Rheumatoid Arthritis

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

Although the SB Charité III artificial lumbar disk has been available commercially in Europe since 1987 and in the United States since last November, some surgeons are reluctant to adopt the technology. And some American insurers still regard it as experimental.

The Food and Drug Administration approved the disk for 18− to 60-year-old patients with degenerative disk disease at one level, either L4/L5 or L5/S1. Contraindications include spondylothesis and osteoporosis.

Several surgeons, however, say they are cautious because few long-term outcomes have been published on the disk's durability, and few data support its hypothetical advantage: By preserving motion at the affected level, it will protect adjacent levels from further degeneration.

The SB Charité III was developed by two orthopedic surgeons in Berlin. Eventually, after a third design revision, the technology was acquired in 2003 by DePuy Spine, a division of Johnson & Johnson.

According to DePuy, 200,000 Americans undergo spinal fusion for degenerative disk disease each year. Surgeons say that so far, few patients seem to be candidates for the disk. “There are no real good indications for this product,” said Greg Graziano, M.D., a professor in the departments of neurosurgery and orthopedic surgery at the University of Michigan.

Dr. Graziano told this newspaper that he believes the ideal candidate is someone who is young, has arthritic degenerative changes, and exhibits minimal posterior arthritis. A patient who needs spinal canal work or decompression surgery isn't suitable, he said.

The University of Michigan Hospital told insurers it was willing to reduce the surgical costs for 20 patients as a means of getting the procedure off the ground at the facility, Dr. Graziano said. But the disk itself is still in the $11,000-$12,000 range, and insurers have balked, he said.

In April, the Blue Cross and Blue Shield (BCBS) Association's Technology Evaluation Center issued a report stating that “current evidence supporting the effectiveness of the artificial vertebral disk is insufficient.” The organization said there were methodologic flaws with the single randomized study used to win FDA approval, and it noted that the study only proved noninferiority to fusion with a Bagby and Kuslich (BAK) cage.

The technology assessments are meant as scientific opinions—although they sometimes form the basis for coverage decisions, a BCBS spokeswoman said. Individual BCBS plans are not under any obligation to follow the recommendations, she added.

DePuy Spine is working with the BCBS plans to provide further evidence that it is a superior technology, said Richard Toselli, M.D., vice president for research and development at the company. In an interview, Dr. Toselli said that several individual BCBS plans, along with Aetna, Kaiser Permanente, and 62 small regional carriers, are paying for implantation of the Charité disk.

“Some evidence shows that it's as good as standard fusion and perhaps better, but we don't know that yet,” Ziya Gokaslan, M.D., vice chairman of the department of neurosurgery at Johns Hopkins Hospital in Baltimore, told this newspaper. Dr. Gokaslan said he has not yet implanted a Charité disk at Hopkins, but he has participated in the implantation of the device in Germany and Brazil.

“I think there is use for this device, and I think there are potential benefits down the line,” he said. But he added, “We do not know the long-term complications of the implantation of this device,” such as whether the plastic core will wear out. If early hip and knee implants are any indication, revisions and replacements could be required within 15–20 years of the original implantations, he said.

DePuy acknowledged that getting at the Charité disk for a revision can be difficult. The company said that if the disk has migrated from the disk space, it needs to be removed through an anterior approach and replaced with another disk or via a fusion done either anteriorly and/or posteriorly. “If the device has not migrated, and the patient continues to complain of pain, then the revision strategy is to do a posterior fusion alone and leave the disk in place,” Dr. Toselli said.

But the company said there's no indication the disks will have a short life span and that there have been few reports of complications in the 10,000 devices implanted worldwide. Dr. Toselli also cited a 10-year follow-up report on 100 cases, published in 2002 by one of the Charité pioneers, J.P. Lemaire, M.D. In that study, “no significant migration of the polyethylene” occurred in any of the implants, and there were only 2 cases (2%) of adjacent functional overload (Rachis [The Spinal Column] 2002;14:271–85). Overall, 62% of the patients had excellent results.

Surgeons need more experience in choosing the correct disk size and placing it properly. “There's an art to placing these things,” Dr. Graziano said, adding that “the reproducibility between surgeons is not there yet.”

DePuy has trained about 2,200 surgeons at its Center for Spine Arthroplasty at the Endo-Surgery Institute in Cincinnati. Surgeons can also train with or observe colleagues who have Charité experience at 50 regional sites.

Dr. Gokaslan and Dr. Graziano agree that artificial disks are at the stage interbody fusion cages were 10 years ago. An initial burst of enthusiasm was followed by the recognition that cages were not a panacea.

“It took 5 years to figure out who should get cages and who shouldn't,” Dr. Graziano said.

Although patients are asking for the Charité disks, surgeons will likely resist the pressure, Dr. Gokaslan said. “It's hard to change the habits of surgeons when there is no serious evidence showing this is better than what they've done in the past,” he said.

Although the SB Charité III artificial lumbar disk has been available commercially in Europe since 1987 and in the United States since last November, some surgeons are reluctant to adopt the technology. And some American insurers still regard it as experimental.

The Food and Drug Administration approved the disk for 18− to 60-year-old patients with degenerative disk disease at one level, either L4/L5 or L5/S1. Contraindications include spondylothesis and osteoporosis.

Several surgeons, however, say they are cautious because few long-term outcomes have been published on the disk's durability, and few data support its hypothetical advantage: By preserving motion at the affected level, it will protect adjacent levels from further degeneration.

The SB Charité III was developed by two orthopedic surgeons in Berlin. Eventually, after a third design revision, the technology was acquired in 2003 by DePuy Spine, a division of Johnson & Johnson.

According to DePuy, 200,000 Americans undergo spinal fusion for degenerative disk disease each year. Surgeons say that so far, few patients seem to be candidates for the disk. “There are no real good indications for this product,” said Greg Graziano, M.D., a professor in the departments of neurosurgery and orthopedic surgery at the University of Michigan.

Dr. Graziano told this newspaper that he believes the ideal candidate is someone who is young, has arthritic degenerative changes, and exhibits minimal posterior arthritis. A patient who needs spinal canal work or decompression surgery isn't suitable, he said.

The University of Michigan Hospital told insurers it was willing to reduce the surgical costs for 20 patients as a means of getting the procedure off the ground at the facility, Dr. Graziano said. But the disk itself is still in the $11,000-$12,000 range, and insurers have balked, he said.

In April, the Blue Cross and Blue Shield (BCBS) Association's Technology Evaluation Center issued a report stating that “current evidence supporting the effectiveness of the artificial vertebral disk is insufficient.” The organization said there were methodologic flaws with the single randomized study used to win FDA approval, and it noted that the study only proved noninferiority to fusion with a Bagby and Kuslich (BAK) cage.

The technology assessments are meant as scientific opinions—although they sometimes form the basis for coverage decisions, a BCBS spokeswoman said. Individual BCBS plans are not under any obligation to follow the recommendations, she added.

DePuy Spine is working with the BCBS plans to provide further evidence that it is a superior technology, said Richard Toselli, M.D., vice president for research and development at the company. In an interview, Dr. Toselli said that several individual BCBS plans, along with Aetna, Kaiser Permanente, and 62 small regional carriers, are paying for implantation of the Charité disk.

“Some evidence shows that it's as good as standard fusion and perhaps better, but we don't know that yet,” Ziya Gokaslan, M.D., vice chairman of the department of neurosurgery at Johns Hopkins Hospital in Baltimore, told this newspaper. Dr. Gokaslan said he has not yet implanted a Charité disk at Hopkins, but he has participated in the implantation of the device in Germany and Brazil.

“I think there is use for this device, and I think there are potential benefits down the line,” he said. But he added, “We do not know the long-term complications of the implantation of this device,” such as whether the plastic core will wear out. If early hip and knee implants are any indication, revisions and replacements could be required within 15–20 years of the original implantations, he said.

DePuy acknowledged that getting at the Charité disk for a revision can be difficult. The company said that if the disk has migrated from the disk space, it needs to be removed through an anterior approach and replaced with another disk or via a fusion done either anteriorly and/or posteriorly. “If the device has not migrated, and the patient continues to complain of pain, then the revision strategy is to do a posterior fusion alone and leave the disk in place,” Dr. Toselli said.

But the company said there's no indication the disks will have a short life span and that there have been few reports of complications in the 10,000 devices implanted worldwide. Dr. Toselli also cited a 10-year follow-up report on 100 cases, published in 2002 by one of the Charité pioneers, J.P. Lemaire, M.D. In that study, “no significant migration of the polyethylene” occurred in any of the implants, and there were only 2 cases (2%) of adjacent functional overload (Rachis [The Spinal Column] 2002;14:271–85). Overall, 62% of the patients had excellent results.

Surgeons need more experience in choosing the correct disk size and placing it properly. “There's an art to placing these things,” Dr. Graziano said, adding that “the reproducibility between surgeons is not there yet.”

DePuy has trained about 2,200 surgeons at its Center for Spine Arthroplasty at the Endo-Surgery Institute in Cincinnati. Surgeons can also train with or observe colleagues who have Charité experience at 50 regional sites.

Dr. Gokaslan and Dr. Graziano agree that artificial disks are at the stage interbody fusion cages were 10 years ago. An initial burst of enthusiasm was followed by the recognition that cages were not a panacea.

“It took 5 years to figure out who should get cages and who shouldn't,” Dr. Graziano said.

Although patients are asking for the Charité disks, surgeons will likely resist the pressure, Dr. Gokaslan said. “It's hard to change the habits of surgeons when there is no serious evidence showing this is better than what they've done in the past,” he said.

Although the SB Charité III artificial lumbar disk has been available commercially in Europe since 1987 and in the United States since last November, some surgeons are reluctant to adopt the technology. And some American insurers still regard it as experimental.

The Food and Drug Administration approved the disk for 18− to 60-year-old patients with degenerative disk disease at one level, either L4/L5 or L5/S1. Contraindications include spondylothesis and osteoporosis.

Several surgeons, however, say they are cautious because few long-term outcomes have been published on the disk's durability, and few data support its hypothetical advantage: By preserving motion at the affected level, it will protect adjacent levels from further degeneration.

The SB Charité III was developed by two orthopedic surgeons in Berlin. Eventually, after a third design revision, the technology was acquired in 2003 by DePuy Spine, a division of Johnson & Johnson.

According to DePuy, 200,000 Americans undergo spinal fusion for degenerative disk disease each year. Surgeons say that so far, few patients seem to be candidates for the disk. “There are no real good indications for this product,” said Greg Graziano, M.D., a professor in the departments of neurosurgery and orthopedic surgery at the University of Michigan.

Dr. Graziano told this newspaper that he believes the ideal candidate is someone who is young, has arthritic degenerative changes, and exhibits minimal posterior arthritis. A patient who needs spinal canal work or decompression surgery isn't suitable, he said.

The University of Michigan Hospital told insurers it was willing to reduce the surgical costs for 20 patients as a means of getting the procedure off the ground at the facility, Dr. Graziano said. But the disk itself is still in the $11,000-$12,000 range, and insurers have balked, he said.

In April, the Blue Cross and Blue Shield (BCBS) Association's Technology Evaluation Center issued a report stating that “current evidence supporting the effectiveness of the artificial vertebral disk is insufficient.” The organization said there were methodologic flaws with the single randomized study used to win FDA approval, and it noted that the study only proved noninferiority to fusion with a Bagby and Kuslich (BAK) cage.

The technology assessments are meant as scientific opinions—although they sometimes form the basis for coverage decisions, a BCBS spokeswoman said. Individual BCBS plans are not under any obligation to follow the recommendations, she added.

DePuy Spine is working with the BCBS plans to provide further evidence that it is a superior technology, said Richard Toselli, M.D., vice president for research and development at the company. In an interview, Dr. Toselli said that several individual BCBS plans, along with Aetna, Kaiser Permanente, and 62 small regional carriers, are paying for implantation of the Charité disk.

“Some evidence shows that it's as good as standard fusion and perhaps better, but we don't know that yet,” Ziya Gokaslan, M.D., vice chairman of the department of neurosurgery at Johns Hopkins Hospital in Baltimore, told this newspaper. Dr. Gokaslan said he has not yet implanted a Charité disk at Hopkins, but he has participated in the implantation of the device in Germany and Brazil.

“I think there is use for this device, and I think there are potential benefits down the line,” he said. But he added, “We do not know the long-term complications of the implantation of this device,” such as whether the plastic core will wear out. If early hip and knee implants are any indication, revisions and replacements could be required within 15–20 years of the original implantations, he said.

DePuy acknowledged that getting at the Charité disk for a revision can be difficult. The company said that if the disk has migrated from the disk space, it needs to be removed through an anterior approach and replaced with another disk or via a fusion done either anteriorly and/or posteriorly. “If the device has not migrated, and the patient continues to complain of pain, then the revision strategy is to do a posterior fusion alone and leave the disk in place,” Dr. Toselli said.

But the company said there's no indication the disks will have a short life span and that there have been few reports of complications in the 10,000 devices implanted worldwide. Dr. Toselli also cited a 10-year follow-up report on 100 cases, published in 2002 by one of the Charité pioneers, J.P. Lemaire, M.D. In that study, “no significant migration of the polyethylene” occurred in any of the implants, and there were only 2 cases (2%) of adjacent functional overload (Rachis [The Spinal Column] 2002;14:271–85). Overall, 62% of the patients had excellent results.

Surgeons need more experience in choosing the correct disk size and placing it properly. “There's an art to placing these things,” Dr. Graziano said, adding that “the reproducibility between surgeons is not there yet.”

DePuy has trained about 2,200 surgeons at its Center for Spine Arthroplasty at the Endo-Surgery Institute in Cincinnati. Surgeons can also train with or observe colleagues who have Charité experience at 50 regional sites.

Dr. Gokaslan and Dr. Graziano agree that artificial disks are at the stage interbody fusion cages were 10 years ago. An initial burst of enthusiasm was followed by the recognition that cages were not a panacea.

“It took 5 years to figure out who should get cages and who shouldn't,” Dr. Graziano said.

Although patients are asking for the Charité disks, surgeons will likely resist the pressure, Dr. Gokaslan said. “It's hard to change the habits of surgeons when there is no serious evidence showing this is better than what they've done in the past,” he said.

Use of concomitant folic acid significantly reduced the efficacy of methotrexate and did not decrease the overall incidence of symptomatic adverse events, according to the findings of a post hoc analysis.

The two phase III, randomized, controlled trials included in the analysis—one conducted in the United States and the other in Europe—compared the effects of 52 weeks of daily leflunomide with weekly methotrexate (MTX) in patients with active rheumatoid arthritis.

Although measuring the effect of folic acid was not the primary objective, the trials provided a look at its effect, because almost all of the patients in the MTX arm of the U.S. study—98%—were given daily folic acid, yet only 10% of the patients receiving MTX in the multinational European study received folate, each of them after they experienced an adverse event.

Previously published articles on the trials reported that 52% of patients in the MTX arm of the U.S. study achieved an American College of Rheumatology (ACR) 20 improvement response, compared with 65% of patients in the European trial.

Investigators of the new post hoc analysis set out to adjust for significant differences in the baseline characteristics of patients that made comparisons at 52 weeks “difficult to interpret,” explained Dinesh Khanna, M.D., of the University of Cincinnati and the Veterans Affairs Medical Center.

Using propensity score matching methods to adjust for these baseline differences, they found that folic acid use reduced the probability of an ACR 20 response by 15%–21%, or an average of 17%, in 225 patients who received the treatment compared with 443 patients who did not (Arthritis Rheum. 2005: 52;3030–38).

The results were consistent when comparing ACR 50 and ACR 70 improvement responses, the investigators said.

When they stratified patients by the presence or absence of rheumatoid factor, they found a statistical trend toward a lower ACR 20 response rate in the RF-negative group taking folic acid compared with the RF-positive group taking folic acid—a finding that “may suggest a preferential response to MTX in patients with active RA based on their RF status,” they said.

Adverse events were reported in 93% of patients in the U.S. study and 94% in the European study.

As expected, patients receiving prophylactic therapy with folic acid had a lower incidence of liver function abnormalities. Elevated levels of alanine aminotransferase and aspartate aminotransferase were seen in 30% and 20%, respectively, of the patients in the U.S. study and in 63% and 47% of the patients in the European study.

But, “surprisingly,” patients in the U.S. study also had a higher incidence of symptomatic side effects (76%, vs. 68%), including a higher incidence of diarrhea, headache, and oral ulcers, compared with the European study group, the investigators reported.

The U.S. study involved 482 patients, 179 of whom received MTX and had RF data available. The European study involved 999 patients, 489 of whom received MTX and had RF data available.

The newly reported post hoc analysis combined all patients from both studies who were taking folic acid (50 from the European study, 175 from the U.S. study), as well as those who were not taking folic acid (439 in Europe and 4 in the U.S).

Patients who did not receive folic acid had a significantly lower mean body weight, a shorter mean duration of RA, and higher mean disease activity, as well as higher scores on the HAQ disability index and the Disease Activity Score in 28 joints (DAS28).

The mean dosage of MTX at 52 weeks was similar in the two trials, and oral folic acid was generally given in both studies at a dosage of 1–2 mg/day.

Use of concomitant folic acid significantly reduced the efficacy of methotrexate and did not decrease the overall incidence of symptomatic adverse events, according to the findings of a post hoc analysis.

The two phase III, randomized, controlled trials included in the analysis—one conducted in the United States and the other in Europe—compared the effects of 52 weeks of daily leflunomide with weekly methotrexate (MTX) in patients with active rheumatoid arthritis.

Although measuring the effect of folic acid was not the primary objective, the trials provided a look at its effect, because almost all of the patients in the MTX arm of the U.S. study—98%—were given daily folic acid, yet only 10% of the patients receiving MTX in the multinational European study received folate, each of them after they experienced an adverse event.

Previously published articles on the trials reported that 52% of patients in the MTX arm of the U.S. study achieved an American College of Rheumatology (ACR) 20 improvement response, compared with 65% of patients in the European trial.

Investigators of the new post hoc analysis set out to adjust for significant differences in the baseline characteristics of patients that made comparisons at 52 weeks “difficult to interpret,” explained Dinesh Khanna, M.D., of the University of Cincinnati and the Veterans Affairs Medical Center.

Using propensity score matching methods to adjust for these baseline differences, they found that folic acid use reduced the probability of an ACR 20 response by 15%–21%, or an average of 17%, in 225 patients who received the treatment compared with 443 patients who did not (Arthritis Rheum. 2005: 52;3030–38).

The results were consistent when comparing ACR 50 and ACR 70 improvement responses, the investigators said.

When they stratified patients by the presence or absence of rheumatoid factor, they found a statistical trend toward a lower ACR 20 response rate in the RF-negative group taking folic acid compared with the RF-positive group taking folic acid—a finding that “may suggest a preferential response to MTX in patients with active RA based on their RF status,” they said.

Adverse events were reported in 93% of patients in the U.S. study and 94% in the European study.

As expected, patients receiving prophylactic therapy with folic acid had a lower incidence of liver function abnormalities. Elevated levels of alanine aminotransferase and aspartate aminotransferase were seen in 30% and 20%, respectively, of the patients in the U.S. study and in 63% and 47% of the patients in the European study.

But, “surprisingly,” patients in the U.S. study also had a higher incidence of symptomatic side effects (76%, vs. 68%), including a higher incidence of diarrhea, headache, and oral ulcers, compared with the European study group, the investigators reported.

The U.S. study involved 482 patients, 179 of whom received MTX and had RF data available. The European study involved 999 patients, 489 of whom received MTX and had RF data available.

The newly reported post hoc analysis combined all patients from both studies who were taking folic acid (50 from the European study, 175 from the U.S. study), as well as those who were not taking folic acid (439 in Europe and 4 in the U.S).

Patients who did not receive folic acid had a significantly lower mean body weight, a shorter mean duration of RA, and higher mean disease activity, as well as higher scores on the HAQ disability index and the Disease Activity Score in 28 joints (DAS28).

The mean dosage of MTX at 52 weeks was similar in the two trials, and oral folic acid was generally given in both studies at a dosage of 1–2 mg/day.

Use of concomitant folic acid significantly reduced the efficacy of methotrexate and did not decrease the overall incidence of symptomatic adverse events, according to the findings of a post hoc analysis.

The two phase III, randomized, controlled trials included in the analysis—one conducted in the United States and the other in Europe—compared the effects of 52 weeks of daily leflunomide with weekly methotrexate (MTX) in patients with active rheumatoid arthritis.

Although measuring the effect of folic acid was not the primary objective, the trials provided a look at its effect, because almost all of the patients in the MTX arm of the U.S. study—98%—were given daily folic acid, yet only 10% of the patients receiving MTX in the multinational European study received folate, each of them after they experienced an adverse event.

Previously published articles on the trials reported that 52% of patients in the MTX arm of the U.S. study achieved an American College of Rheumatology (ACR) 20 improvement response, compared with 65% of patients in the European trial.

Investigators of the new post hoc analysis set out to adjust for significant differences in the baseline characteristics of patients that made comparisons at 52 weeks “difficult to interpret,” explained Dinesh Khanna, M.D., of the University of Cincinnati and the Veterans Affairs Medical Center.

Using propensity score matching methods to adjust for these baseline differences, they found that folic acid use reduced the probability of an ACR 20 response by 15%–21%, or an average of 17%, in 225 patients who received the treatment compared with 443 patients who did not (Arthritis Rheum. 2005: 52;3030–38).

The results were consistent when comparing ACR 50 and ACR 70 improvement responses, the investigators said.

When they stratified patients by the presence or absence of rheumatoid factor, they found a statistical trend toward a lower ACR 20 response rate in the RF-negative group taking folic acid compared with the RF-positive group taking folic acid—a finding that “may suggest a preferential response to MTX in patients with active RA based on their RF status,” they said.

Adverse events were reported in 93% of patients in the U.S. study and 94% in the European study.

As expected, patients receiving prophylactic therapy with folic acid had a lower incidence of liver function abnormalities. Elevated levels of alanine aminotransferase and aspartate aminotransferase were seen in 30% and 20%, respectively, of the patients in the U.S. study and in 63% and 47% of the patients in the European study.

But, “surprisingly,” patients in the U.S. study also had a higher incidence of symptomatic side effects (76%, vs. 68%), including a higher incidence of diarrhea, headache, and oral ulcers, compared with the European study group, the investigators reported.

The U.S. study involved 482 patients, 179 of whom received MTX and had RF data available. The European study involved 999 patients, 489 of whom received MTX and had RF data available.

The newly reported post hoc analysis combined all patients from both studies who were taking folic acid (50 from the European study, 175 from the U.S. study), as well as those who were not taking folic acid (439 in Europe and 4 in the U.S).

Patients who did not receive folic acid had a significantly lower mean body weight, a shorter mean duration of RA, and higher mean disease activity, as well as higher scores on the HAQ disability index and the Disease Activity Score in 28 joints (DAS28).

The mean dosage of MTX at 52 weeks was similar in the two trials, and oral folic acid was generally given in both studies at a dosage of 1–2 mg/day.

PHILADELPHIA — A pneumatic vest was more effective than a conventional back brace for relieving back and leg pain in patients with discopathy in a controlled study with 36 patients followed for 1 year.

Patients treated with the Orthotrac pneumatic vest plus conventional, conservative therapy also showed a trend toward improved function compared with patients treated with conservative therapy and an EZ form brace, John Triano, D.C., Ph.D., said at the annual meeting of the North American Spine Society.

The rationale behind the pneumatic vest is that it creates an axial load that reduces the cross-section dimensions of the spinal canal.

“The hypothesis is that if you change the internal pressure [in the spinal canal], you may be able to reduce symptoms,” said Dr. Triano, director of the chiropractic division at the Texas Back Institute in Plano.

The Orthotrac pneumatic vest has been approved by the Food and Drug Administration and is marketed by Orthofix, which sponsored the study. Neither Dr. Triano nor his associates in the study have a financial relationship with Orthofix.

The study began with 62 eligible patients, aged 21–55 years, who had back pain and radiating leg pain secondary to discopathy despite 4 weeks of standard, conservative treatment. Of these, 21 opted for surgical management and 5 withdrew from the study. The remaining 36 were randomized to treatment with either the pneumatic vest or a form brace. The devices were prescribed for use in 30-minute intervals four times a day.

Despite randomization, at baseline patients in the vest group had an average pain score of 59.6 on a visual analog scale, compared with an average score of 42.4 among the patients in the form-brace group.

The biggest change in pain score was seen during the first 12 weeks of treatment. The average score fell by about 39 units in the vest group compared with an average decline of about 15 units in the brace group.

The difference in pain relief was maintained through a year of follow-up. After a year of treatment, the average pain level had dropped by 40 units compared with baseline in the vest group, and by 19 units in the brace group, a statistically significant difference, said Dr. Triano.

Patients treated with the pneumatic vest also had significant improvements in their mental health and energy/fatigue scores, measured using the short form-36.

An MRI shows disk herniation without Orthotrac unloading.

With Orthotrac unloading, the difference in space is about 1 mm, usually enough. Orthofix Inc.

PHILADELPHIA — A pneumatic vest was more effective than a conventional back brace for relieving back and leg pain in patients with discopathy in a controlled study with 36 patients followed for 1 year.

Patients treated with the Orthotrac pneumatic vest plus conventional, conservative therapy also showed a trend toward improved function compared with patients treated with conservative therapy and an EZ form brace, John Triano, D.C., Ph.D., said at the annual meeting of the North American Spine Society.

The rationale behind the pneumatic vest is that it creates an axial load that reduces the cross-section dimensions of the spinal canal.

“The hypothesis is that if you change the internal pressure [in the spinal canal], you may be able to reduce symptoms,” said Dr. Triano, director of the chiropractic division at the Texas Back Institute in Plano.

The Orthotrac pneumatic vest has been approved by the Food and Drug Administration and is marketed by Orthofix, which sponsored the study. Neither Dr. Triano nor his associates in the study have a financial relationship with Orthofix.

The study began with 62 eligible patients, aged 21–55 years, who had back pain and radiating leg pain secondary to discopathy despite 4 weeks of standard, conservative treatment. Of these, 21 opted for surgical management and 5 withdrew from the study. The remaining 36 were randomized to treatment with either the pneumatic vest or a form brace. The devices were prescribed for use in 30-minute intervals four times a day.

Despite randomization, at baseline patients in the vest group had an average pain score of 59.6 on a visual analog scale, compared with an average score of 42.4 among the patients in the form-brace group.

The biggest change in pain score was seen during the first 12 weeks of treatment. The average score fell by about 39 units in the vest group compared with an average decline of about 15 units in the brace group.

The difference in pain relief was maintained through a year of follow-up. After a year of treatment, the average pain level had dropped by 40 units compared with baseline in the vest group, and by 19 units in the brace group, a statistically significant difference, said Dr. Triano.

Patients treated with the pneumatic vest also had significant improvements in their mental health and energy/fatigue scores, measured using the short form-36.

An MRI shows disk herniation without Orthotrac unloading.

With Orthotrac unloading, the difference in space is about 1 mm, usually enough. Orthofix Inc.

PHILADELPHIA — A pneumatic vest was more effective than a conventional back brace for relieving back and leg pain in patients with discopathy in a controlled study with 36 patients followed for 1 year.

Patients treated with the Orthotrac pneumatic vest plus conventional, conservative therapy also showed a trend toward improved function compared with patients treated with conservative therapy and an EZ form brace, John Triano, D.C., Ph.D., said at the annual meeting of the North American Spine Society.

The rationale behind the pneumatic vest is that it creates an axial load that reduces the cross-section dimensions of the spinal canal.

“The hypothesis is that if you change the internal pressure [in the spinal canal], you may be able to reduce symptoms,” said Dr. Triano, director of the chiropractic division at the Texas Back Institute in Plano.

The Orthotrac pneumatic vest has been approved by the Food and Drug Administration and is marketed by Orthofix, which sponsored the study. Neither Dr. Triano nor his associates in the study have a financial relationship with Orthofix.

The study began with 62 eligible patients, aged 21–55 years, who had back pain and radiating leg pain secondary to discopathy despite 4 weeks of standard, conservative treatment. Of these, 21 opted for surgical management and 5 withdrew from the study. The remaining 36 were randomized to treatment with either the pneumatic vest or a form brace. The devices were prescribed for use in 30-minute intervals four times a day.

Despite randomization, at baseline patients in the vest group had an average pain score of 59.6 on a visual analog scale, compared with an average score of 42.4 among the patients in the form-brace group.

The biggest change in pain score was seen during the first 12 weeks of treatment. The average score fell by about 39 units in the vest group compared with an average decline of about 15 units in the brace group.

The difference in pain relief was maintained through a year of follow-up. After a year of treatment, the average pain level had dropped by 40 units compared with baseline in the vest group, and by 19 units in the brace group, a statistically significant difference, said Dr. Triano.

Patients treated with the pneumatic vest also had significant improvements in their mental health and energy/fatigue scores, measured using the short form-36.

An MRI shows disk herniation without Orthotrac unloading.

With Orthotrac unloading, the difference in space is about 1 mm, usually enough. Orthofix Inc.

VIENNA — While practice guidelines emphatically agree that physical exercise is a crucial element of knee osteoarthritis management, no expert consensus exists regarding how best to deliver such treatment.

Given the lack of specific recommendations, it's particularly instructive to consider the lessons offered by one landmark study in the field: the Fitness Arthritis and Seniors Trial (FAST), Leena Sharma, M.D., said at the annual European Congress of Rheumatology.

FAST stands out in a number of ways, not least that the 18-month duration of the exercise interventions was unusually long compared with other studies in this area—and altogether fitting given that exercise is today presented to osteoarthritis patients as a lifelong intervention, noted Dr. Sharma of Northwestern University, Chicago.

In addition, FAST's primary end point was highly clinically relevant: prevention of new disability in activities of daily living, such as bathing, dressing, and moving from bed to chair. The adjusted relative risk of developing such disability was reduced by 47% in the aerobic exercise group compared with controls, and by 40% in those randomized to resistance exercise (Arch. Intern. Med. 2001;161:2309–16).

“That's a very big result. And I think that the exercise programs used in FAST are imminently doable by most people with knee osteoarthritis,” the rheumatologist added.

FAST was a two-center, single-blind, randomized trial involving 439 community-dwelling patients with symptomatic knee osteoarthritis. Participants were assigned to one of three groups: aerobic exercise, strength training, or a control arm featuring an 18-month health education and support program. Both exercise arms began with a 3-month facility-based supervised program followed by a 15-month home-based program.

“There was a lot of contact—and this is crucial for osteoarthritis management,” Dr. Sharma stressed. Indeed, the exercise leader visited patients at home on four occasions and phoned them six times during months 4–6, talked with them on the phone every 3 weeks during months 7–9, and talked with them monthly thereafter.

Participants kept exercise logs during the 18 months. Adherence was defined as number of exercise sessions completed divided by the number prescribed. Dr. Sharma is convinced this played a key role in the low study dropout rates—9.8% in the resistance exercise arm, 13.6% with the aerobic program—and that log-keeping also boosts compliance in routine clinical practice.

The aerobic exercise intervention entailed three 1-hour workouts per week. Each began with a 10-minute warmup involving slow walking and flexibility stretches. This was followed by 40 minutes of walking at 50%–70% of heart rate reserve as determined in an exercise stress test, then a 10-minute cool-down. A more practical alternative to the stress test is to have patients rely upon the positive talk test or aim for a target heart rate equal to 50%–75% of 220 minus their age, Dr. Sharma said.

During disease flare-ups, short rest periods could be interspersed within the workout sessions.

Resistance training in FAST also involved three hour-long sessions per week. Patients performed two sets of 12 repetitions of nine exercises working the upper and lower extremities. Dumbbells and cuff weights were used to increase resistance. Patients began using very light weights and gradually increased them so long as they could complete two sets of 12 repetitions.

Unlike in the controlled setting of FAST, however, in clinical practice an exercise prescription is not an either/or matter of aerobics or strengthening. As emphasized in the 2003 EULAR guidelines and the more recent MOVE consensus recommendations by a multidisciplinary British expert panel (Rheumatology 2005;44:67–73), the exercise prescription for patients with osteoarthritis should include both aerobic and resistance training tailored to the individual, Dr. Sharma noted.

VIENNA — While practice guidelines emphatically agree that physical exercise is a crucial element of knee osteoarthritis management, no expert consensus exists regarding how best to deliver such treatment.

Given the lack of specific recommendations, it's particularly instructive to consider the lessons offered by one landmark study in the field: the Fitness Arthritis and Seniors Trial (FAST), Leena Sharma, M.D., said at the annual European Congress of Rheumatology.

FAST stands out in a number of ways, not least that the 18-month duration of the exercise interventions was unusually long compared with other studies in this area—and altogether fitting given that exercise is today presented to osteoarthritis patients as a lifelong intervention, noted Dr. Sharma of Northwestern University, Chicago.

In addition, FAST's primary end point was highly clinically relevant: prevention of new disability in activities of daily living, such as bathing, dressing, and moving from bed to chair. The adjusted relative risk of developing such disability was reduced by 47% in the aerobic exercise group compared with controls, and by 40% in those randomized to resistance exercise (Arch. Intern. Med. 2001;161:2309–16).

“That's a very big result. And I think that the exercise programs used in FAST are imminently doable by most people with knee osteoarthritis,” the rheumatologist added.

FAST was a two-center, single-blind, randomized trial involving 439 community-dwelling patients with symptomatic knee osteoarthritis. Participants were assigned to one of three groups: aerobic exercise, strength training, or a control arm featuring an 18-month health education and support program. Both exercise arms began with a 3-month facility-based supervised program followed by a 15-month home-based program.

“There was a lot of contact—and this is crucial for osteoarthritis management,” Dr. Sharma stressed. Indeed, the exercise leader visited patients at home on four occasions and phoned them six times during months 4–6, talked with them on the phone every 3 weeks during months 7–9, and talked with them monthly thereafter.

Participants kept exercise logs during the 18 months. Adherence was defined as number of exercise sessions completed divided by the number prescribed. Dr. Sharma is convinced this played a key role in the low study dropout rates—9.8% in the resistance exercise arm, 13.6% with the aerobic program—and that log-keeping also boosts compliance in routine clinical practice.

The aerobic exercise intervention entailed three 1-hour workouts per week. Each began with a 10-minute warmup involving slow walking and flexibility stretches. This was followed by 40 minutes of walking at 50%–70% of heart rate reserve as determined in an exercise stress test, then a 10-minute cool-down. A more practical alternative to the stress test is to have patients rely upon the positive talk test or aim for a target heart rate equal to 50%–75% of 220 minus their age, Dr. Sharma said.

During disease flare-ups, short rest periods could be interspersed within the workout sessions.

Resistance training in FAST also involved three hour-long sessions per week. Patients performed two sets of 12 repetitions of nine exercises working the upper and lower extremities. Dumbbells and cuff weights were used to increase resistance. Patients began using very light weights and gradually increased them so long as they could complete two sets of 12 repetitions.

Unlike in the controlled setting of FAST, however, in clinical practice an exercise prescription is not an either/or matter of aerobics or strengthening. As emphasized in the 2003 EULAR guidelines and the more recent MOVE consensus recommendations by a multidisciplinary British expert panel (Rheumatology 2005;44:67–73), the exercise prescription for patients with osteoarthritis should include both aerobic and resistance training tailored to the individual, Dr. Sharma noted.

VIENNA — While practice guidelines emphatically agree that physical exercise is a crucial element of knee osteoarthritis management, no expert consensus exists regarding how best to deliver such treatment.

Given the lack of specific recommendations, it's particularly instructive to consider the lessons offered by one landmark study in the field: the Fitness Arthritis and Seniors Trial (FAST), Leena Sharma, M.D., said at the annual European Congress of Rheumatology.

FAST stands out in a number of ways, not least that the 18-month duration of the exercise interventions was unusually long compared with other studies in this area—and altogether fitting given that exercise is today presented to osteoarthritis patients as a lifelong intervention, noted Dr. Sharma of Northwestern University, Chicago.

In addition, FAST's primary end point was highly clinically relevant: prevention of new disability in activities of daily living, such as bathing, dressing, and moving from bed to chair. The adjusted relative risk of developing such disability was reduced by 47% in the aerobic exercise group compared with controls, and by 40% in those randomized to resistance exercise (Arch. Intern. Med. 2001;161:2309–16).

“That's a very big result. And I think that the exercise programs used in FAST are imminently doable by most people with knee osteoarthritis,” the rheumatologist added.

FAST was a two-center, single-blind, randomized trial involving 439 community-dwelling patients with symptomatic knee osteoarthritis. Participants were assigned to one of three groups: aerobic exercise, strength training, or a control arm featuring an 18-month health education and support program. Both exercise arms began with a 3-month facility-based supervised program followed by a 15-month home-based program.

“There was a lot of contact—and this is crucial for osteoarthritis management,” Dr. Sharma stressed. Indeed, the exercise leader visited patients at home on four occasions and phoned them six times during months 4–6, talked with them on the phone every 3 weeks during months 7–9, and talked with them monthly thereafter.

Participants kept exercise logs during the 18 months. Adherence was defined as number of exercise sessions completed divided by the number prescribed. Dr. Sharma is convinced this played a key role in the low study dropout rates—9.8% in the resistance exercise arm, 13.6% with the aerobic program—and that log-keeping also boosts compliance in routine clinical practice.

The aerobic exercise intervention entailed three 1-hour workouts per week. Each began with a 10-minute warmup involving slow walking and flexibility stretches. This was followed by 40 minutes of walking at 50%–70% of heart rate reserve as determined in an exercise stress test, then a 10-minute cool-down. A more practical alternative to the stress test is to have patients rely upon the positive talk test or aim for a target heart rate equal to 50%–75% of 220 minus their age, Dr. Sharma said.

During disease flare-ups, short rest periods could be interspersed within the workout sessions.

Resistance training in FAST also involved three hour-long sessions per week. Patients performed two sets of 12 repetitions of nine exercises working the upper and lower extremities. Dumbbells and cuff weights were used to increase resistance. Patients began using very light weights and gradually increased them so long as they could complete two sets of 12 repetitions.

Unlike in the controlled setting of FAST, however, in clinical practice an exercise prescription is not an either/or matter of aerobics or strengthening. As emphasized in the 2003 EULAR guidelines and the more recent MOVE consensus recommendations by a multidisciplinary British expert panel (Rheumatology 2005;44:67–73), the exercise prescription for patients with osteoarthritis should include both aerobic and resistance training tailored to the individual, Dr. Sharma noted.

VERSAILLES, FRANCE — Custom-made foot orthoses produced immediate and significant benefits for juvenile idiopathic arthritis patients, according to the results of a study conducted in Stockholm.

Youngsters with cavovarus foot position showed the most pronounced improvements when they began wearing the device, investigator Marie André reported in a poster at the 12th European Pediatric Rheumatology Congress.

Children with oligoarthritis and polyarthritis had better results than those with enthesitis-related arthritis, according to Ms. André of Astrid Lindgren Children's Hospital at Karolinska University Hospital, and her colleagues.

“We know children need to be physically active,” she said in an interview at the meeting. “If you give them orthoses, there may be pain relief and … improvements in balance, and then maybe they can be more physically active.”

The youngsters, aged 8–17 years, performed five standardized capacity tests with and without orthoses: standing, jumping, running, climbing stairs, and walking 200 meters at their own pace. The researchers recorded walking and running times, and assessed balance capacity. With each test, the children rated their pain on a visual analog scale.

The most pronounced improvements were in balance and in pain scores while running. For each measure, 34 children had better results with their orthoses while 5 saw no change, and 9 fared worse.

Many children did significantly better on the timed walking test (31 improved, 3 unchanged, 14 worse). Pain scores were significantly improved when the children were standing (26 better, 14 unchanged, 8 worse), and climbing stairs (27 better, 10 unchanged, 11 worse).

The differences in pain while jumping and walking were not significant, however. Likewise, while 19 children had better running times with orthoses, 16 saw no change, and 13 performed worse.

“In this study we looked at improvement in immediate effects, but orthoses are a long-term treatment, and we are planning a long-term study, too,” she said.

VERSAILLES, FRANCE — Custom-made foot orthoses produced immediate and significant benefits for juvenile idiopathic arthritis patients, according to the results of a study conducted in Stockholm.

Youngsters with cavovarus foot position showed the most pronounced improvements when they began wearing the device, investigator Marie André reported in a poster at the 12th European Pediatric Rheumatology Congress.

Children with oligoarthritis and polyarthritis had better results than those with enthesitis-related arthritis, according to Ms. André of Astrid Lindgren Children's Hospital at Karolinska University Hospital, and her colleagues.

“We know children need to be physically active,” she said in an interview at the meeting. “If you give them orthoses, there may be pain relief and … improvements in balance, and then maybe they can be more physically active.”

The youngsters, aged 8–17 years, performed five standardized capacity tests with and without orthoses: standing, jumping, running, climbing stairs, and walking 200 meters at their own pace. The researchers recorded walking and running times, and assessed balance capacity. With each test, the children rated their pain on a visual analog scale.

The most pronounced improvements were in balance and in pain scores while running. For each measure, 34 children had better results with their orthoses while 5 saw no change, and 9 fared worse.

Many children did significantly better on the timed walking test (31 improved, 3 unchanged, 14 worse). Pain scores were significantly improved when the children were standing (26 better, 14 unchanged, 8 worse), and climbing stairs (27 better, 10 unchanged, 11 worse).

The differences in pain while jumping and walking were not significant, however. Likewise, while 19 children had better running times with orthoses, 16 saw no change, and 13 performed worse.

“In this study we looked at improvement in immediate effects, but orthoses are a long-term treatment, and we are planning a long-term study, too,” she said.

VERSAILLES, FRANCE — Custom-made foot orthoses produced immediate and significant benefits for juvenile idiopathic arthritis patients, according to the results of a study conducted in Stockholm.

Youngsters with cavovarus foot position showed the most pronounced improvements when they began wearing the device, investigator Marie André reported in a poster at the 12th European Pediatric Rheumatology Congress.

Children with oligoarthritis and polyarthritis had better results than those with enthesitis-related arthritis, according to Ms. André of Astrid Lindgren Children's Hospital at Karolinska University Hospital, and her colleagues.

“We know children need to be physically active,” she said in an interview at the meeting. “If you give them orthoses, there may be pain relief and … improvements in balance, and then maybe they can be more physically active.”

The youngsters, aged 8–17 years, performed five standardized capacity tests with and without orthoses: standing, jumping, running, climbing stairs, and walking 200 meters at their own pace. The researchers recorded walking and running times, and assessed balance capacity. With each test, the children rated their pain on a visual analog scale.

The most pronounced improvements were in balance and in pain scores while running. For each measure, 34 children had better results with their orthoses while 5 saw no change, and 9 fared worse.

Many children did significantly better on the timed walking test (31 improved, 3 unchanged, 14 worse). Pain scores were significantly improved when the children were standing (26 better, 14 unchanged, 8 worse), and climbing stairs (27 better, 10 unchanged, 11 worse).

The differences in pain while jumping and walking were not significant, however. Likewise, while 19 children had better running times with orthoses, 16 saw no change, and 13 performed worse.

“In this study we looked at improvement in immediate effects, but orthoses are a long-term treatment, and we are planning a long-term study, too,” she said.

VERSAILLES, FRANCE — A Dutch study of 21 adolescents with juvenile idiopathic arthritis found significant impairment in anaerobic fitness when the youngsters were asked to ride a bicycle as fast as they could.

At peak power, girls reached only 53% of the anaerobic fitness predicted for their weight, while boys did only slightly better, at 71%. Both genders also showed moderate impairment in aerobic fitness at peak power: The girls performed at 78% of predicted levels, and the boys performed at 83%.

“Their fitness is about 20% reduced, compared to normal children. … They don't feel at ease with exercise,” researcher Otto Lelieveld, a physical therapist, said in an interview at the annual scientific meeting of the European Pediatric Rheumatology Congress, where he presented the results in a poster.

Nine boys and 12 girls, aged 16–18, took part in the study. On average, 7.6 years had elapsed since the boys were diagnosed, and 8.9 years had elapsed for the girls.

The teenagers were required to perform the Wingate sprint test. Mr. Lelieveld of University Medical Center Groningen (the Netherlands) described this as 5 minutes of steady bicycle riding at low speed, followed by a 30-second sprint at peak power.

Study participants did slightly better in measurements of mean power, both aerobic and anaerobic, during the first part of the test, but still showed moderate impairment. In the measurement of muscle endurance, the boys achieved 78% of the mean anaerobic fitness predicted for their weight; the girls achieved 68%. Mean aerobic fitness reached 83% of prediction for the boys and 78% for the girls.

Based on these results, Mr. Lelieveld and his coinvestigators called for the development of exercise programs with more anaerobic and aerobic training for children with juvenile idiopathic arthritis.

“We know now from adult rheumatology that physical therapists are training at too low a level,” he said.

The children also are afraid to train themselves, he added. “When they are in remission they can have more pain than in the period when they are acute,” he said. “When they start functioning at a higher level, they put more strain on their joints. It is like a vicious circle.”

VERSAILLES, FRANCE — A Dutch study of 21 adolescents with juvenile idiopathic arthritis found significant impairment in anaerobic fitness when the youngsters were asked to ride a bicycle as fast as they could.

At peak power, girls reached only 53% of the anaerobic fitness predicted for their weight, while boys did only slightly better, at 71%. Both genders also showed moderate impairment in aerobic fitness at peak power: The girls performed at 78% of predicted levels, and the boys performed at 83%.

“Their fitness is about 20% reduced, compared to normal children. … They don't feel at ease with exercise,” researcher Otto Lelieveld, a physical therapist, said in an interview at the annual scientific meeting of the European Pediatric Rheumatology Congress, where he presented the results in a poster.

Nine boys and 12 girls, aged 16–18, took part in the study. On average, 7.6 years had elapsed since the boys were diagnosed, and 8.9 years had elapsed for the girls.

The teenagers were required to perform the Wingate sprint test. Mr. Lelieveld of University Medical Center Groningen (the Netherlands) described this as 5 minutes of steady bicycle riding at low speed, followed by a 30-second sprint at peak power.

Study participants did slightly better in measurements of mean power, both aerobic and anaerobic, during the first part of the test, but still showed moderate impairment. In the measurement of muscle endurance, the boys achieved 78% of the mean anaerobic fitness predicted for their weight; the girls achieved 68%. Mean aerobic fitness reached 83% of prediction for the boys and 78% for the girls.

Based on these results, Mr. Lelieveld and his coinvestigators called for the development of exercise programs with more anaerobic and aerobic training for children with juvenile idiopathic arthritis.

“We know now from adult rheumatology that physical therapists are training at too low a level,” he said.

The children also are afraid to train themselves, he added. “When they are in remission they can have more pain than in the period when they are acute,” he said. “When they start functioning at a higher level, they put more strain on their joints. It is like a vicious circle.”

VERSAILLES, FRANCE — A Dutch study of 21 adolescents with juvenile idiopathic arthritis found significant impairment in anaerobic fitness when the youngsters were asked to ride a bicycle as fast as they could.

At peak power, girls reached only 53% of the anaerobic fitness predicted for their weight, while boys did only slightly better, at 71%. Both genders also showed moderate impairment in aerobic fitness at peak power: The girls performed at 78% of predicted levels, and the boys performed at 83%.

“Their fitness is about 20% reduced, compared to normal children. … They don't feel at ease with exercise,” researcher Otto Lelieveld, a physical therapist, said in an interview at the annual scientific meeting of the European Pediatric Rheumatology Congress, where he presented the results in a poster.

Nine boys and 12 girls, aged 16–18, took part in the study. On average, 7.6 years had elapsed since the boys were diagnosed, and 8.9 years had elapsed for the girls.

The teenagers were required to perform the Wingate sprint test. Mr. Lelieveld of University Medical Center Groningen (the Netherlands) described this as 5 minutes of steady bicycle riding at low speed, followed by a 30-second sprint at peak power.

Study participants did slightly better in measurements of mean power, both aerobic and anaerobic, during the first part of the test, but still showed moderate impairment. In the measurement of muscle endurance, the boys achieved 78% of the mean anaerobic fitness predicted for their weight; the girls achieved 68%. Mean aerobic fitness reached 83% of prediction for the boys and 78% for the girls.

Based on these results, Mr. Lelieveld and his coinvestigators called for the development of exercise programs with more anaerobic and aerobic training for children with juvenile idiopathic arthritis.

“We know now from adult rheumatology that physical therapists are training at too low a level,” he said.

The children also are afraid to train themselves, he added. “When they are in remission they can have more pain than in the period when they are acute,” he said. “When they start functioning at a higher level, they put more strain on their joints. It is like a vicious circle.”

VIENNA — Infliximab appears to be useful first-line therapy in patients with polymyalgia rheumatica complicated by comorbid diabetes and/or osteoporosis, according to Alberto Migliore, M.D., of San Pietro Hospital, Rome.

The tumor necrosis factor-α blocker is particularly advantageous in this situation because it enables such patients to avoid exposure to corticosteroids, which typically result in the worsening of their comorbid conditions, he explained at the annual European Congress of Rheumatology.

Dr. Migliore presented a series of seven patients with polymyalgia rheumatica: five who had comorbid diabetes and were being treated with oral agents or insulin, and two who had osteoporosis and vertebral fractures.

After undergoing a negative screen for tuberculosis, hepatitis B and C, and urinary tract infections, the seven patients received a series of four 3-mg/kg intravenous infliximab infusions over a 14-week period to induce clinical and serologic remission.

Methotrexate at 7.5–10 mg/week was then introduced to maintain the remission, Dr. Migliore said.

After a mean 8 months of follow-up, all seven patients remained in clinical remission.

Their C-reactive protein levels and erythrocyte sedimentation rates were significantly improved, compared with baseline, he added at the meeting, which was sponsored by the European League Against Rheumatism.

None of the infliximab-treated patients experienced deterioration in glycosylated hemoglobin or required a change in their diabetes medications.

There were no significant infliximab infusion reactions, Dr. Migliore said.

VIENNA — Infliximab appears to be useful first-line therapy in patients with polymyalgia rheumatica complicated by comorbid diabetes and/or osteoporosis, according to Alberto Migliore, M.D., of San Pietro Hospital, Rome.

The tumor necrosis factor-α blocker is particularly advantageous in this situation because it enables such patients to avoid exposure to corticosteroids, which typically result in the worsening of their comorbid conditions, he explained at the annual European Congress of Rheumatology.

Dr. Migliore presented a series of seven patients with polymyalgia rheumatica: five who had comorbid diabetes and were being treated with oral agents or insulin, and two who had osteoporosis and vertebral fractures.

After undergoing a negative screen for tuberculosis, hepatitis B and C, and urinary tract infections, the seven patients received a series of four 3-mg/kg intravenous infliximab infusions over a 14-week period to induce clinical and serologic remission.

Methotrexate at 7.5–10 mg/week was then introduced to maintain the remission, Dr. Migliore said.

After a mean 8 months of follow-up, all seven patients remained in clinical remission.

Their C-reactive protein levels and erythrocyte sedimentation rates were significantly improved, compared with baseline, he added at the meeting, which was sponsored by the European League Against Rheumatism.

None of the infliximab-treated patients experienced deterioration in glycosylated hemoglobin or required a change in their diabetes medications.

There were no significant infliximab infusion reactions, Dr. Migliore said.

VIENNA — Infliximab appears to be useful first-line therapy in patients with polymyalgia rheumatica complicated by comorbid diabetes and/or osteoporosis, according to Alberto Migliore, M.D., of San Pietro Hospital, Rome.

The tumor necrosis factor-α blocker is particularly advantageous in this situation because it enables such patients to avoid exposure to corticosteroids, which typically result in the worsening of their comorbid conditions, he explained at the annual European Congress of Rheumatology.

Dr. Migliore presented a series of seven patients with polymyalgia rheumatica: five who had comorbid diabetes and were being treated with oral agents or insulin, and two who had osteoporosis and vertebral fractures.

After undergoing a negative screen for tuberculosis, hepatitis B and C, and urinary tract infections, the seven patients received a series of four 3-mg/kg intravenous infliximab infusions over a 14-week period to induce clinical and serologic remission.

Methotrexate at 7.5–10 mg/week was then introduced to maintain the remission, Dr. Migliore said.

After a mean 8 months of follow-up, all seven patients remained in clinical remission.

Their C-reactive protein levels and erythrocyte sedimentation rates were significantly improved, compared with baseline, he added at the meeting, which was sponsored by the European League Against Rheumatism.

None of the infliximab-treated patients experienced deterioration in glycosylated hemoglobin or required a change in their diabetes medications.

There were no significant infliximab infusion reactions, Dr. Migliore said.

VIENNA — The time has come for a change in thinking regarding nongouty asymptomatic hyperuricemia, traditionally dismissed as a clinically irrelevant laboratory abnormality, George Nuki, M.D., asserted at the annual European Congress of Rheumatology.

“We actually need at this time a serious paradigm shift in thinking about the significance of asymptomatic hyperuricemia. We should think of it in terms of being a major prognostic marker. Asymptomatic hyperuricemia, as for gout itself, should be a red flag. When we see such a patient, we should ask ourselves why they're hyperuricemic, but we also need to assess them very well for cardiovascular risk factors and very carefully for metabolic syndrome,” said Dr. Nuki, professor of medicine at the University of Edinburgh.

Serum uric acid can be measured simply and inexpensively. But the central question regarding its clinical significance in asymptomatic individuals remains unanswered: Is it an independent risk factor for cardiovascular and all-cause mortality, or merely a biologic marker for other more causal risk factors?

The evidence on this score remains conflicting. A Framingham Study analysis concluded that asymptomatic hyperuricemia was not an independent cardiovascular risk factor. But in several recent studies it was.

For example, in a prospective cohort study of 1,423 healthy middle-aged Finnish men followed for nearly 12 years, Leo K. Niskanen, M.D., professor of medicine at Kuopio (Finland) University, and coworkers found that men in the top one-third in terms of baseline serum uric acid (SUA) levels were an age-adjusted 70% more likely to die of any cause than those in the lowest third. They were also 3.7-fold more likely to die of cardiovascular disease (Arch. Intern. Med. 2004;164:1546–51).

Similarly, in an analysis of data from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, Aud Hoiggen, M.D., of Ullevâl University Hospital, Oslo, and coinvestigators reported that baseline SUA was significantly associated with the cardiovascular event rate during 4.8 years of follow-up.

SUA rose over time in hypertensive patients randomized to a losartan-based antihypertensive regimen and in those assigned to an atenolol-based regimen, but the increase in the losartan group was 62% less. The investigators calculated that 29% of losartan's treatment effect on the primary LIFE composite end point of cardiovascular death, nonfatal MI, or stroke was attributable to its effect upon SUA (Kidney Int. 2004;65:1041–9).

Dr. Nuki said these studies are particularly intriguing in light of animal data showing that when SUA levels in rats are raised pharmacologically, the result is hypertension and intrarenal vascular disease, both of which are reversible with SUA-lowering using allopurinol.

Laboratory studies suggest a plausible mechanism by which asymptomatic hyperuricemia might be an independent risk factor for cardiovascular and renal disease. Soluble uric acid activates inflammatory pathways capable of inducing vascular smooth muscle cell proliferation and atherosclerosis. The pathways involve platelet-derived growth factor-A, cyclooxygenase-2, the monocyte chemokine MCP-1, and mitogen-activated protein kinases, he said.

Despite growing evidence implicating nongouty asymptomatic hyperuricemia as a cardiovascular risk factor, Dr. Nuki argued there are insufficient data to warrant using allopurinol or other SUA-lowering drugs in affected individuals.

“At the present time, my view certainly is that uric acid-lowering drug therapy isn't indicated,” Dr. Nuki said.

Instead, he advocated lifestyle modification to reduce the hyperuricemia—less dietary intake of high-purine animal protein and alcohol, more exercise, weight reduction—coupled with aggressive pharmacotherapy of any treatment-amenable components of the metabolic syndrome present, including hypertension and dyslipidemia.

VIENNA — The time has come for a change in thinking regarding nongouty asymptomatic hyperuricemia, traditionally dismissed as a clinically irrelevant laboratory abnormality, George Nuki, M.D., asserted at the annual European Congress of Rheumatology.

“We actually need at this time a serious paradigm shift in thinking about the significance of asymptomatic hyperuricemia. We should think of it in terms of being a major prognostic marker. Asymptomatic hyperuricemia, as for gout itself, should be a red flag. When we see such a patient, we should ask ourselves why they're hyperuricemic, but we also need to assess them very well for cardiovascular risk factors and very carefully for metabolic syndrome,” said Dr. Nuki, professor of medicine at the University of Edinburgh.

Serum uric acid can be measured simply and inexpensively. But the central question regarding its clinical significance in asymptomatic individuals remains unanswered: Is it an independent risk factor for cardiovascular and all-cause mortality, or merely a biologic marker for other more causal risk factors?

The evidence on this score remains conflicting. A Framingham Study analysis concluded that asymptomatic hyperuricemia was not an independent cardiovascular risk factor. But in several recent studies it was.

For example, in a prospective cohort study of 1,423 healthy middle-aged Finnish men followed for nearly 12 years, Leo K. Niskanen, M.D., professor of medicine at Kuopio (Finland) University, and coworkers found that men in the top one-third in terms of baseline serum uric acid (SUA) levels were an age-adjusted 70% more likely to die of any cause than those in the lowest third. They were also 3.7-fold more likely to die of cardiovascular disease (Arch. Intern. Med. 2004;164:1546–51).

Similarly, in an analysis of data from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, Aud Hoiggen, M.D., of Ullevâl University Hospital, Oslo, and coinvestigators reported that baseline SUA was significantly associated with the cardiovascular event rate during 4.8 years of follow-up.

SUA rose over time in hypertensive patients randomized to a losartan-based antihypertensive regimen and in those assigned to an atenolol-based regimen, but the increase in the losartan group was 62% less. The investigators calculated that 29% of losartan's treatment effect on the primary LIFE composite end point of cardiovascular death, nonfatal MI, or stroke was attributable to its effect upon SUA (Kidney Int. 2004;65:1041–9).

Dr. Nuki said these studies are particularly intriguing in light of animal data showing that when SUA levels in rats are raised pharmacologically, the result is hypertension and intrarenal vascular disease, both of which are reversible with SUA-lowering using allopurinol.

Laboratory studies suggest a plausible mechanism by which asymptomatic hyperuricemia might be an independent risk factor for cardiovascular and renal disease. Soluble uric acid activates inflammatory pathways capable of inducing vascular smooth muscle cell proliferation and atherosclerosis. The pathways involve platelet-derived growth factor-A, cyclooxygenase-2, the monocyte chemokine MCP-1, and mitogen-activated protein kinases, he said.

Despite growing evidence implicating nongouty asymptomatic hyperuricemia as a cardiovascular risk factor, Dr. Nuki argued there are insufficient data to warrant using allopurinol or other SUA-lowering drugs in affected individuals.

“At the present time, my view certainly is that uric acid-lowering drug therapy isn't indicated,” Dr. Nuki said.

Instead, he advocated lifestyle modification to reduce the hyperuricemia—less dietary intake of high-purine animal protein and alcohol, more exercise, weight reduction—coupled with aggressive pharmacotherapy of any treatment-amenable components of the metabolic syndrome present, including hypertension and dyslipidemia.

VIENNA — The time has come for a change in thinking regarding nongouty asymptomatic hyperuricemia, traditionally dismissed as a clinically irrelevant laboratory abnormality, George Nuki, M.D., asserted at the annual European Congress of Rheumatology.

“We actually need at this time a serious paradigm shift in thinking about the significance of asymptomatic hyperuricemia. We should think of it in terms of being a major prognostic marker. Asymptomatic hyperuricemia, as for gout itself, should be a red flag. When we see such a patient, we should ask ourselves why they're hyperuricemic, but we also need to assess them very well for cardiovascular risk factors and very carefully for metabolic syndrome,” said Dr. Nuki, professor of medicine at the University of Edinburgh.

Serum uric acid can be measured simply and inexpensively. But the central question regarding its clinical significance in asymptomatic individuals remains unanswered: Is it an independent risk factor for cardiovascular and all-cause mortality, or merely a biologic marker for other more causal risk factors?

The evidence on this score remains conflicting. A Framingham Study analysis concluded that asymptomatic hyperuricemia was not an independent cardiovascular risk factor. But in several recent studies it was.

For example, in a prospective cohort study of 1,423 healthy middle-aged Finnish men followed for nearly 12 years, Leo K. Niskanen, M.D., professor of medicine at Kuopio (Finland) University, and coworkers found that men in the top one-third in terms of baseline serum uric acid (SUA) levels were an age-adjusted 70% more likely to die of any cause than those in the lowest third. They were also 3.7-fold more likely to die of cardiovascular disease (Arch. Intern. Med. 2004;164:1546–51).

Similarly, in an analysis of data from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, Aud Hoiggen, M.D., of Ullevâl University Hospital, Oslo, and coinvestigators reported that baseline SUA was significantly associated with the cardiovascular event rate during 4.8 years of follow-up.

SUA rose over time in hypertensive patients randomized to a losartan-based antihypertensive regimen and in those assigned to an atenolol-based regimen, but the increase in the losartan group was 62% less. The investigators calculated that 29% of losartan's treatment effect on the primary LIFE composite end point of cardiovascular death, nonfatal MI, or stroke was attributable to its effect upon SUA (Kidney Int. 2004;65:1041–9).

Dr. Nuki said these studies are particularly intriguing in light of animal data showing that when SUA levels in rats are raised pharmacologically, the result is hypertension and intrarenal vascular disease, both of which are reversible with SUA-lowering using allopurinol.

Laboratory studies suggest a plausible mechanism by which asymptomatic hyperuricemia might be an independent risk factor for cardiovascular and renal disease. Soluble uric acid activates inflammatory pathways capable of inducing vascular smooth muscle cell proliferation and atherosclerosis. The pathways involve platelet-derived growth factor-A, cyclooxygenase-2, the monocyte chemokine MCP-1, and mitogen-activated protein kinases, he said.

Despite growing evidence implicating nongouty asymptomatic hyperuricemia as a cardiovascular risk factor, Dr. Nuki argued there are insufficient data to warrant using allopurinol or other SUA-lowering drugs in affected individuals.

“At the present time, my view certainly is that uric acid-lowering drug therapy isn't indicated,” Dr. Nuki said.

Instead, he advocated lifestyle modification to reduce the hyperuricemia—less dietary intake of high-purine animal protein and alcohol, more exercise, weight reduction—coupled with aggressive pharmacotherapy of any treatment-amenable components of the metabolic syndrome present, including hypertension and dyslipidemia.

VIENNA — Americans attending the annual European Congress of Rheumatology are often impressed by the discussion of unfamiliar, even exotic therapies not available in the United States.

The most intriguing of these are supported by encouraging clinical trials data. Yet many of the therapies may never reach the U.S. market because they are the property of small companies that find the Food and Drug Administration approval process too fiscally daunting.

Here is a sample of novel therapies, currently unavailable in the United States, that were the subject of research presentations at the meeting, sponsored by the European League Against Rheumatism.

Diacerein

This plant-derived anthraquinone derivative blocks the downstream proinflammatory effects associated with stimulation of the interleukin-1 receptors located on chondrocytes and inflammatory cells. It doesn't affect prostaglandin synthesis.

EULAR guidelines categorize diacerein as a symptomatic slow-acting drug for both knee and hip osteoarthritis (OA). It is widely used for this purpose in much of Europe, where it has been the subject of more than a dozen randomized controlled trials.

At the EULAR meeting, Worowit Louthrenoo, M.D., presented the first randomized double-blind controlled trial of diacerein in an Asian population.

The Thai study involved 161 OA patients randomized to 50 mg b.i.d. of diacerein or 10 mg b.i.d. of piroxicam for 16 weeks, with an additional 8 weeks of follow-up post discontinuation, Dr. Louthrenoo said.

The primary end point in the TRB Chemedica-sponsored trial was pain relief as reflected in WOMAC scores.

At week 16 of the investigation, the diacerein group showed a mean 70% improvement in WOMAC scores, compared with baseline—not significantly different from the 74% improvement in the piroxicam group.

However, at week 20—which was 4 weeks following discontinuation—the mean improvement in the diacerein group remained at 67%, compared with 47% for piroxicam.

And at week 24, the diacerein group maintained a 70% improvement in WOMAC scores, versus a 27% improvement in the piroxicam group, said Dr. Louthrenoo, professor of medicine at Chiang Mai (Thailand) University.

The most frequent adverse event in the diacerein group was diarrhea; it was less common than the abdominal pain reported by piroxicam users.

Nuclear Magnetic Resonance Therapy for Low Back Pain

That's right—MRI not for imaging purposes, but as treatment. Therapeutic MRI, called MultiBioSignal Nuclear Resonance Therapy (MBST) was developed by a German company, Medtec Medizintechnik GmbH, after physicians serendipitously noted that patients with disabling chronic low back pain who had to undergo repeated conventional MRIs because of technical imaging problems reported feeling much better afterward.

Physicians and physicists came up with a basic science rationale to explain the effect, then modified conventional MRI equipment to enhance it. They created a device that generates a static magnetic field and a three-dimensional alternating radiofrequency field designed to induce resonant vibration of hydrogen atoms within cartilage and bone in order to stimulate cell proliferation. Investigators at the University of Munich have previously demonstrated that MBST increases cartilage thickness in patients with knee osteoarthritis.

Sound flaky? Medical officials at one of Austria's largest workers' compensation insurer-funded inpatient rehabilitation centers don't think so, Werner C. Kullich, Ph.D., told this newspaper.

Dr. Kullich explained that the prevailing workers'-comp philosophy in German-speaking Europe is that rehabilitation of patients with chronic disabling low back pain is best accomplished through a 3- to 4-week inpatient stay at specialized centers that provide multimodal therapy, including extensive education, exercises, massage, hydrotherapy, and electrical stimulation. The results, though shown to be superior to the outpatient therapies that are the norm in much of the rest of the world, leave much to be desired—thus the insurance industry's interest in MBST and other novel approaches.

Dr. Kullich presented an insurer-sponsored, double-blind, placebo-controlled trial of MBST versus sham therapy in 62 rehab-clinic patients with chronic low back pain.

In addition to the standardized intensive 3-week inpatient rehab program, study participants received hour-long MBST or sham therapy sessions on 5 consecutive days. The study end points were changes in pain and function at 1 and 12 weeks post MBST.

Both groups showed significant improvements in low back pain as assessed by the Roland-Morris Questionnaire at 1 week; by 3 months, however, scores in the rehabilitation-plus-placebo group had retreated to baseline levels, while the MBST group showed further significant improvement.

Similar results were seen on the Oswestry Disability Questionnaire. Particularly striking was the finding that after 3 months 74% of MBST-treated patients rated their ability to provide personal care as improved, and none indicated it had deteriorated, compared with baseline.

In contrast, only 37% of controls rated their personal care capability as improved, while 11% said it had deteriorated. Walking, sitting, standing, and lifting were areas where both groups showed significant improvement at 3 months, with greater gains recorded in the MBST group, said Dr. Kullich of the Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases in Saalfelden, Austria.

Topical Diclofenac for Knee OA

A metaanalysis of four randomized controlled 4- to 12-week trials totaling 1,412 patients with symptomatic knee OA showed the topical agent's efficacy was equal to oral diclofenac and significantly better than placebo for the end points of stiffness, physical function, and pain on walking, according to Michael Doherty, M.D., professor of rheumatology at the University of Nottingham (England).

The number of patients needed to be treated with topical diclofenac for one patient to achieve greater than 50% pain reduction was six.

The chief advantage of topical as compared with oral diclofenac was that GI side effects were 43% less common with the topical agent and no more frequent than with placebo.

Topical diclofenac is contained in a dimethyl sulfoxide vehicle. The main adverse event associated with the topical therapy was local skin reactions, mainly dry skin and itching, which were 3.6-fold more frequent than with placebo.

The topical diclofenac solution, called Pennsaid, is approved for treatment of knee OA in Canada and seven European countries. A spokesman for Dimethaid Health Care Ltd., of Markham, Canada, told this newspaper the company hopes to gain U.S. marketing approval for Pennsaid in early 2007. The FDA has asked for two additional long-term safety studies, both of which are nearly completed.

Pentosan Polysulfate for OA

A non-commercially funded randomized double-blind placebo-controlled trial involving 114 patients with knee OA demonstrated that 4 weekly 3-mg/kg IM injections of pentosan polysulfate resulted in significantly greater improvements in pain at rest and walking, stiffness, and physical functioning involved in activities of daily living out to 24 weeks follow-up post treatment, reported Peter Ghosh, Ph.D., of the Institute of Bone and Joint Research at Royal North Shore Hospital, Sydney, Australia.

Pentosan polysulfate (approved in the United States only for interstitial cystitis) has been used in Europe for nearly 50 years as a postsurgery thromboprophylaxis agent. It promotes fibrinolysis and has anticoagulant activity. Dr. Ghosh saw its potential as a chondroprotective agent. “We have probably 50 papers of its effect in animals and in vitro. The rationale for its use in arthritis is solid as a rock,” he told this newspaper.

“It mobilizes the clots in subchondral bone, it's anti-inflammatory, it protects the cartilage, and it stimulates the production in synovial fluid of hyaluronic acid. So it has all the markings of a disease-modifying drug for osteoarthritis,” he said.

Pentosan polysulfate is marketed by bene-Arzneimittel GmbH of Munich. It's a small, family-owned company that does not have the financial resources to conduct a multiyear radiographic study with preservation of joint space as the end point, which is what the FDA insists upon if an OA drug is to obtain an indication as disease modifying.

“They're looking for partners in Japan,” he said.

In Europe, Canada, and Australia, pentosan polysulfate has become the leading drug for the prevention of progressive OA in dogs and horses. “In fact, we've been able to move much faster in the veterinary field than we have in humans,” Dr. Ghosh added.

Emu Oil

Daily oral or topical use of oil rendered from the emu, a large flightless bird, resulted in a 2.34-fold greater reduction in pain than a canola oil placebo in a randomized double-blind trial involving 101 patients with OA hand pain. The observed treatment effect was medium to large, and it was apparent from week 4 onward in the 8-week trial, reported Melainie Cameron, Ph.D., of Victoria University, Melbourne, Australia.

As early as 1860, naturalists reported that Australian aborigines and early Anglo settlers used emu oil to treat wounds and relieve musculoskeletal pain, Dr. Cameron added.

Daily application of emu oil reduced hand OA pain significantly better than canola oil or placebo. James Reinaker

VIENNA — Americans attending the annual European Congress of Rheumatology are often impressed by the discussion of unfamiliar, even exotic therapies not available in the United States.

The most intriguing of these are supported by encouraging clinical trials data. Yet many of the therapies may never reach the U.S. market because they are the property of small companies that find the Food and Drug Administration approval process too fiscally daunting.

Here is a sample of novel therapies, currently unavailable in the United States, that were the subject of research presentations at the meeting, sponsored by the European League Against Rheumatism.

Diacerein

This plant-derived anthraquinone derivative blocks the downstream proinflammatory effects associated with stimulation of the interleukin-1 receptors located on chondrocytes and inflammatory cells. It doesn't affect prostaglandin synthesis.

EULAR guidelines categorize diacerein as a symptomatic slow-acting drug for both knee and hip osteoarthritis (OA). It is widely used for this purpose in much of Europe, where it has been the subject of more than a dozen randomized controlled trials.

At the EULAR meeting, Worowit Louthrenoo, M.D., presented the first randomized double-blind controlled trial of diacerein in an Asian population.

The Thai study involved 161 OA patients randomized to 50 mg b.i.d. of diacerein or 10 mg b.i.d. of piroxicam for 16 weeks, with an additional 8 weeks of follow-up post discontinuation, Dr. Louthrenoo said.

The primary end point in the TRB Chemedica-sponsored trial was pain relief as reflected in WOMAC scores.

At week 16 of the investigation, the diacerein group showed a mean 70% improvement in WOMAC scores, compared with baseline—not significantly different from the 74% improvement in the piroxicam group.

However, at week 20—which was 4 weeks following discontinuation—the mean improvement in the diacerein group remained at 67%, compared with 47% for piroxicam.

And at week 24, the diacerein group maintained a 70% improvement in WOMAC scores, versus a 27% improvement in the piroxicam group, said Dr. Louthrenoo, professor of medicine at Chiang Mai (Thailand) University.

The most frequent adverse event in the diacerein group was diarrhea; it was less common than the abdominal pain reported by piroxicam users.

Nuclear Magnetic Resonance Therapy for Low Back Pain

That's right—MRI not for imaging purposes, but as treatment. Therapeutic MRI, called MultiBioSignal Nuclear Resonance Therapy (MBST) was developed by a German company, Medtec Medizintechnik GmbH, after physicians serendipitously noted that patients with disabling chronic low back pain who had to undergo repeated conventional MRIs because of technical imaging problems reported feeling much better afterward.

Physicians and physicists came up with a basic science rationale to explain the effect, then modified conventional MRI equipment to enhance it. They created a device that generates a static magnetic field and a three-dimensional alternating radiofrequency field designed to induce resonant vibration of hydrogen atoms within cartilage and bone in order to stimulate cell proliferation. Investigators at the University of Munich have previously demonstrated that MBST increases cartilage thickness in patients with knee osteoarthritis.

Sound flaky? Medical officials at one of Austria's largest workers' compensation insurer-funded inpatient rehabilitation centers don't think so, Werner C. Kullich, Ph.D., told this newspaper.

Dr. Kullich explained that the prevailing workers'-comp philosophy in German-speaking Europe is that rehabilitation of patients with chronic disabling low back pain is best accomplished through a 3- to 4-week inpatient stay at specialized centers that provide multimodal therapy, including extensive education, exercises, massage, hydrotherapy, and electrical stimulation. The results, though shown to be superior to the outpatient therapies that are the norm in much of the rest of the world, leave much to be desired—thus the insurance industry's interest in MBST and other novel approaches.

Dr. Kullich presented an insurer-sponsored, double-blind, placebo-controlled trial of MBST versus sham therapy in 62 rehab-clinic patients with chronic low back pain.

In addition to the standardized intensive 3-week inpatient rehab program, study participants received hour-long MBST or sham therapy sessions on 5 consecutive days. The study end points were changes in pain and function at 1 and 12 weeks post MBST.

Both groups showed significant improvements in low back pain as assessed by the Roland-Morris Questionnaire at 1 week; by 3 months, however, scores in the rehabilitation-plus-placebo group had retreated to baseline levels, while the MBST group showed further significant improvement.

Similar results were seen on the Oswestry Disability Questionnaire. Particularly striking was the finding that after 3 months 74% of MBST-treated patients rated their ability to provide personal care as improved, and none indicated it had deteriorated, compared with baseline.

In contrast, only 37% of controls rated their personal care capability as improved, while 11% said it had deteriorated. Walking, sitting, standing, and lifting were areas where both groups showed significant improvement at 3 months, with greater gains recorded in the MBST group, said Dr. Kullich of the Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases in Saalfelden, Austria.

Topical Diclofenac for Knee OA

A metaanalysis of four randomized controlled 4- to 12-week trials totaling 1,412 patients with symptomatic knee OA showed the topical agent's efficacy was equal to oral diclofenac and significantly better than placebo for the end points of stiffness, physical function, and pain on walking, according to Michael Doherty, M.D., professor of rheumatology at the University of Nottingham (England).

The number of patients needed to be treated with topical diclofenac for one patient to achieve greater than 50% pain reduction was six.

The chief advantage of topical as compared with oral diclofenac was that GI side effects were 43% less common with the topical agent and no more frequent than with placebo.

Topical diclofenac is contained in a dimethyl sulfoxide vehicle. The main adverse event associated with the topical therapy was local skin reactions, mainly dry skin and itching, which were 3.6-fold more frequent than with placebo.

The topical diclofenac solution, called Pennsaid, is approved for treatment of knee OA in Canada and seven European countries. A spokesman for Dimethaid Health Care Ltd., of Markham, Canada, told this newspaper the company hopes to gain U.S. marketing approval for Pennsaid in early 2007. The FDA has asked for two additional long-term safety studies, both of which are nearly completed.

Pentosan Polysulfate for OA

A non-commercially funded randomized double-blind placebo-controlled trial involving 114 patients with knee OA demonstrated that 4 weekly 3-mg/kg IM injections of pentosan polysulfate resulted in significantly greater improvements in pain at rest and walking, stiffness, and physical functioning involved in activities of daily living out to 24 weeks follow-up post treatment, reported Peter Ghosh, Ph.D., of the Institute of Bone and Joint Research at Royal North Shore Hospital, Sydney, Australia.

Pentosan polysulfate (approved in the United States only for interstitial cystitis) has been used in Europe for nearly 50 years as a postsurgery thromboprophylaxis agent. It promotes fibrinolysis and has anticoagulant activity. Dr. Ghosh saw its potential as a chondroprotective agent. “We have probably 50 papers of its effect in animals and in vitro. The rationale for its use in arthritis is solid as a rock,” he told this newspaper.

“It mobilizes the clots in subchondral bone, it's anti-inflammatory, it protects the cartilage, and it stimulates the production in synovial fluid of hyaluronic acid. So it has all the markings of a disease-modifying drug for osteoarthritis,” he said.

Pentosan polysulfate is marketed by bene-Arzneimittel GmbH of Munich. It's a small, family-owned company that does not have the financial resources to conduct a multiyear radiographic study with preservation of joint space as the end point, which is what the FDA insists upon if an OA drug is to obtain an indication as disease modifying.

“They're looking for partners in Japan,” he said.

In Europe, Canada, and Australia, pentosan polysulfate has become the leading drug for the prevention of progressive OA in dogs and horses. “In fact, we've been able to move much faster in the veterinary field than we have in humans,” Dr. Ghosh added.

Emu Oil

Daily oral or topical use of oil rendered from the emu, a large flightless bird, resulted in a 2.34-fold greater reduction in pain than a canola oil placebo in a randomized double-blind trial involving 101 patients with OA hand pain. The observed treatment effect was medium to large, and it was apparent from week 4 onward in the 8-week trial, reported Melainie Cameron, Ph.D., of Victoria University, Melbourne, Australia.

As early as 1860, naturalists reported that Australian aborigines and early Anglo settlers used emu oil to treat wounds and relieve musculoskeletal pain, Dr. Cameron added.

Daily application of emu oil reduced hand OA pain significantly better than canola oil or placebo. James Reinaker

VIENNA — Americans attending the annual European Congress of Rheumatology are often impressed by the discussion of unfamiliar, even exotic therapies not available in the United States.

The most intriguing of these are supported by encouraging clinical trials data. Yet many of the therapies may never reach the U.S. market because they are the property of small companies that find the Food and Drug Administration approval process too fiscally daunting.

Here is a sample of novel therapies, currently unavailable in the United States, that were the subject of research presentations at the meeting, sponsored by the European League Against Rheumatism.

Diacerein

This plant-derived anthraquinone derivative blocks the downstream proinflammatory effects associated with stimulation of the interleukin-1 receptors located on chondrocytes and inflammatory cells. It doesn't affect prostaglandin synthesis.

EULAR guidelines categorize diacerein as a symptomatic slow-acting drug for both knee and hip osteoarthritis (OA). It is widely used for this purpose in much of Europe, where it has been the subject of more than a dozen randomized controlled trials.

At the EULAR meeting, Worowit Louthrenoo, M.D., presented the first randomized double-blind controlled trial of diacerein in an Asian population.

The Thai study involved 161 OA patients randomized to 50 mg b.i.d. of diacerein or 10 mg b.i.d. of piroxicam for 16 weeks, with an additional 8 weeks of follow-up post discontinuation, Dr. Louthrenoo said.

The primary end point in the TRB Chemedica-sponsored trial was pain relief as reflected in WOMAC scores.

At week 16 of the investigation, the diacerein group showed a mean 70% improvement in WOMAC scores, compared with baseline—not significantly different from the 74% improvement in the piroxicam group.

However, at week 20—which was 4 weeks following discontinuation—the mean improvement in the diacerein group remained at 67%, compared with 47% for piroxicam.

And at week 24, the diacerein group maintained a 70% improvement in WOMAC scores, versus a 27% improvement in the piroxicam group, said Dr. Louthrenoo, professor of medicine at Chiang Mai (Thailand) University.

The most frequent adverse event in the diacerein group was diarrhea; it was less common than the abdominal pain reported by piroxicam users.

Nuclear Magnetic Resonance Therapy for Low Back Pain

That's right—MRI not for imaging purposes, but as treatment. Therapeutic MRI, called MultiBioSignal Nuclear Resonance Therapy (MBST) was developed by a German company, Medtec Medizintechnik GmbH, after physicians serendipitously noted that patients with disabling chronic low back pain who had to undergo repeated conventional MRIs because of technical imaging problems reported feeling much better afterward.

Physicians and physicists came up with a basic science rationale to explain the effect, then modified conventional MRI equipment to enhance it. They created a device that generates a static magnetic field and a three-dimensional alternating radiofrequency field designed to induce resonant vibration of hydrogen atoms within cartilage and bone in order to stimulate cell proliferation. Investigators at the University of Munich have previously demonstrated that MBST increases cartilage thickness in patients with knee osteoarthritis.

Sound flaky? Medical officials at one of Austria's largest workers' compensation insurer-funded inpatient rehabilitation centers don't think so, Werner C. Kullich, Ph.D., told this newspaper.

Dr. Kullich explained that the prevailing workers'-comp philosophy in German-speaking Europe is that rehabilitation of patients with chronic disabling low back pain is best accomplished through a 3- to 4-week inpatient stay at specialized centers that provide multimodal therapy, including extensive education, exercises, massage, hydrotherapy, and electrical stimulation. The results, though shown to be superior to the outpatient therapies that are the norm in much of the rest of the world, leave much to be desired—thus the insurance industry's interest in MBST and other novel approaches.

Dr. Kullich presented an insurer-sponsored, double-blind, placebo-controlled trial of MBST versus sham therapy in 62 rehab-clinic patients with chronic low back pain.

In addition to the standardized intensive 3-week inpatient rehab program, study participants received hour-long MBST or sham therapy sessions on 5 consecutive days. The study end points were changes in pain and function at 1 and 12 weeks post MBST.

Both groups showed significant improvements in low back pain as assessed by the Roland-Morris Questionnaire at 1 week; by 3 months, however, scores in the rehabilitation-plus-placebo group had retreated to baseline levels, while the MBST group showed further significant improvement.

Similar results were seen on the Oswestry Disability Questionnaire. Particularly striking was the finding that after 3 months 74% of MBST-treated patients rated their ability to provide personal care as improved, and none indicated it had deteriorated, compared with baseline.

In contrast, only 37% of controls rated their personal care capability as improved, while 11% said it had deteriorated. Walking, sitting, standing, and lifting were areas where both groups showed significant improvement at 3 months, with greater gains recorded in the MBST group, said Dr. Kullich of the Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases in Saalfelden, Austria.

Topical Diclofenac for Knee OA

A metaanalysis of four randomized controlled 4- to 12-week trials totaling 1,412 patients with symptomatic knee OA showed the topical agent's efficacy was equal to oral diclofenac and significantly better than placebo for the end points of stiffness, physical function, and pain on walking, according to Michael Doherty, M.D., professor of rheumatology at the University of Nottingham (England).

The number of patients needed to be treated with topical diclofenac for one patient to achieve greater than 50% pain reduction was six.

The chief advantage of topical as compared with oral diclofenac was that GI side effects were 43% less common with the topical agent and no more frequent than with placebo.

Topical diclofenac is contained in a dimethyl sulfoxide vehicle. The main adverse event associated with the topical therapy was local skin reactions, mainly dry skin and itching, which were 3.6-fold more frequent than with placebo.

The topical diclofenac solution, called Pennsaid, is approved for treatment of knee OA in Canada and seven European countries. A spokesman for Dimethaid Health Care Ltd., of Markham, Canada, told this newspaper the company hopes to gain U.S. marketing approval for Pennsaid in early 2007. The FDA has asked for two additional long-term safety studies, both of which are nearly completed.

Pentosan Polysulfate for OA

A non-commercially funded randomized double-blind placebo-controlled trial involving 114 patients with knee OA demonstrated that 4 weekly 3-mg/kg IM injections of pentosan polysulfate resulted in significantly greater improvements in pain at rest and walking, stiffness, and physical functioning involved in activities of daily living out to 24 weeks follow-up post treatment, reported Peter Ghosh, Ph.D., of the Institute of Bone and Joint Research at Royal North Shore Hospital, Sydney, Australia.

Pentosan polysulfate (approved in the United States only for interstitial cystitis) has been used in Europe for nearly 50 years as a postsurgery thromboprophylaxis agent. It promotes fibrinolysis and has anticoagulant activity. Dr. Ghosh saw its potential as a chondroprotective agent. “We have probably 50 papers of its effect in animals and in vitro. The rationale for its use in arthritis is solid as a rock,” he told this newspaper.

“It mobilizes the clots in subchondral bone, it's anti-inflammatory, it protects the cartilage, and it stimulates the production in synovial fluid of hyaluronic acid. So it has all the markings of a disease-modifying drug for osteoarthritis,” he said.

Pentosan polysulfate is marketed by bene-Arzneimittel GmbH of Munich. It's a small, family-owned company that does not have the financial resources to conduct a multiyear radiographic study with preservation of joint space as the end point, which is what the FDA insists upon if an OA drug is to obtain an indication as disease modifying.

“They're looking for partners in Japan,” he said.

In Europe, Canada, and Australia, pentosan polysulfate has become the leading drug for the prevention of progressive OA in dogs and horses. “In fact, we've been able to move much faster in the veterinary field than we have in humans,” Dr. Ghosh added.

Emu Oil

Daily oral or topical use of oil rendered from the emu, a large flightless bird, resulted in a 2.34-fold greater reduction in pain than a canola oil placebo in a randomized double-blind trial involving 101 patients with OA hand pain. The observed treatment effect was medium to large, and it was apparent from week 4 onward in the 8-week trial, reported Melainie Cameron, Ph.D., of Victoria University, Melbourne, Australia.

As early as 1860, naturalists reported that Australian aborigines and early Anglo settlers used emu oil to treat wounds and relieve musculoskeletal pain, Dr. Cameron added.

Daily application of emu oil reduced hand OA pain significantly better than canola oil or placebo. James Reinaker