Nancy Walsh

The presence of peripheral neuropathy was associated with a low urinary flow rate measured urodynamically in the first study to investigate whether microvascular complications can predict the development of cystopathy in diabetic patients without voiding symptoms.

Diabetic cystopathy is a common complication of long-standing diabetes, and traditionally has been described as the triad of decreased bladder sensitivity, increased bladder capacity, and impaired detrusor contractility, according to a study published recently in Diabetes Research and Clinical Practice.

The condition may result from an alteration in physiology of the detrusor smooth muscle cell, from changes in the innervation or function of the neuronal component, or from urothelial dysfunction and multiple other abnormalities that have been reported in urodynamic studies of patients with diabetes (Diabetes Res. Clin. Pract. 2007;78:42–50).

Urodynamic studies are accurate and sensitive, but also are invasive, costly, and time consuming. Easy-to-measure correlates would be potentially valuable in screening for this complication in asymptomatic patients, reported Dr. Alireza Esteghamati of the Endocrine Research Center, Vali-Asr Hospital, Tehran (Iran) University of Medical Sciences, and colleagues.

In order to identify a possible association between bladder abnormalities and microvascular complications, researchers enrolled 66 patients with type 2 diabetes. A total of 40 were female, and their ages ranged from 30 to 82 years. The mean duration of diabetes was 14.4 years. All patients underwent ophthalmologic and neurologic examinations to identify retinopathy and peripheral somatic neuropathy; in addition, 24-hour urine samples were collected to screen for proteinuria. The urodynamic studies consisted of uroflowmetry, filling cystometry, voiding cystometry, and urethral pressure profilometry.

Parameters that were included in the analysis were detrusor activity, bladder capacity, bladder compliance, first sensation of filling, flow rate, bladder outlet status, and postvoiding residue.

Microvascular complications were present in 80.3%, with 71.2% having diabetic neuropathy and 36.4% having retinopathy. Microalbuminuria was present in 32.3% and macroalbuminuria in 15.4%.

All patients had at least one abnormal finding in the urodynamic studies. The prevalence of abnormalities in detrusor activity was 13.6%; in bladder capacity, 84.6%; in bladder compliance, 65.2%; in first sensation of filling, 46.9%; in flow rate, 71%; in bladder outlet obstruction, 11.3%; and in postvoiding residue, 45.5%.

The researchers found that the presence of diabetic neuropathy in the lower limbs was associated with an almost fivefold increased risk of having a low flow rate. Analyses of age, sex, and hemoglobin A_1c, microvascular complications, and urodynamic abnormalities revealed that female sex was associated with increased bladder capacity, while male sex was associated with decreased bladder compliance and bladder outlet obstruction. Older age predicted a low flow rate and outlet obstruction.

The investigators noted that older age and both reduced flow rate and outlet obstruction in men are commonly caused by benign prostatic hypertrophy, but men with a history of this condition had been excluded from their study.

They explained that outlet resistance, which is the primary determinant of flow rate, can vary according to both mechanical factors such as prostatic hypertrophy and functional factors such as sphincteric activity. Sphincteric overactivity, which results in increased outlet resistance and reduced flow rate, is primarily a neuropathic phenomenon and must be considered along with mechanical factors in these patients, the researchers wrote.

The researchers also reported that their findings suggest that diabetic cystopathy begins long before symptoms appear, and wrote, “If, as suggested by our study, microvascular complications cause or are associated with damage to the vascular and neurological innervation of the bladder, then intensive glycemic control may prevent or improve the severity of urologic complications.

The presence of peripheral neuropathy was associated with a low urinary flow rate measured urodynamically in the first study to investigate whether microvascular complications can predict the development of cystopathy in diabetic patients without voiding symptoms.

Diabetic cystopathy is a common complication of long-standing diabetes, and traditionally has been described as the triad of decreased bladder sensitivity, increased bladder capacity, and impaired detrusor contractility, according to a study published recently in Diabetes Research and Clinical Practice.

The condition may result from an alteration in physiology of the detrusor smooth muscle cell, from changes in the innervation or function of the neuronal component, or from urothelial dysfunction and multiple other abnormalities that have been reported in urodynamic studies of patients with diabetes (Diabetes Res. Clin. Pract. 2007;78:42–50).

Urodynamic studies are accurate and sensitive, but also are invasive, costly, and time consuming. Easy-to-measure correlates would be potentially valuable in screening for this complication in asymptomatic patients, reported Dr. Alireza Esteghamati of the Endocrine Research Center, Vali-Asr Hospital, Tehran (Iran) University of Medical Sciences, and colleagues.

In order to identify a possible association between bladder abnormalities and microvascular complications, researchers enrolled 66 patients with type 2 diabetes. A total of 40 were female, and their ages ranged from 30 to 82 years. The mean duration of diabetes was 14.4 years. All patients underwent ophthalmologic and neurologic examinations to identify retinopathy and peripheral somatic neuropathy; in addition, 24-hour urine samples were collected to screen for proteinuria. The urodynamic studies consisted of uroflowmetry, filling cystometry, voiding cystometry, and urethral pressure profilometry.

Parameters that were included in the analysis were detrusor activity, bladder capacity, bladder compliance, first sensation of filling, flow rate, bladder outlet status, and postvoiding residue.

Microvascular complications were present in 80.3%, with 71.2% having diabetic neuropathy and 36.4% having retinopathy. Microalbuminuria was present in 32.3% and macroalbuminuria in 15.4%.

All patients had at least one abnormal finding in the urodynamic studies. The prevalence of abnormalities in detrusor activity was 13.6%; in bladder capacity, 84.6%; in bladder compliance, 65.2%; in first sensation of filling, 46.9%; in flow rate, 71%; in bladder outlet obstruction, 11.3%; and in postvoiding residue, 45.5%.

The researchers found that the presence of diabetic neuropathy in the lower limbs was associated with an almost fivefold increased risk of having a low flow rate. Analyses of age, sex, and hemoglobin A_1c, microvascular complications, and urodynamic abnormalities revealed that female sex was associated with increased bladder capacity, while male sex was associated with decreased bladder compliance and bladder outlet obstruction. Older age predicted a low flow rate and outlet obstruction.

The investigators noted that older age and both reduced flow rate and outlet obstruction in men are commonly caused by benign prostatic hypertrophy, but men with a history of this condition had been excluded from their study.

They explained that outlet resistance, which is the primary determinant of flow rate, can vary according to both mechanical factors such as prostatic hypertrophy and functional factors such as sphincteric activity. Sphincteric overactivity, which results in increased outlet resistance and reduced flow rate, is primarily a neuropathic phenomenon and must be considered along with mechanical factors in these patients, the researchers wrote.

The researchers also reported that their findings suggest that diabetic cystopathy begins long before symptoms appear, and wrote, “If, as suggested by our study, microvascular complications cause or are associated with damage to the vascular and neurological innervation of the bladder, then intensive glycemic control may prevent or improve the severity of urologic complications.

The presence of peripheral neuropathy was associated with a low urinary flow rate measured urodynamically in the first study to investigate whether microvascular complications can predict the development of cystopathy in diabetic patients without voiding symptoms.

Diabetic cystopathy is a common complication of long-standing diabetes, and traditionally has been described as the triad of decreased bladder sensitivity, increased bladder capacity, and impaired detrusor contractility, according to a study published recently in Diabetes Research and Clinical Practice.

The condition may result from an alteration in physiology of the detrusor smooth muscle cell, from changes in the innervation or function of the neuronal component, or from urothelial dysfunction and multiple other abnormalities that have been reported in urodynamic studies of patients with diabetes (Diabetes Res. Clin. Pract. 2007;78:42–50).

Urodynamic studies are accurate and sensitive, but also are invasive, costly, and time consuming. Easy-to-measure correlates would be potentially valuable in screening for this complication in asymptomatic patients, reported Dr. Alireza Esteghamati of the Endocrine Research Center, Vali-Asr Hospital, Tehran (Iran) University of Medical Sciences, and colleagues.

In order to identify a possible association between bladder abnormalities and microvascular complications, researchers enrolled 66 patients with type 2 diabetes. A total of 40 were female, and their ages ranged from 30 to 82 years. The mean duration of diabetes was 14.4 years. All patients underwent ophthalmologic and neurologic examinations to identify retinopathy and peripheral somatic neuropathy; in addition, 24-hour urine samples were collected to screen for proteinuria. The urodynamic studies consisted of uroflowmetry, filling cystometry, voiding cystometry, and urethral pressure profilometry.

Parameters that were included in the analysis were detrusor activity, bladder capacity, bladder compliance, first sensation of filling, flow rate, bladder outlet status, and postvoiding residue.

Microvascular complications were present in 80.3%, with 71.2% having diabetic neuropathy and 36.4% having retinopathy. Microalbuminuria was present in 32.3% and macroalbuminuria in 15.4%.

All patients had at least one abnormal finding in the urodynamic studies. The prevalence of abnormalities in detrusor activity was 13.6%; in bladder capacity, 84.6%; in bladder compliance, 65.2%; in first sensation of filling, 46.9%; in flow rate, 71%; in bladder outlet obstruction, 11.3%; and in postvoiding residue, 45.5%.

The researchers found that the presence of diabetic neuropathy in the lower limbs was associated with an almost fivefold increased risk of having a low flow rate. Analyses of age, sex, and hemoglobin A_1c, microvascular complications, and urodynamic abnormalities revealed that female sex was associated with increased bladder capacity, while male sex was associated with decreased bladder compliance and bladder outlet obstruction. Older age predicted a low flow rate and outlet obstruction.

The investigators noted that older age and both reduced flow rate and outlet obstruction in men are commonly caused by benign prostatic hypertrophy, but men with a history of this condition had been excluded from their study.

They explained that outlet resistance, which is the primary determinant of flow rate, can vary according to both mechanical factors such as prostatic hypertrophy and functional factors such as sphincteric activity. Sphincteric overactivity, which results in increased outlet resistance and reduced flow rate, is primarily a neuropathic phenomenon and must be considered along with mechanical factors in these patients, the researchers wrote.

The researchers also reported that their findings suggest that diabetic cystopathy begins long before symptoms appear, and wrote, “If, as suggested by our study, microvascular complications cause or are associated with damage to the vascular and neurological innervation of the bladder, then intensive glycemic control may prevent or improve the severity of urologic complications.

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

Patients' mean age was 51 years, and more than half were women. Mean disease duration was 7.5 years, and study participants had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen.

All patients had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. Among patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. Among those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

Among patients in the tocilizumab 4 mg/kg and 8 mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey.

Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, Dr. Alten wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140-6736(07)60784-3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

Patients' mean age was 51 years, and more than half were women. Mean disease duration was 7.5 years, and study participants had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen.

All patients had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. Among patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. Among those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

Among patients in the tocilizumab 4 mg/kg and 8 mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey.

Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, Dr. Alten wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140-6736(07)60784-3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

Patients' mean age was 51 years, and more than half were women. Mean disease duration was 7.5 years, and study participants had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen.

All patients had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. Among patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. Among those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

Among patients in the tocilizumab 4 mg/kg and 8 mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey.

Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, Dr. Alten wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140-6736(07)60784-3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

The fibromyalgia guidelines issued by EULAR represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist at the Univeristy of Washington, Seattle, and chief of clinical research at the Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context. Treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence-based where possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high-quality” trials, according to the investigators.

They reported that tailored exercise programs including aerobic exercise and strength training can be useful for some patients, and noted that the evidence in the literature for this recommendation is poor, with many open trials and inadequate blinding. However, given the safety and overall health benefits associated with exercise, they felt this should be included in the recommendations.

They also suggested cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

Other therapies such as relaxation, rehabilitation, physiotherapy, and psychological support also may be used, depending on individual needs. Some experimental evidence exists for the use of physiotherapy and connective tissue massage, but the recommendation for other such therapies, again, was based on expert opinion.

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Another limitation acknowledged by the investigators was that for outcome measures they primarily relied on changes in pain assessed by VAS, and function as measured by the Fibromyalgia Impact Questionnaire (FIQ). They did not include the Short Form Health Survey (SF-36) or a patient global response, and today the outcome triad being used by the Food and Drug Administration to evaluate drugs for fibromyalgia includes a pain measure, some measure of function, and a patient global measure, said Dr. Mease, who chairs the international initiative on improving outcome measures in rheumatology known as OMERACT.

Finally, the investigators stated tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by the EULAR group. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center, with fewer patients and, importantly, permitted the use of background drugs including opioids, he said.

“This was a Herculean effort that was timely and appropriate, given the rising interest in fibromyalgia as a common condition that needs more attention,” he said.

Another fibromyalgia expert, Dr. Robert M. Bennett of Oregon Health and Science University, Portland, offered a caution about pharmacotherapy in fibromyalgia. For instance, no mention is made of sleep medications or the adverse interactions of medications. “Tramadol has a dual action, as a weak opioid and a serotonin and norepinephrine reuptake inhibitor, and may interact with antidepressants, especially the monoamine oxidase inhibitors moclobemide and pirlindole, to induce a serotonin syndrome,” Dr. Bennett explained in an interview.

The guidelines will be updated every 5 years, with the hope that good quality clinical trials will continue to add to the available evidence, wrote the investigators.

'Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different.' DR. MEASE

The fibromyalgia guidelines issued by EULAR represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist at the Univeristy of Washington, Seattle, and chief of clinical research at the Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context. Treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence-based where possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high-quality” trials, according to the investigators.

They reported that tailored exercise programs including aerobic exercise and strength training can be useful for some patients, and noted that the evidence in the literature for this recommendation is poor, with many open trials and inadequate blinding. However, given the safety and overall health benefits associated with exercise, they felt this should be included in the recommendations.

They also suggested cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

Other therapies such as relaxation, rehabilitation, physiotherapy, and psychological support also may be used, depending on individual needs. Some experimental evidence exists for the use of physiotherapy and connective tissue massage, but the recommendation for other such therapies, again, was based on expert opinion.

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Another limitation acknowledged by the investigators was that for outcome measures they primarily relied on changes in pain assessed by VAS, and function as measured by the Fibromyalgia Impact Questionnaire (FIQ). They did not include the Short Form Health Survey (SF-36) or a patient global response, and today the outcome triad being used by the Food and Drug Administration to evaluate drugs for fibromyalgia includes a pain measure, some measure of function, and a patient global measure, said Dr. Mease, who chairs the international initiative on improving outcome measures in rheumatology known as OMERACT.

Finally, the investigators stated tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by the EULAR group. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center, with fewer patients and, importantly, permitted the use of background drugs including opioids, he said.

“This was a Herculean effort that was timely and appropriate, given the rising interest in fibromyalgia as a common condition that needs more attention,” he said.

Another fibromyalgia expert, Dr. Robert M. Bennett of Oregon Health and Science University, Portland, offered a caution about pharmacotherapy in fibromyalgia. For instance, no mention is made of sleep medications or the adverse interactions of medications. “Tramadol has a dual action, as a weak opioid and a serotonin and norepinephrine reuptake inhibitor, and may interact with antidepressants, especially the monoamine oxidase inhibitors moclobemide and pirlindole, to induce a serotonin syndrome,” Dr. Bennett explained in an interview.

The guidelines will be updated every 5 years, with the hope that good quality clinical trials will continue to add to the available evidence, wrote the investigators.

'Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different.' DR. MEASE

The fibromyalgia guidelines issued by EULAR represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist at the Univeristy of Washington, Seattle, and chief of clinical research at the Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context. Treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence-based where possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high-quality” trials, according to the investigators.

They reported that tailored exercise programs including aerobic exercise and strength training can be useful for some patients, and noted that the evidence in the literature for this recommendation is poor, with many open trials and inadequate blinding. However, given the safety and overall health benefits associated with exercise, they felt this should be included in the recommendations.

They also suggested cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

Other therapies such as relaxation, rehabilitation, physiotherapy, and psychological support also may be used, depending on individual needs. Some experimental evidence exists for the use of physiotherapy and connective tissue massage, but the recommendation for other such therapies, again, was based on expert opinion.

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Another limitation acknowledged by the investigators was that for outcome measures they primarily relied on changes in pain assessed by VAS, and function as measured by the Fibromyalgia Impact Questionnaire (FIQ). They did not include the Short Form Health Survey (SF-36) or a patient global response, and today the outcome triad being used by the Food and Drug Administration to evaluate drugs for fibromyalgia includes a pain measure, some measure of function, and a patient global measure, said Dr. Mease, who chairs the international initiative on improving outcome measures in rheumatology known as OMERACT.

Finally, the investigators stated tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by the EULAR group. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center, with fewer patients and, importantly, permitted the use of background drugs including opioids, he said.

“This was a Herculean effort that was timely and appropriate, given the rising interest in fibromyalgia as a common condition that needs more attention,” he said.

Another fibromyalgia expert, Dr. Robert M. Bennett of Oregon Health and Science University, Portland, offered a caution about pharmacotherapy in fibromyalgia. For instance, no mention is made of sleep medications or the adverse interactions of medications. “Tramadol has a dual action, as a weak opioid and a serotonin and norepinephrine reuptake inhibitor, and may interact with antidepressants, especially the monoamine oxidase inhibitors moclobemide and pirlindole, to induce a serotonin syndrome,” Dr. Bennett explained in an interview.

The guidelines will be updated every 5 years, with the hope that good quality clinical trials will continue to add to the available evidence, wrote the investigators.

'Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different.' DR. MEASE

BARCELONA — Cumulative improvements were seen in rheumatoid arthritis patients treated with abatacept, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

The Abatacept in Inadequate responders to Methotrexate (AIM) trial was 1 year, double blind, and placebo controlled. RA patients, mean age 51 years, were randomized to intravenous abatacept (10 mg/kg) or placebo on days 1, 15, and 29 and every 4 weeks after, plus background methotrexate. In a subsequent open-label phase, all patients received abatacept for up to 2 years. Among the 652 patients in the first phase, 385 (89%) in the abatacept group completed the 1-year treatment, versus 162 (74%) in the placebo group. Moreover, a significantly greater proportion of abatacept patients achieved an American College of Rheumatology (ACR) 20, 50, or 70 at 1 year than patients on placebo (Ann. Intern. Med. 2006;144:865-76).

Of those who had an ACR 20 at 6 months, 43% of abatacept patients had at least an ACR 50 at 1 year, versus 14% of placebo patients. The proportion who had an ACR 70 at 1 year was 21% in the abatacept group and 2% in the placebo group. A total of 15% of abatacept patients who achieved an ACR 20 at 6 months lost this response at 1 year, as did 37% of placebo patients. Significantly more patients on abatacept also achieved a low disease activity score (LDAS), of 3.2 or less. A total of 43% of abatacept patients achieved this, versus 10% of placebo patients. Of those who had an LDAS at 6 months, 36% of abatacept-treated patients and no placebo-treated patients achieved a DAS28 remission at 1 year. Thirty-two percent of abatacept patients had an LDAS at 6 months but not 1 year, versus 57% of placebo patients.

AIM was sponsored by Bristol-Myers Squibb.

BARCELONA — Cumulative improvements were seen in rheumatoid arthritis patients treated with abatacept, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

The Abatacept in Inadequate responders to Methotrexate (AIM) trial was 1 year, double blind, and placebo controlled. RA patients, mean age 51 years, were randomized to intravenous abatacept (10 mg/kg) or placebo on days 1, 15, and 29 and every 4 weeks after, plus background methotrexate. In a subsequent open-label phase, all patients received abatacept for up to 2 years. Among the 652 patients in the first phase, 385 (89%) in the abatacept group completed the 1-year treatment, versus 162 (74%) in the placebo group. Moreover, a significantly greater proportion of abatacept patients achieved an American College of Rheumatology (ACR) 20, 50, or 70 at 1 year than patients on placebo (Ann. Intern. Med. 2006;144:865-76).

Of those who had an ACR 20 at 6 months, 43% of abatacept patients had at least an ACR 50 at 1 year, versus 14% of placebo patients. The proportion who had an ACR 70 at 1 year was 21% in the abatacept group and 2% in the placebo group. A total of 15% of abatacept patients who achieved an ACR 20 at 6 months lost this response at 1 year, as did 37% of placebo patients. Significantly more patients on abatacept also achieved a low disease activity score (LDAS), of 3.2 or less. A total of 43% of abatacept patients achieved this, versus 10% of placebo patients. Of those who had an LDAS at 6 months, 36% of abatacept-treated patients and no placebo-treated patients achieved a DAS28 remission at 1 year. Thirty-two percent of abatacept patients had an LDAS at 6 months but not 1 year, versus 57% of placebo patients.

AIM was sponsored by Bristol-Myers Squibb.

BARCELONA — Cumulative improvements were seen in rheumatoid arthritis patients treated with abatacept, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

The Abatacept in Inadequate responders to Methotrexate (AIM) trial was 1 year, double blind, and placebo controlled. RA patients, mean age 51 years, were randomized to intravenous abatacept (10 mg/kg) or placebo on days 1, 15, and 29 and every 4 weeks after, plus background methotrexate. In a subsequent open-label phase, all patients received abatacept for up to 2 years. Among the 652 patients in the first phase, 385 (89%) in the abatacept group completed the 1-year treatment, versus 162 (74%) in the placebo group. Moreover, a significantly greater proportion of abatacept patients achieved an American College of Rheumatology (ACR) 20, 50, or 70 at 1 year than patients on placebo (Ann. Intern. Med. 2006;144:865-76).

Of those who had an ACR 20 at 6 months, 43% of abatacept patients had at least an ACR 50 at 1 year, versus 14% of placebo patients. The proportion who had an ACR 70 at 1 year was 21% in the abatacept group and 2% in the placebo group. A total of 15% of abatacept patients who achieved an ACR 20 at 6 months lost this response at 1 year, as did 37% of placebo patients. Significantly more patients on abatacept also achieved a low disease activity score (LDAS), of 3.2 or less. A total of 43% of abatacept patients achieved this, versus 10% of placebo patients. Of those who had an LDAS at 6 months, 36% of abatacept-treated patients and no placebo-treated patients achieved a DAS28 remission at 1 year. Thirty-two percent of abatacept patients had an LDAS at 6 months but not 1 year, versus 57% of placebo patients.

AIM was sponsored by Bristol-Myers Squibb.

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by antibodies directed against tRNA synthetase. The most common is anti-Jo-1, in 80% of cases. Anti-SSA, anti-PL-7, and anti-PL-12 are also sometimes found.

Clinical manifestations include interstitial lung disease (which can be severe), arthritis, Raynaud's phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years. In one-third disease onset was before age 40. Two-thirds were women. Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL. Muscular manifestations rarely caused significant disability and were present at the onset of disease in only six cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren's syndrome, were detected in 50% but rarely were tied to dry eyes and mouth, Dr. Palm wrote in a poster.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab. Four patients died. Two had type I pulmonary involvement. “While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted,” according to Dr.Palm.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by antibodies directed against tRNA synthetase. The most common is anti-Jo-1, in 80% of cases. Anti-SSA, anti-PL-7, and anti-PL-12 are also sometimes found.

Clinical manifestations include interstitial lung disease (which can be severe), arthritis, Raynaud's phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years. In one-third disease onset was before age 40. Two-thirds were women. Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL. Muscular manifestations rarely caused significant disability and were present at the onset of disease in only six cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren's syndrome, were detected in 50% but rarely were tied to dry eyes and mouth, Dr. Palm wrote in a poster.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab. Four patients died. Two had type I pulmonary involvement. “While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted,” according to Dr.Palm.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by antibodies directed against tRNA synthetase. The most common is anti-Jo-1, in 80% of cases. Anti-SSA, anti-PL-7, and anti-PL-12 are also sometimes found.

Clinical manifestations include interstitial lung disease (which can be severe), arthritis, Raynaud's phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years. In one-third disease onset was before age 40. Two-thirds were women. Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL. Muscular manifestations rarely caused significant disability and were present at the onset of disease in only six cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren's syndrome, were detected in 50% but rarely were tied to dry eyes and mouth, Dr. Palm wrote in a poster.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab. Four patients died. Two had type I pulmonary involvement. “While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted,” according to Dr.Palm.

ELSEVIER GLOBAL MEDICAL NEWS

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

The patients' mean age was 51 years, and more than half were women. Their mean disease duration was 7.5 years, and they had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen. All of them had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. In patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. In those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

In patients in the tocilizumab 4- mg/kg and 8-mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, he wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140–6736(07)60784–3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

The patients' mean age was 51 years, and more than half were women. Their mean disease duration was 7.5 years, and they had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen. All of them had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. In patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. In those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

In patients in the tocilizumab 4- mg/kg and 8-mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, he wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140–6736(07)60784–3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — In a multicenter double-blind study, treatment with the interleukin-6 signaling blocker tocilizumab not only significantly reduced disease activity among patients with rheumatoid arthritis but also improved physical function, fatigue, and quality of life.

A total of 622 patients with moderate to severe rheumatoid arthritis (RA) were randomized to receive intravenous tocilizumab in doses of 4 mg/kg or 8 mg/kg every 4 weeks or placebo. They also received background methotrexate in doses of 10–25 mg/week and corticosteroids in doses of 10 mg/day or less, according to Dr. Rieke H.E. Alten of the Schlosspark Klinik, Berlin.

The patients' mean age was 51 years, and more than half were women. Their mean disease duration was 7.5 years, and they had taken a mean of 1.5 disease-modifying antirheumatic drugs before undertaking the experimental regimen. All of them had swollen joint counts of six or more and tender joint counts of at least eight.

By week 24, a significantly greater proportion of patients treated with tocilizumab achieved an American College of Rheumatology (ACR) 20 response than did those who received placebo. In patients in the low-dose tocilizumab group, 13.5% achieved this level of response, as did 27.5% of those in the high-dose group. In those receiving placebo, 0.8% reached an ACR20 level of response, Dr. Alten reported in a poster session at the annual European Congress of Rheumatology.

Tocilizumab treatment also resulted in a marked increase in the proportion of patients who achieved moderate or good response according to the criteria of the European League Against Rheumatism. A total of 61.9% and 79.5% of patients in the low- and high-dose groups, respectively, had moderate or good responses.

On the Health Assessment Questionnaire Disability Index (HAQ-DI), clinically relevant improvements were seen in patients in both tocilizumab groups, starting at week 4, and with greater mean reductions than the protocol-defined minimally clinically difference of −0.25.

In patients in the tocilizumab 4- mg/kg and 8-mg/kg groups, 64.8% and 63.1%, respectively, had a 20% or greater improvement in HAQ-DI, compared with 47.5% of the placebo patients.

All treatment groups showed improvements in the physical and mental components of the Short Form-36 Health Survey. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale scores also improved in all treatment groups, but greater mean changes were consistently observed for patients in the tocilizumab groups, he wrote.

Moreover, the FACIT fatigue score increased by a clinically meaningful four points or more from baseline by week 4 in both tocilizumab groups.

RA is associated with functional disability, limitation of daily activities, and decreased quality of life. Fatigue is a particular problem, with more than 40% of patients reporting clinically important levels of fatigue, Dr. Alten noted.

The rationale for targeting IL-6 in RA lies in observations that this cytokine appears to play a role in the damage to periarticular bone and cartilage. It also activates T cells, B cells, and macrophages and is a central mediator of the hepatic acute phase response (Lancet 2007; [doi:10.1016/S0140–6736(07)60784–3]).

The study was sponsored by Hoffmann-La Roche Inc.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of the patient with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, said Dr. Sulica.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can only be made by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director, Beth Israel Pulmonary Hypertension Program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

Newly released guidelines from the American College of Chest Physicians emphasize the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183/09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respiratory Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index. But improved understanding of pathophysiology and recent advances in medical therapy may change this.

“What we have learned so far is that screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of the patient with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, said Dr. Sulica.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can only be made by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director, Beth Israel Pulmonary Hypertension Program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

Newly released guidelines from the American College of Chest Physicians emphasize the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183/09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respiratory Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index. But improved understanding of pathophysiology and recent advances in medical therapy may change this.

“What we have learned so far is that screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of the patient with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, said Dr. Sulica.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can only be made by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director, Beth Israel Pulmonary Hypertension Program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

Newly released guidelines from the American College of Chest Physicians emphasize the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183/09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respiratory Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index. But improved understanding of pathophysiology and recent advances in medical therapy may change this.

“What we have learned so far is that screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

Supplementing standard x-rays with extremity magnetic resonance imaging for the in-office diagnosis and monitoring of patients with rheumatoid arthritis could significantly improve the quality of care, according to Dr. Norman B. Gaylis, a rheumatologist in Aventura, Fla.

With biologic therapy having revolutionized the treatment of rheumatoid arthritis (RA), the key concern now is the early identification of erosive disease, Dr. Gaylis explained. “We're faced every day with the dilemma of which patients to put on a biologic agent. If you see erosions you are more likely to go with a biologic agent rather than staying with a conventional disease-modifying drug.”

But early erosions and other early poor prognostic signs such as bone edema and synovial inflammation extending into bone and marrow cannot be visualized on standard x-rays. By the time these erosions can be seen radiographically it's too late—the damage has been done, he said.

Unlike x-ray, magnetic resonance imaging can detect early bone changes, where marrow is being replaced by inflammatory synovial tissue, a process that results in penetration of the cortical barrier, invasion of the cortical bone, and exposure of the marrow to inflammatory triggers (J. Immunol. 2005;175:2579–88).

That MRI is more sensitive than radiography for detecting synovitis and marrow edema is not in question. However, the conventional large-magnet high-field machines are typically used in hospital diagnostic facilities and are impractical for day-to-day-use in rheumatology, Dr. Gaylis said in an interview. The recent introduction of smaller, less expensive, in-office MRI units designed for use on the extremities eliminates these obstacles to access.

Studies have shown that the results obtained with these extremity MRIs in the evaluation of rheumatoid hands are equivalent to those obtained with the standard units. In one study that compared extremity low-field MRI with conventional MRI and radiography, sensitivity and specificity for both types of MRI read by more than one radiologist exceeded 90% (Ann. Rheum. Dis. 2005;64:1280–7).

The American College of Rheumatology (ACR) has remained skeptical about the utility of extremity MRI for RA. In a white paper 2 years ago, ACR indicated that, in their view, more work needed to be done to establish its validity.

Two central questions raised by the naysayers, according to Dr. Gaylis, are whether the MRI findings, invisible on x-rays, are indeed erosions, and whether these MRI findings are consistently reproducible.

An answer to the question of whether MRI-detected erosions and edema are valid signs of early RA, however, was recently shown in a study in which patients scheduled for joint replacement surgery underwent MRI the day before surgery. Following removal, sequential sections of the joint were analyzed histologically for bone marrow changes. The erosions and edema that had been detected on MRI clearly correlated with inflammation of the bone marrow and synovium (Arthritis Rheum. 2007;56:1118–24).

Extremity MRI also encourages adherence to therapy. The situation is very similar to what happened with bone densitometry for osteoporosis. “When bone density measurement first was available, the only treatment for osteoporosis was calcium as well as the off-label use of medications such as sodium fluoride and etidronate disodium. Since bone densitometry was introduced, there has been an explosion of new medicines. We also have learned to make the diagnosis earlier and to more closely monitor disease activity, and it has certainly helped with patient compliance,” Dr. Gaylis said. Patients will be much more inclined to continue taking their medication if they can see concrete results, he said.

Baseline (left) shows erosions in the 2nd and 4th meta-carpal heads. They have healed on follow-up MRI (right). Courtesy Dr. Norman B. Gaylis

Supplementing standard x-rays with extremity magnetic resonance imaging for the in-office diagnosis and monitoring of patients with rheumatoid arthritis could significantly improve the quality of care, according to Dr. Norman B. Gaylis, a rheumatologist in Aventura, Fla.

With biologic therapy having revolutionized the treatment of rheumatoid arthritis (RA), the key concern now is the early identification of erosive disease, Dr. Gaylis explained. “We're faced every day with the dilemma of which patients to put on a biologic agent. If you see erosions you are more likely to go with a biologic agent rather than staying with a conventional disease-modifying drug.”

But early erosions and other early poor prognostic signs such as bone edema and synovial inflammation extending into bone and marrow cannot be visualized on standard x-rays. By the time these erosions can be seen radiographically it's too late—the damage has been done, he said.

Unlike x-ray, magnetic resonance imaging can detect early bone changes, where marrow is being replaced by inflammatory synovial tissue, a process that results in penetration of the cortical barrier, invasion of the cortical bone, and exposure of the marrow to inflammatory triggers (J. Immunol. 2005;175:2579–88).

That MRI is more sensitive than radiography for detecting synovitis and marrow edema is not in question. However, the conventional large-magnet high-field machines are typically used in hospital diagnostic facilities and are impractical for day-to-day-use in rheumatology, Dr. Gaylis said in an interview. The recent introduction of smaller, less expensive, in-office MRI units designed for use on the extremities eliminates these obstacles to access.

Studies have shown that the results obtained with these extremity MRIs in the evaluation of rheumatoid hands are equivalent to those obtained with the standard units. In one study that compared extremity low-field MRI with conventional MRI and radiography, sensitivity and specificity for both types of MRI read by more than one radiologist exceeded 90% (Ann. Rheum. Dis. 2005;64:1280–7).

The American College of Rheumatology (ACR) has remained skeptical about the utility of extremity MRI for RA. In a white paper 2 years ago, ACR indicated that, in their view, more work needed to be done to establish its validity.

Two central questions raised by the naysayers, according to Dr. Gaylis, are whether the MRI findings, invisible on x-rays, are indeed erosions, and whether these MRI findings are consistently reproducible.

An answer to the question of whether MRI-detected erosions and edema are valid signs of early RA, however, was recently shown in a study in which patients scheduled for joint replacement surgery underwent MRI the day before surgery. Following removal, sequential sections of the joint were analyzed histologically for bone marrow changes. The erosions and edema that had been detected on MRI clearly correlated with inflammation of the bone marrow and synovium (Arthritis Rheum. 2007;56:1118–24).

Extremity MRI also encourages adherence to therapy. The situation is very similar to what happened with bone densitometry for osteoporosis. “When bone density measurement first was available, the only treatment for osteoporosis was calcium as well as the off-label use of medications such as sodium fluoride and etidronate disodium. Since bone densitometry was introduced, there has been an explosion of new medicines. We also have learned to make the diagnosis earlier and to more closely monitor disease activity, and it has certainly helped with patient compliance,” Dr. Gaylis said. Patients will be much more inclined to continue taking their medication if they can see concrete results, he said.

Baseline (left) shows erosions in the 2nd and 4th meta-carpal heads. They have healed on follow-up MRI (right). Courtesy Dr. Norman B. Gaylis

Supplementing standard x-rays with extremity magnetic resonance imaging for the in-office diagnosis and monitoring of patients with rheumatoid arthritis could significantly improve the quality of care, according to Dr. Norman B. Gaylis, a rheumatologist in Aventura, Fla.

With biologic therapy having revolutionized the treatment of rheumatoid arthritis (RA), the key concern now is the early identification of erosive disease, Dr. Gaylis explained. “We're faced every day with the dilemma of which patients to put on a biologic agent. If you see erosions you are more likely to go with a biologic agent rather than staying with a conventional disease-modifying drug.”

But early erosions and other early poor prognostic signs such as bone edema and synovial inflammation extending into bone and marrow cannot be visualized on standard x-rays. By the time these erosions can be seen radiographically it's too late—the damage has been done, he said.

Unlike x-ray, magnetic resonance imaging can detect early bone changes, where marrow is being replaced by inflammatory synovial tissue, a process that results in penetration of the cortical barrier, invasion of the cortical bone, and exposure of the marrow to inflammatory triggers (J. Immunol. 2005;175:2579–88).

That MRI is more sensitive than radiography for detecting synovitis and marrow edema is not in question. However, the conventional large-magnet high-field machines are typically used in hospital diagnostic facilities and are impractical for day-to-day-use in rheumatology, Dr. Gaylis said in an interview. The recent introduction of smaller, less expensive, in-office MRI units designed for use on the extremities eliminates these obstacles to access.

Studies have shown that the results obtained with these extremity MRIs in the evaluation of rheumatoid hands are equivalent to those obtained with the standard units. In one study that compared extremity low-field MRI with conventional MRI and radiography, sensitivity and specificity for both types of MRI read by more than one radiologist exceeded 90% (Ann. Rheum. Dis. 2005;64:1280–7).

The American College of Rheumatology (ACR) has remained skeptical about the utility of extremity MRI for RA. In a white paper 2 years ago, ACR indicated that, in their view, more work needed to be done to establish its validity.

Two central questions raised by the naysayers, according to Dr. Gaylis, are whether the MRI findings, invisible on x-rays, are indeed erosions, and whether these MRI findings are consistently reproducible.

An answer to the question of whether MRI-detected erosions and edema are valid signs of early RA, however, was recently shown in a study in which patients scheduled for joint replacement surgery underwent MRI the day before surgery. Following removal, sequential sections of the joint were analyzed histologically for bone marrow changes. The erosions and edema that had been detected on MRI clearly correlated with inflammation of the bone marrow and synovium (Arthritis Rheum. 2007;56:1118–24).

Extremity MRI also encourages adherence to therapy. The situation is very similar to what happened with bone densitometry for osteoporosis. “When bone density measurement first was available, the only treatment for osteoporosis was calcium as well as the off-label use of medications such as sodium fluoride and etidronate disodium. Since bone densitometry was introduced, there has been an explosion of new medicines. We also have learned to make the diagnosis earlier and to more closely monitor disease activity, and it has certainly helped with patient compliance,” Dr. Gaylis said. Patients will be much more inclined to continue taking their medication if they can see concrete results, he said.

Baseline (left) shows erosions in the 2nd and 4th meta-carpal heads. They have healed on follow-up MRI (right). Courtesy Dr. Norman B. Gaylis