 18% of those in the less-intensive group; there was no difference between the groups in number of days free of organ failure.

“We then looked at 1-year mortality and again there was no difference, with a total mortality of 34% in each group. Among patients who survived to day 60 there was an additional 20% mortality at 1 year,” he said. Not only was mortality not decreased with the intensive therapy, but a greater percentage of patients undergoing intensive therapy experienced treatment-related hypotension and had more hypocalcemia and hypophosphatemia, he noted.

Dr. Palevsky disclosed no conflicts of interest.

FORT LAUDERDALE, FLA. — An international group of dermatologists and rheumatologists has published new recommendations for the treatment of the heterogeneous manifestations of psoriatic arthritis, but they caution that randomized data remain sparse and the recommendations may change as new data emerge.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), which has 250 members from North America, Europe, and elsewhere, performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis, and formulated treatment guidelines based on this systematic review and consensus opinion.

Significant challenges exist in the management of psoriatic arthritis (PsA), according to lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine in PsA, so there is an inadequate evidence base for the use of these drugs. There is also no evidence that the traditional agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, explained Dr. Ritchlin, who is professor of medicine and director of clinical immunology, University of Rochester (N.Y.) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the paucity of data for methotrexate, with only one older double-blind randomized trial having been done, which failed to show efficacy (Arthritis Rheum. 1984;27:376–81). “But that study was underdosed and underpowered,” Dr. Ritchlin said.

Improvements in trial design in the intervening years, incorporating more useful and measurable outcomes in PsA, favor the newer biologic agents over the older disease-modifying antirheumatic drugs (DMARDs). While there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors—with these drugs clearly being effective in many patients—there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

GRAPPA, therefore, has attempted to fill these knowledge gaps, to provide physicians with available evidence-based information, and to help physicians in their diagnostic and therapeutic decision making (Ann. Rheum. Dis. 2008 Oct. 24 [Epub doi:10.1136/ard.2008.094946

The GRAPPA investigators noted that their efforts were hampered by a lack of validated tools. For example, they wrote that the assessment and treatment of axial manifestations of PsA are particularly challenging and that by consensus they agreed to follow guidelines of the Assessments in Ankylosing Spondylitis Working Group and adopt the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for determination of severity and response until validated measures for axial disease in PsA can be developed.

In general, the recommendations include the following:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors may be given.

While TNF inhibitors are recommended for use in patients who have failed at least one DMARD, the recommendations also note that the patient whose prognosis is poor can be considered for a TNF agent without prior DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life.

Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment options include NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but DMARDs or infliximab can be tried if symptoms are resistant.

▸ For mild enthesitis, typically of the Achilles tendon area, NSAIDs, physical therapy, and corticosteroids can be used, while moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

The guidelines also emphasized that many new treatments are in the pipeline, “which will offer new and possibly less expensive therapeutic options.”

Dr. Ritchlin also discussed larger management issues in PsA at the meeting. “The evidence is abundantly clear that psoriatic arthritis is an independent risk factor for coronary vascular disease. A lot of these patients are young, and they don't go to their primary care physicians. They come to the rheumatologists and the dermatologists,” he said.

“No one is following their cholesterol profiles or advising them about smoking and weight loss, so it's really incumbent on us to make sure these issues are addressed in this patient population. This is a really significant intervention we can make, maybe even more important in some cases than treating their joint and skin disease,” Dr. Ritchlin said.

Dr. Ritchlin disclosed that he has received grant research support from Centocor Inc. and is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and this newspaper are owned by Elsevier.

'It's not that we know these [traditional] drugs don't work—the studies simply haven't been done.' DR. RITCHLIN

FORT LAUDERDALE, FLA. — An international group of dermatologists and rheumatologists has published new recommendations for the treatment of the heterogeneous manifestations of psoriatic arthritis, but they caution that randomized data remain sparse and the recommendations may change as new data emerge.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), which has 250 members from North America, Europe, and elsewhere, performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis, and formulated treatment guidelines based on this systematic review and consensus opinion.

Significant challenges exist in the management of psoriatic arthritis (PsA), according to lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine in PsA, so there is an inadequate evidence base for the use of these drugs. There is also no evidence that the traditional agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, explained Dr. Ritchlin, who is professor of medicine and director of clinical immunology, University of Rochester (N.Y.) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the paucity of data for methotrexate, with only one older double-blind randomized trial having been done, which failed to show efficacy (Arthritis Rheum. 1984;27:376–81). “But that study was underdosed and underpowered,” Dr. Ritchlin said.

Improvements in trial design in the intervening years, incorporating more useful and measurable outcomes in PsA, favor the newer biologic agents over the older disease-modifying antirheumatic drugs (DMARDs). While there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors—with these drugs clearly being effective in many patients—there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

GRAPPA, therefore, has attempted to fill these knowledge gaps, to provide physicians with available evidence-based information, and to help physicians in their diagnostic and therapeutic decision making (Ann. Rheum. Dis. 2008 Oct. 24 [Epub doi:10.1136/ard.2008.094946

The GRAPPA investigators noted that their efforts were hampered by a lack of validated tools. For example, they wrote that the assessment and treatment of axial manifestations of PsA are particularly challenging and that by consensus they agreed to follow guidelines of the Assessments in Ankylosing Spondylitis Working Group and adopt the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for determination of severity and response until validated measures for axial disease in PsA can be developed.

In general, the recommendations include the following:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors may be given.

While TNF inhibitors are recommended for use in patients who have failed at least one DMARD, the recommendations also note that the patient whose prognosis is poor can be considered for a TNF agent without prior DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life.

Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment options include NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but DMARDs or infliximab can be tried if symptoms are resistant.

▸ For mild enthesitis, typically of the Achilles tendon area, NSAIDs, physical therapy, and corticosteroids can be used, while moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

The guidelines also emphasized that many new treatments are in the pipeline, “which will offer new and possibly less expensive therapeutic options.”

Dr. Ritchlin also discussed larger management issues in PsA at the meeting. “The evidence is abundantly clear that psoriatic arthritis is an independent risk factor for coronary vascular disease. A lot of these patients are young, and they don't go to their primary care physicians. They come to the rheumatologists and the dermatologists,” he said.

“No one is following their cholesterol profiles or advising them about smoking and weight loss, so it's really incumbent on us to make sure these issues are addressed in this patient population. This is a really significant intervention we can make, maybe even more important in some cases than treating their joint and skin disease,” Dr. Ritchlin said.

Dr. Ritchlin disclosed that he has received grant research support from Centocor Inc. and is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and this newspaper are owned by Elsevier.

'It's not that we know these [traditional] drugs don't work—the studies simply haven't been done.' DR. RITCHLIN

FORT LAUDERDALE, FLA. — An international group of dermatologists and rheumatologists has published new recommendations for the treatment of the heterogeneous manifestations of psoriatic arthritis, but they caution that randomized data remain sparse and the recommendations may change as new data emerge.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), which has 250 members from North America, Europe, and elsewhere, performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis, and formulated treatment guidelines based on this systematic review and consensus opinion.

Significant challenges exist in the management of psoriatic arthritis (PsA), according to lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine in PsA, so there is an inadequate evidence base for the use of these drugs. There is also no evidence that the traditional agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, explained Dr. Ritchlin, who is professor of medicine and director of clinical immunology, University of Rochester (N.Y.) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the paucity of data for methotrexate, with only one older double-blind randomized trial having been done, which failed to show efficacy (Arthritis Rheum. 1984;27:376–81). “But that study was underdosed and underpowered,” Dr. Ritchlin said.

Improvements in trial design in the intervening years, incorporating more useful and measurable outcomes in PsA, favor the newer biologic agents over the older disease-modifying antirheumatic drugs (DMARDs). While there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors—with these drugs clearly being effective in many patients—there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

GRAPPA, therefore, has attempted to fill these knowledge gaps, to provide physicians with available evidence-based information, and to help physicians in their diagnostic and therapeutic decision making (Ann. Rheum. Dis. 2008 Oct. 24 [Epub doi:10.1136/ard.2008.094946

The GRAPPA investigators noted that their efforts were hampered by a lack of validated tools. For example, they wrote that the assessment and treatment of axial manifestations of PsA are particularly challenging and that by consensus they agreed to follow guidelines of the Assessments in Ankylosing Spondylitis Working Group and adopt the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for determination of severity and response until validated measures for axial disease in PsA can be developed.

In general, the recommendations include the following:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors may be given.

While TNF inhibitors are recommended for use in patients who have failed at least one DMARD, the recommendations also note that the patient whose prognosis is poor can be considered for a TNF agent without prior DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life.

Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment options include NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but DMARDs or infliximab can be tried if symptoms are resistant.

▸ For mild enthesitis, typically of the Achilles tendon area, NSAIDs, physical therapy, and corticosteroids can be used, while moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

The guidelines also emphasized that many new treatments are in the pipeline, “which will offer new and possibly less expensive therapeutic options.”

Dr. Ritchlin also discussed larger management issues in PsA at the meeting. “The evidence is abundantly clear that psoriatic arthritis is an independent risk factor for coronary vascular disease. A lot of these patients are young, and they don't go to their primary care physicians. They come to the rheumatologists and the dermatologists,” he said.

“No one is following their cholesterol profiles or advising them about smoking and weight loss, so it's really incumbent on us to make sure these issues are addressed in this patient population. This is a really significant intervention we can make, maybe even more important in some cases than treating their joint and skin disease,” Dr. Ritchlin said.

Dr. Ritchlin disclosed that he has received grant research support from Centocor Inc. and is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and this newspaper are owned by Elsevier.

'It's not that we know these [traditional] drugs don't work—the studies simply haven't been done.' DR. RITCHLIN

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for treating gout means there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments for gout have been approved since 1964, but late last year the advisory panel of the Food and Drug Administration (FDA) voted 12–0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. The FDA usually follows the recommendations of its advisory panel.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis, said Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

There also have been no reports of hypersensitivity reactions, even in patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, according to Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol … all you are doing is retarding the rate at which the crystals will deposit,” he said.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

SDEF and this news organization are owned by Elsevier.

This proton density image shows a low to intermediate signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for treating gout means there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments for gout have been approved since 1964, but late last year the advisory panel of the Food and Drug Administration (FDA) voted 12–0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. The FDA usually follows the recommendations of its advisory panel.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis, said Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

There also have been no reports of hypersensitivity reactions, even in patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, according to Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol … all you are doing is retarding the rate at which the crystals will deposit,” he said.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

SDEF and this news organization are owned by Elsevier.

This proton density image shows a low to intermediate signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for treating gout means there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments for gout have been approved since 1964, but late last year the advisory panel of the Food and Drug Administration (FDA) voted 12–0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. The FDA usually follows the recommendations of its advisory panel.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis, said Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

There also have been no reports of hypersensitivity reactions, even in patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, according to Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol … all you are doing is retarding the rate at which the crystals will deposit,” he said.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

SDEF and this news organization are owned by Elsevier.

This proton density image shows a low to intermediate signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and RA is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, said Dr. Daniel Edmundowicz.

“But in any case, the process is driven by dyslipidemia,” he said. “We are born with LDL cholesterol levels around 35-40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble.”

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral arterial disease who have a high prevalence of CAD events like fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol. “Patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg, you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads can be very beneficial, he said.

Dr. Edmundowicz consults for GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this newspaper are owned by Elsevier.

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and RA is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, said Dr. Daniel Edmundowicz.

“But in any case, the process is driven by dyslipidemia,” he said. “We are born with LDL cholesterol levels around 35-40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble.”

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral arterial disease who have a high prevalence of CAD events like fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol. “Patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg, you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads can be very beneficial, he said.

Dr. Edmundowicz consults for GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this newspaper are owned by Elsevier.

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and RA is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, said Dr. Daniel Edmundowicz.

“But in any case, the process is driven by dyslipidemia,” he said. “We are born with LDL cholesterol levels around 35-40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble.”

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral arterial disease who have a high prevalence of CAD events like fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol. “Patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg, you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads can be very beneficial, he said.

Dr. Edmundowicz consults for GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this newspaper are owned by Elsevier.

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement.

The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who is in group practice in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is less. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction.

A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

A vulvar aphthous ulcer is shown as typically found in a patient with Behçet's disease. Courtesy Dr. Andrew T. Goldstein

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement.

The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who is in group practice in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is less. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction.

A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

A vulvar aphthous ulcer is shown as typically found in a patient with Behçet's disease. Courtesy Dr. Andrew T. Goldstein

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement.

The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who is in group practice in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is less. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction.

A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

A vulvar aphthous ulcer is shown as typically found in a patient with Behçet's disease. Courtesy Dr. Andrew T. Goldstein

LAKE BUENA VISTA, FLA. — The cornerstones of an evaluation for chronic pelvic pain are a complete and thorough history and a physical examination directed toward detecting the location of the pain and replicating it through systematic palpation.

Having the patient fill out a questionnaire before an initial consultation is essential for eliciting the necessary historical details in this complex, multifactorial condition, said Dr. Fred M. Howard, professor of obstetrics and gynecology, University of Rochester (N.Y.) Medical Center. A comprehensive questionnaire developed by the International Pelvic Pain Society (www.pelvicpain.org

During the initial consultation, listen to the patient and take the time to establish trust. “Dismiss nothing as ridiculous, impossible, or unimportant,” Dr. Howard said.

The history should be a multidimensional assessment of pain, encompassing gastrointestinal, gynecologic, urinary, and musculoskeletal causes, and should address the patient's symptoms, lifestyle, and psychological state. How the patient understands and interprets her pain is also important, he said at the annual meeting of the International Pelvic Pain Society.

Prominent among potential gastrointestinal causes is irritable bowel syndrome (IBS), which today is defined by the Rome criteria as a pain syndrome. IBS can be identified with questions about whether, during the previous 3 months, the patient had at least 3 days of abdominal pain or discomfort that was relieved by a bowel movement or if there was a change in stool frequency, form, or appearance.

Possible sources of pain in the reproductive tract are endometriosis and pelvic congestion syndrome. Endometriosis is a likely cause if the pain worsens with or before menses, it is associated with deep penetration during intercourse, or there are problems with conceiving.

Pelvic congestion syndrome can be associated with dull, aching low back pain and premenstrual exacerbations, as well as with deep dyspareunia with postcoital ache that can last up to 24 hours. Other common causes include abdominal wall myofascial pain in a patient reporting activity that could acutely or repetitively overload the pelvic or abdominal muscles, such as gymnastics, or a history of trauma or injury.

Findings suggesting pelvic floor pain syndrome include pain that is aching or throbbing or described as “heaviness,” that presents acutely in the rectum or vagina or increases with sitting or standing in one position at length.

In doing the work-up, laboratory and imaging studies don't add much to the evaluation. “Only tests that are needed to rule out life-threatening diseases or that will definitively confirm your clinical diagnoses should be ordered.”

The physical exam should focus on “pain mapping” to detect the locations of pain and tenderness, and replicate the pain with palpation in a “four S” sequence: standing, sitting, supine, and in stirrups, he said. “If the patient is anxious, try palpating gently with your stethoscope. Patients don't expect that to hurt.”

While the patient is standing, evaluate her for groin and abdominal hernias, injuries to the pubic symphysis, fibromyalgia, and short leg syndrome. Also palpate any possible abdominal trigger points, pushing only hard enough to reach the rectus or external oblique muscles, which should reproduce all or part of her pain.

When she is sitting, look for asymmetric posture, which can be a manifestation of pain in the buttocks or perineum. In the supine position, inspect and palpate for lordosis or pelvic tilt, as well as for distension or masses.

Dr. Howard leaves the pelvic examination for last. “It helps to do it last when she may be less anxious.”

Always consider the possibility of depression, a major psychological comorbidity with chronic pain, and particularly ask about suicidality. And be mindful of other unrelated problems, he warned.

'Dismiss nothing as ridiculous, impossible, or unimportant,' and ask about depression and suicidality. DR. HOWARD

LAKE BUENA VISTA, FLA. — The cornerstones of an evaluation for chronic pelvic pain are a complete and thorough history and a physical examination directed toward detecting the location of the pain and replicating it through systematic palpation.

Having the patient fill out a questionnaire before an initial consultation is essential for eliciting the necessary historical details in this complex, multifactorial condition, said Dr. Fred M. Howard, professor of obstetrics and gynecology, University of Rochester (N.Y.) Medical Center. A comprehensive questionnaire developed by the International Pelvic Pain Society (www.pelvicpain.org

During the initial consultation, listen to the patient and take the time to establish trust. “Dismiss nothing as ridiculous, impossible, or unimportant,” Dr. Howard said.

The history should be a multidimensional assessment of pain, encompassing gastrointestinal, gynecologic, urinary, and musculoskeletal causes, and should address the patient's symptoms, lifestyle, and psychological state. How the patient understands and interprets her pain is also important, he said at the annual meeting of the International Pelvic Pain Society.

Prominent among potential gastrointestinal causes is irritable bowel syndrome (IBS), which today is defined by the Rome criteria as a pain syndrome. IBS can be identified with questions about whether, during the previous 3 months, the patient had at least 3 days of abdominal pain or discomfort that was relieved by a bowel movement or if there was a change in stool frequency, form, or appearance.

Possible sources of pain in the reproductive tract are endometriosis and pelvic congestion syndrome. Endometriosis is a likely cause if the pain worsens with or before menses, it is associated with deep penetration during intercourse, or there are problems with conceiving.

Pelvic congestion syndrome can be associated with dull, aching low back pain and premenstrual exacerbations, as well as with deep dyspareunia with postcoital ache that can last up to 24 hours. Other common causes include abdominal wall myofascial pain in a patient reporting activity that could acutely or repetitively overload the pelvic or abdominal muscles, such as gymnastics, or a history of trauma or injury.

Findings suggesting pelvic floor pain syndrome include pain that is aching or throbbing or described as “heaviness,” that presents acutely in the rectum or vagina or increases with sitting or standing in one position at length.

In doing the work-up, laboratory and imaging studies don't add much to the evaluation. “Only tests that are needed to rule out life-threatening diseases or that will definitively confirm your clinical diagnoses should be ordered.”

The physical exam should focus on “pain mapping” to detect the locations of pain and tenderness, and replicate the pain with palpation in a “four S” sequence: standing, sitting, supine, and in stirrups, he said. “If the patient is anxious, try palpating gently with your stethoscope. Patients don't expect that to hurt.”

While the patient is standing, evaluate her for groin and abdominal hernias, injuries to the pubic symphysis, fibromyalgia, and short leg syndrome. Also palpate any possible abdominal trigger points, pushing only hard enough to reach the rectus or external oblique muscles, which should reproduce all or part of her pain.

When she is sitting, look for asymmetric posture, which can be a manifestation of pain in the buttocks or perineum. In the supine position, inspect and palpate for lordosis or pelvic tilt, as well as for distension or masses.

Dr. Howard leaves the pelvic examination for last. “It helps to do it last when she may be less anxious.”

Always consider the possibility of depression, a major psychological comorbidity with chronic pain, and particularly ask about suicidality. And be mindful of other unrelated problems, he warned.

'Dismiss nothing as ridiculous, impossible, or unimportant,' and ask about depression and suicidality. DR. HOWARD

LAKE BUENA VISTA, FLA. — The cornerstones of an evaluation for chronic pelvic pain are a complete and thorough history and a physical examination directed toward detecting the location of the pain and replicating it through systematic palpation.

Having the patient fill out a questionnaire before an initial consultation is essential for eliciting the necessary historical details in this complex, multifactorial condition, said Dr. Fred M. Howard, professor of obstetrics and gynecology, University of Rochester (N.Y.) Medical Center. A comprehensive questionnaire developed by the International Pelvic Pain Society (www.pelvicpain.org

During the initial consultation, listen to the patient and take the time to establish trust. “Dismiss nothing as ridiculous, impossible, or unimportant,” Dr. Howard said.

The history should be a multidimensional assessment of pain, encompassing gastrointestinal, gynecologic, urinary, and musculoskeletal causes, and should address the patient's symptoms, lifestyle, and psychological state. How the patient understands and interprets her pain is also important, he said at the annual meeting of the International Pelvic Pain Society.

Prominent among potential gastrointestinal causes is irritable bowel syndrome (IBS), which today is defined by the Rome criteria as a pain syndrome. IBS can be identified with questions about whether, during the previous 3 months, the patient had at least 3 days of abdominal pain or discomfort that was relieved by a bowel movement or if there was a change in stool frequency, form, or appearance.

Possible sources of pain in the reproductive tract are endometriosis and pelvic congestion syndrome. Endometriosis is a likely cause if the pain worsens with or before menses, it is associated with deep penetration during intercourse, or there are problems with conceiving.

Pelvic congestion syndrome can be associated with dull, aching low back pain and premenstrual exacerbations, as well as with deep dyspareunia with postcoital ache that can last up to 24 hours. Other common causes include abdominal wall myofascial pain in a patient reporting activity that could acutely or repetitively overload the pelvic or abdominal muscles, such as gymnastics, or a history of trauma or injury.

Findings suggesting pelvic floor pain syndrome include pain that is aching or throbbing or described as “heaviness,” that presents acutely in the rectum or vagina or increases with sitting or standing in one position at length.

In doing the work-up, laboratory and imaging studies don't add much to the evaluation. “Only tests that are needed to rule out life-threatening diseases or that will definitively confirm your clinical diagnoses should be ordered.”

The physical exam should focus on “pain mapping” to detect the locations of pain and tenderness, and replicate the pain with palpation in a “four S” sequence: standing, sitting, supine, and in stirrups, he said. “If the patient is anxious, try palpating gently with your stethoscope. Patients don't expect that to hurt.”

While the patient is standing, evaluate her for groin and abdominal hernias, injuries to the pubic symphysis, fibromyalgia, and short leg syndrome. Also palpate any possible abdominal trigger points, pushing only hard enough to reach the rectus or external oblique muscles, which should reproduce all or part of her pain.

When she is sitting, look for asymmetric posture, which can be a manifestation of pain in the buttocks or perineum. In the supine position, inspect and palpate for lordosis or pelvic tilt, as well as for distension or masses.

Dr. Howard leaves the pelvic examination for last. “It helps to do it last when she may be less anxious.”

Always consider the possibility of depression, a major psychological comorbidity with chronic pain, and particularly ask about suicidality. And be mindful of other unrelated problems, he warned.

'Dismiss nothing as ridiculous, impossible, or unimportant,' and ask about depression and suicidality. DR. HOWARD

LAKE BUENA VISTA, FLA. — An extensive work-up that includes tests such as colonoscopy should generally be avoided for patients suspected of having irritable bowel syndrome, which is a biopsychosocial disorder characterized by altered colonic motility and enhanced visceral pain perception.

Only when there are atypical or alarming symptoms such as fever, anemia, hematochezia, or a family history of colon cancer should an extensive diagnostic work-up including colonoscopy or barium enema be undertaken, according to Dr. Georgine M. Lamvu.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, affecting 3%–15% of adults worldwide. The condition is three times more common in women than in men, Dr. Lamvu said at the annual meeting of the International Pelvic Pain Society.

The Rome criteria for IBS require at least 3 months of continuous or recurrent symptoms of pain relieved with defecation, and/or changes in frequency or consistency of stool. Bloating and distension also are common features, said Dr. Lamvu of the department of obstetrics and gynecology at Florida Hospital, Orlando.

The disorder is classified as being constipation predominant, diarrhea predominant, or alternating, and it may be exacerbated by psychological distress.

The choice of diagnostic studies should be determined by findings on the history and physical examination. For most patients, the history should focus on travel; the presence of rectal bleeding or dark, tarry stools; and the chronicity of symptoms.

Patients often report generalized pain, which can be crampy, sharp, and shooting—most notably in the left lower quadrant. Rule out masses and any signs of acute abdomen, including rigidity and tympanic bowel sounds, Dr. Lamvu said.

An appropriate diagnostic work-up includes a complete blood count, which can rule out anemia, inflammation, and infection; a chemistry panel to detect electrolyte abnormalities associated with inflammatory bowel disease; and a stool culture for occult blood, white blood cells, and ova and parasites, she said.

A hydrogen breath test can rule out lactose intolerance and, if the patient has had exposure to antibiotics within 6 weeks, testing for Clostridium difficile toxin also may be useful.

If the patient's symptoms are constipation predominant, it also is necessary to differentiate IBS from functional constipation, which is characterized by straining, lumpy hard stools, a sensation of incomplete evacuation or obstruction, and fewer than three defecations per week.

“And importantly, functional constipation is not associated with pain, which is required for a diagnosis of IBS,” Dr. Lamvu said.

To treat constipation-predominant IBS, use bulking agents such as fiber to improve colonic transit and ease stool passage. Many randomized trials have confirmed improvements in bowel function with these products, but effects on pain have been mixed.

Osmotic laxatives also can be used, but patients with constipation-predominant IBS need to know that improvements will not be immediate and, even once bowel motility is achieved, it can take weeks or even months for reductions in pain levels to occur, Dr. Lamvu said.

Treatments for diarrhea-predominant IBS include dicyclomine and hyoscyamine, and if the diarrhea is accompanied by prominent pain, tricyclic antidepressants may be helpful.

Several other agents are being made available or investigated, including lubiprostone (Amitiza), GnRH (gonadotropin-releasing hormone) analogues, and alosetron (Lotronex).

Tegaserod (Zelnorm) has been removed from the market because risks of cardiovascular events were seen in pooled data from 29 short-term clinical studies. “A lot of us were a little disappointed when this drug was recalled, but so many trials are going on now that in 5 years we may have 5–10 additional therapies available,” she said.

And always remember when dealing with IBS patients that central to successful treatment are communication, patience, and the development of long-term treatment plans, she concluded.

Dr. Lamvu stated that she had no financial interest in any of the products she discussed.

LAKE BUENA VISTA, FLA. — An extensive work-up that includes tests such as colonoscopy should generally be avoided for patients suspected of having irritable bowel syndrome, which is a biopsychosocial disorder characterized by altered colonic motility and enhanced visceral pain perception.

Only when there are atypical or alarming symptoms such as fever, anemia, hematochezia, or a family history of colon cancer should an extensive diagnostic work-up including colonoscopy or barium enema be undertaken, according to Dr. Georgine M. Lamvu.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, affecting 3%–15% of adults worldwide. The condition is three times more common in women than in men, Dr. Lamvu said at the annual meeting of the International Pelvic Pain Society.

The Rome criteria for IBS require at least 3 months of continuous or recurrent symptoms of pain relieved with defecation, and/or changes in frequency or consistency of stool. Bloating and distension also are common features, said Dr. Lamvu of the department of obstetrics and gynecology at Florida Hospital, Orlando.

The disorder is classified as being constipation predominant, diarrhea predominant, or alternating, and it may be exacerbated by psychological distress.

The choice of diagnostic studies should be determined by findings on the history and physical examination. For most patients, the history should focus on travel; the presence of rectal bleeding or dark, tarry stools; and the chronicity of symptoms.

Patients often report generalized pain, which can be crampy, sharp, and shooting—most notably in the left lower quadrant. Rule out masses and any signs of acute abdomen, including rigidity and tympanic bowel sounds, Dr. Lamvu said.

An appropriate diagnostic work-up includes a complete blood count, which can rule out anemia, inflammation, and infection; a chemistry panel to detect electrolyte abnormalities associated with inflammatory bowel disease; and a stool culture for occult blood, white blood cells, and ova and parasites, she said.

A hydrogen breath test can rule out lactose intolerance and, if the patient has had exposure to antibiotics within 6 weeks, testing for Clostridium difficile toxin also may be useful.

If the patient's symptoms are constipation predominant, it also is necessary to differentiate IBS from functional constipation, which is characterized by straining, lumpy hard stools, a sensation of incomplete evacuation or obstruction, and fewer than three defecations per week.

“And importantly, functional constipation is not associated with pain, which is required for a diagnosis of IBS,” Dr. Lamvu said.

To treat constipation-predominant IBS, use bulking agents such as fiber to improve colonic transit and ease stool passage. Many randomized trials have confirmed improvements in bowel function with these products, but effects on pain have been mixed.

Osmotic laxatives also can be used, but patients with constipation-predominant IBS need to know that improvements will not be immediate and, even once bowel motility is achieved, it can take weeks or even months for reductions in pain levels to occur, Dr. Lamvu said.

Treatments for diarrhea-predominant IBS include dicyclomine and hyoscyamine, and if the diarrhea is accompanied by prominent pain, tricyclic antidepressants may be helpful.

Several other agents are being made available or investigated, including lubiprostone (Amitiza), GnRH (gonadotropin-releasing hormone) analogues, and alosetron (Lotronex).

Tegaserod (Zelnorm) has been removed from the market because risks of cardiovascular events were seen in pooled data from 29 short-term clinical studies. “A lot of us were a little disappointed when this drug was recalled, but so many trials are going on now that in 5 years we may have 5–10 additional therapies available,” she said.

And always remember when dealing with IBS patients that central to successful treatment are communication, patience, and the development of long-term treatment plans, she concluded.

Dr. Lamvu stated that she had no financial interest in any of the products she discussed.

LAKE BUENA VISTA, FLA. — An extensive work-up that includes tests such as colonoscopy should generally be avoided for patients suspected of having irritable bowel syndrome, which is a biopsychosocial disorder characterized by altered colonic motility and enhanced visceral pain perception.

Only when there are atypical or alarming symptoms such as fever, anemia, hematochezia, or a family history of colon cancer should an extensive diagnostic work-up including colonoscopy or barium enema be undertaken, according to Dr. Georgine M. Lamvu.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, affecting 3%–15% of adults worldwide. The condition is three times more common in women than in men, Dr. Lamvu said at the annual meeting of the International Pelvic Pain Society.

The Rome criteria for IBS require at least 3 months of continuous or recurrent symptoms of pain relieved with defecation, and/or changes in frequency or consistency of stool. Bloating and distension also are common features, said Dr. Lamvu of the department of obstetrics and gynecology at Florida Hospital, Orlando.

The disorder is classified as being constipation predominant, diarrhea predominant, or alternating, and it may be exacerbated by psychological distress.

The choice of diagnostic studies should be determined by findings on the history and physical examination. For most patients, the history should focus on travel; the presence of rectal bleeding or dark, tarry stools; and the chronicity of symptoms.

Patients often report generalized pain, which can be crampy, sharp, and shooting—most notably in the left lower quadrant. Rule out masses and any signs of acute abdomen, including rigidity and tympanic bowel sounds, Dr. Lamvu said.

An appropriate diagnostic work-up includes a complete blood count, which can rule out anemia, inflammation, and infection; a chemistry panel to detect electrolyte abnormalities associated with inflammatory bowel disease; and a stool culture for occult blood, white blood cells, and ova and parasites, she said.

A hydrogen breath test can rule out lactose intolerance and, if the patient has had exposure to antibiotics within 6 weeks, testing for Clostridium difficile toxin also may be useful.

If the patient's symptoms are constipation predominant, it also is necessary to differentiate IBS from functional constipation, which is characterized by straining, lumpy hard stools, a sensation of incomplete evacuation or obstruction, and fewer than three defecations per week.

“And importantly, functional constipation is not associated with pain, which is required for a diagnosis of IBS,” Dr. Lamvu said.

To treat constipation-predominant IBS, use bulking agents such as fiber to improve colonic transit and ease stool passage. Many randomized trials have confirmed improvements in bowel function with these products, but effects on pain have been mixed.

Osmotic laxatives also can be used, but patients with constipation-predominant IBS need to know that improvements will not be immediate and, even once bowel motility is achieved, it can take weeks or even months for reductions in pain levels to occur, Dr. Lamvu said.

Treatments for diarrhea-predominant IBS include dicyclomine and hyoscyamine, and if the diarrhea is accompanied by prominent pain, tricyclic antidepressants may be helpful.

Several other agents are being made available or investigated, including lubiprostone (Amitiza), GnRH (gonadotropin-releasing hormone) analogues, and alosetron (Lotronex).

Tegaserod (Zelnorm) has been removed from the market because risks of cardiovascular events were seen in pooled data from 29 short-term clinical studies. “A lot of us were a little disappointed when this drug was recalled, but so many trials are going on now that in 5 years we may have 5–10 additional therapies available,” she said.

And always remember when dealing with IBS patients that central to successful treatment are communication, patience, and the development of long-term treatment plans, she concluded.

Dr. Lamvu stated that she had no financial interest in any of the products she discussed.

PHILADELPHIA — Nearly 5 years of treatment with the angiotensin type 1 receptor blocker candesartan did not provide statistical benefit in the prevention of microalbuminuria in patients with diabetes, according to a new post hoc analysis.

The Diabetic Retinopathy Candesartan Trials (DIRECT) program consisted of three randomized, double-blind, placebo-controlled trials that took place in 309 centers in 30 countries worldwide. These trials were primarily intended to assess whether candesartan could reduce the incidence and progression of diabetic retinopathy. The program was sponsored by AstraZeneca and Takeda, which jointly developed the drug.

In type 1 diabetes, the drug reduced the incidence of retinopathy but did not hinder its progression (Lancet 2008;372:1394-402). In type 2 diabetes, there was a nonsignificant reduction in progression of retinopathy and a significant regression of retinopathy in patients with mild to moderate ocular involvement (Lancet 2008;372:1385-93).

“Agents that block the renin-angiotensin system [RAS] also reduce albuminuria and progression of established diabetic nephropathy, but their role in the primary prevention of microalbuminuria remains to be established,” Dr. Rudy W. Bilous said in a late-breaking abstract session at the annual meeting of the American Society of Nephrology.

Accordingly, he and his colleagues undertook an analysis of data from the retinopathy trials, using prespecified renal end points of the development of microalbuminuria, defined by the presence of at least three out of four consecutive overnight albumin excretion rates over 20 mcg/min, and the annual rate of change in excretion rates.

A total of 5,231 patients, whose average age was 40 years and whose mean duration of diabetes was 9 years, were randomized to placebo or candesartan at an initial dose of 16 mg/day. The dose was increased to 32 mg/day after 1 month.

At baseline, none of the patients had microalbuminuria. For inclusion in the study, blood pressure in the type 1 diabetes patients had to be less than 130/85 mm Hg, and in type 2 patients it had to be less than 160/90 mm Hg with antihypertensive treatment. The mean baseline blood pressure was 118/74 mm Hg among the normotensive patients and 139/79 mm Hg among the treated hypertensives.

Diabetes control at baseline was modest, with a mean hemoglobin A_1c of 8.3%, said Dr. Bilous of Newcastle University, Newcastle upon Tyne (England).

During the first month of the study there were significant reductions in blood pressure of 3 mm Hg systolic and 2 mm Hg diastolic; this was maintained throughout the study, with patients being followed for a median of 4.7 years.

The 401 patients who developed microalbuminuria during the study were more likely to be male, to be older, and to have higher baseline HbA_1c and systolic blood pressures.

“These findings were in accordance with previously published data on risk factors for the development of incident microalbuminuria in diabetes. But when we looked at the microalbuminuria incidence in the two treatment arms, there was absolutely no difference,” Dr. Bilous said.

Furthermore, after adjustment for baseline HbA_1c, albumin excretion rate, systolic blood pressure, and antihypertensive therapy; and after further adjustment for achieved systolic blood pressure, there were no differences in hazard ratios for the two arms, he said.

The secondary renal end point of rate of change in overnight albumin excretion showed a statistically significant 5.7% annual decrease. “However, this represented only a difference of 0.11 mcg/min, and the clinical significance is uncertain over the long term,” Dr. Bilous said.

“In conclusion … we found no statistical benefit to candesartan in prevention of microalbuminuria over a median follow-up of 4.7 years, although there was a modest reduction in the annualized rate of change. So we cannot conclude that candesartan is of benefit in preventing diabetic nephropathy in patients with normal albuminuria over this short period of time,” he said.

Dr. Bilous disclosed that he and his coinvestigators have acted as consultants to Takeda and AstraZeneca; were on the steering committee of this investigator-initiated study; and received fees for attendance at meetings of the steering committee.

PHILADELPHIA — Nearly 5 years of treatment with the angiotensin type 1 receptor blocker candesartan did not provide statistical benefit in the prevention of microalbuminuria in patients with diabetes, according to a new post hoc analysis.

The Diabetic Retinopathy Candesartan Trials (DIRECT) program consisted of three randomized, double-blind, placebo-controlled trials that took place in 309 centers in 30 countries worldwide. These trials were primarily intended to assess whether candesartan could reduce the incidence and progression of diabetic retinopathy. The program was sponsored by AstraZeneca and Takeda, which jointly developed the drug.

In type 1 diabetes, the drug reduced the incidence of retinopathy but did not hinder its progression (Lancet 2008;372:1394-402). In type 2 diabetes, there was a nonsignificant reduction in progression of retinopathy and a significant regression of retinopathy in patients with mild to moderate ocular involvement (Lancet 2008;372:1385-93).

“Agents that block the renin-angiotensin system [RAS] also reduce albuminuria and progression of established diabetic nephropathy, but their role in the primary prevention of microalbuminuria remains to be established,” Dr. Rudy W. Bilous said in a late-breaking abstract session at the annual meeting of the American Society of Nephrology.

Accordingly, he and his colleagues undertook an analysis of data from the retinopathy trials, using prespecified renal end points of the development of microalbuminuria, defined by the presence of at least three out of four consecutive overnight albumin excretion rates over 20 mcg/min, and the annual rate of change in excretion rates.

A total of 5,231 patients, whose average age was 40 years and whose mean duration of diabetes was 9 years, were randomized to placebo or candesartan at an initial dose of 16 mg/day. The dose was increased to 32 mg/day after 1 month.

At baseline, none of the patients had microalbuminuria. For inclusion in the study, blood pressure in the type 1 diabetes patients had to be less than 130/85 mm Hg, and in type 2 patients it had to be less than 160/90 mm Hg with antihypertensive treatment. The mean baseline blood pressure was 118/74 mm Hg among the normotensive patients and 139/79 mm Hg among the treated hypertensives.

Diabetes control at baseline was modest, with a mean hemoglobin A_1c of 8.3%, said Dr. Bilous of Newcastle University, Newcastle upon Tyne (England).

During the first month of the study there were significant reductions in blood pressure of 3 mm Hg systolic and 2 mm Hg diastolic; this was maintained throughout the study, with patients being followed for a median of 4.7 years.

The 401 patients who developed microalbuminuria during the study were more likely to be male, to be older, and to have higher baseline HbA_1c and systolic blood pressures.

“These findings were in accordance with previously published data on risk factors for the development of incident microalbuminuria in diabetes. But when we looked at the microalbuminuria incidence in the two treatment arms, there was absolutely no difference,” Dr. Bilous said.

Furthermore, after adjustment for baseline HbA_1c, albumin excretion rate, systolic blood pressure, and antihypertensive therapy; and after further adjustment for achieved systolic blood pressure, there were no differences in hazard ratios for the two arms, he said.

The secondary renal end point of rate of change in overnight albumin excretion showed a statistically significant 5.7% annual decrease. “However, this represented only a difference of 0.11 mcg/min, and the clinical significance is uncertain over the long term,” Dr. Bilous said.

“In conclusion … we found no statistical benefit to candesartan in prevention of microalbuminuria over a median follow-up of 4.7 years, although there was a modest reduction in the annualized rate of change. So we cannot conclude that candesartan is of benefit in preventing diabetic nephropathy in patients with normal albuminuria over this short period of time,” he said.

Dr. Bilous disclosed that he and his coinvestigators have acted as consultants to Takeda and AstraZeneca; were on the steering committee of this investigator-initiated study; and received fees for attendance at meetings of the steering committee.

PHILADELPHIA — Nearly 5 years of treatment with the angiotensin type 1 receptor blocker candesartan did not provide statistical benefit in the prevention of microalbuminuria in patients with diabetes, according to a new post hoc analysis.

The Diabetic Retinopathy Candesartan Trials (DIRECT) program consisted of three randomized, double-blind, placebo-controlled trials that took place in 309 centers in 30 countries worldwide. These trials were primarily intended to assess whether candesartan could reduce the incidence and progression of diabetic retinopathy. The program was sponsored by AstraZeneca and Takeda, which jointly developed the drug.

In type 1 diabetes, the drug reduced the incidence of retinopathy but did not hinder its progression (Lancet 2008;372:1394-402). In type 2 diabetes, there was a nonsignificant reduction in progression of retinopathy and a significant regression of retinopathy in patients with mild to moderate ocular involvement (Lancet 2008;372:1385-93).

“Agents that block the renin-angiotensin system [RAS] also reduce albuminuria and progression of established diabetic nephropathy, but their role in the primary prevention of microalbuminuria remains to be established,” Dr. Rudy W. Bilous said in a late-breaking abstract session at the annual meeting of the American Society of Nephrology.

Accordingly, he and his colleagues undertook an analysis of data from the retinopathy trials, using prespecified renal end points of the development of microalbuminuria, defined by the presence of at least three out of four consecutive overnight albumin excretion rates over 20 mcg/min, and the annual rate of change in excretion rates.

A total of 5,231 patients, whose average age was 40 years and whose mean duration of diabetes was 9 years, were randomized to placebo or candesartan at an initial dose of 16 mg/day. The dose was increased to 32 mg/day after 1 month.

At baseline, none of the patients had microalbuminuria. For inclusion in the study, blood pressure in the type 1 diabetes patients had to be less than 130/85 mm Hg, and in type 2 patients it had to be less than 160/90 mm Hg with antihypertensive treatment. The mean baseline blood pressure was 118/74 mm Hg among the normotensive patients and 139/79 mm Hg among the treated hypertensives.

Diabetes control at baseline was modest, with a mean hemoglobin A_1c of 8.3%, said Dr. Bilous of Newcastle University, Newcastle upon Tyne (England).

During the first month of the study there were significant reductions in blood pressure of 3 mm Hg systolic and 2 mm Hg diastolic; this was maintained throughout the study, with patients being followed for a median of 4.7 years.

The 401 patients who developed microalbuminuria during the study were more likely to be male, to be older, and to have higher baseline HbA_1c and systolic blood pressures.

“These findings were in accordance with previously published data on risk factors for the development of incident microalbuminuria in diabetes. But when we looked at the microalbuminuria incidence in the two treatment arms, there was absolutely no difference,” Dr. Bilous said.

Furthermore, after adjustment for baseline HbA_1c, albumin excretion rate, systolic blood pressure, and antihypertensive therapy; and after further adjustment for achieved systolic blood pressure, there were no differences in hazard ratios for the two arms, he said.

The secondary renal end point of rate of change in overnight albumin excretion showed a statistically significant 5.7% annual decrease. “However, this represented only a difference of 0.11 mcg/min, and the clinical significance is uncertain over the long term,” Dr. Bilous said.

“In conclusion … we found no statistical benefit to candesartan in prevention of microalbuminuria over a median follow-up of 4.7 years, although there was a modest reduction in the annualized rate of change. So we cannot conclude that candesartan is of benefit in preventing diabetic nephropathy in patients with normal albuminuria over this short period of time,” he said.

Dr. Bilous disclosed that he and his coinvestigators have acted as consultants to Takeda and AstraZeneca; were on the steering committee of this investigator-initiated study; and received fees for attendance at meetings of the steering committee.