Christine Kilgore

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies, both of which appear in the June issue of Pediatrics, show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media. “Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation. Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than what they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said. Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

Dr. McCormick and his colleagues assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores. However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said, adding that “practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to most accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies, both of which appear in the June issue of Pediatrics, show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media. “Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation. Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than what they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said. Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

Dr. McCormick and his colleagues assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores. However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said, adding that “practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to most accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies, both of which appear in the June issue of Pediatrics, show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media. “Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation. Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than what they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said. Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

Dr. McCormick and his colleagues assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores. However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said, adding that “practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to most accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

WASHINGTON — Mobile-bearing knee implants are hyped in advertisements and demanded by patients, but the jury is still out on whether the devices deliver what's promised.

During a panel discussion on “controversial issues and hot topics” in primary total knee replacement at the annual meeting of the American Academy of Orthopaedic Surgeons, several panelists objected to the idea that rotating platform knee implants are superior in many ways to fixed-bearing designs.

“There's certainly some skepticism here about whether mobile-bearing designs are really more forgiving [of rotational misalignment of the femoral and tibial components] and whether there truly is less wear,” said William J. Maloney, M.D., professor of orthopedic surgery at Stanford (Calif.) University, who moderated the discussion.

Rotating platform, or mobile-bearing, knee replacements are designed for potentially longer performance with less wear to parts of the prosthesis. The devices have been marketed and are recommended by some physicians, particularly for younger, active, or overweight patients.

The mobile-bearing knees use three components—just like fixed-bearing replacements—but have a different bearing surface. The metallic femoral component and the metallic tibial tray both move across a mobile polyethylene insert. The insert creates a dual-surface articulation, absorbing force across a greater contact surface and ensuring congruent contact between the femoral and tibial components.

These implants, said panelist Douglas A. Dennis, M.D., “allow increased conformity in both planes without dramatically increasing fixation stresses and the risk of component loosening.”

This, he said, reduces polyethylene wear—which should be the focus of “any total knee design.” Polyethylene wear has been the major mode of total knee replacement failure, said Dr. Dennis, of the Rocky Mountain Musculoskeletal Research Laboratory in Denver.

“We have seen in our laboratory better kinematics in gait with mobile bearings. They're more tolerant of condylar lift-off, which should reduce the potential for polyethylene wear, and I think they're more forgiving of component rotational mal-alignment—the bearing has the potential to self-correct,” he said.

In a 10-year study of total knee replacements, Dr. Dennis and his colleagues found that mobile-bearing knees allow for a wider range of axial rotation without creating excessive polyethylene stresses. “A fairly large number [of mobile-bearing knees] rotated greater than 20 degrees, which is beyond the rotational boundaries of most fixed-bearing designs,” he said.

Arlen D. Hanssen, M.D., argued that several studies have shown no difference in motion and no difference in patello-femoral mechanics between fixed and mobile-bearing knees. Early dislocation and instability continue to be a problem with the rotating-platform knee, and recently there have been reports of late dislocation.

“Late dislocation occurs in this knee because of advanced wear,” said Dr. Hanssen, of the Mayo Clinic in Rochester, Minn.

“One of the reasons to use the rotating-platform knee has been to avoid osteolysis wear … but osteolysis seems to be significantly higher [in patients with the mobile-bearing knee],” he said.

The rigid tibial trays that are required in the rotating platform design also contribute to stress shielding of the proximal tibia, he said.

“Why would you take a knee that [has only been studied] in the elderly, has no better motion, no better patello-femoral mechanics, has the unique complication of dislocation and instability, and now appears to have some wear and osteolysis problems and stress shielding problems?” Dr. Hanssen asked. “My answer is no thanks.”

Other panelists agreed. “The advertisements say [the mobile-bearing knee] is the best thing, that it's going to give us 20 years,” said Merrill A. Ritter, M.D., of the Center for Hip and Knee Surgery in Mooresville, Ind. “There [are] no data to support this, and there are too many things that do work.”

Leo A. Whiteside, M.D., of the Missouri Bone and Joint Center in St. Louis, said that theoretically, the mobile-bearing design should perform better. “What worries me [are] the multiple reports of higher wear,” he said.

Bearing surface is just one of several choices surgeons make when performing total knee arthroplasty. The type of fixation, the modularity of implants, and surgical technique are also controversial, Dr. Maloney added.

WASHINGTON — Mobile-bearing knee implants are hyped in advertisements and demanded by patients, but the jury is still out on whether the devices deliver what's promised.

During a panel discussion on “controversial issues and hot topics” in primary total knee replacement at the annual meeting of the American Academy of Orthopaedic Surgeons, several panelists objected to the idea that rotating platform knee implants are superior in many ways to fixed-bearing designs.

“There's certainly some skepticism here about whether mobile-bearing designs are really more forgiving [of rotational misalignment of the femoral and tibial components] and whether there truly is less wear,” said William J. Maloney, M.D., professor of orthopedic surgery at Stanford (Calif.) University, who moderated the discussion.

Rotating platform, or mobile-bearing, knee replacements are designed for potentially longer performance with less wear to parts of the prosthesis. The devices have been marketed and are recommended by some physicians, particularly for younger, active, or overweight patients.

The mobile-bearing knees use three components—just like fixed-bearing replacements—but have a different bearing surface. The metallic femoral component and the metallic tibial tray both move across a mobile polyethylene insert. The insert creates a dual-surface articulation, absorbing force across a greater contact surface and ensuring congruent contact between the femoral and tibial components.

These implants, said panelist Douglas A. Dennis, M.D., “allow increased conformity in both planes without dramatically increasing fixation stresses and the risk of component loosening.”

This, he said, reduces polyethylene wear—which should be the focus of “any total knee design.” Polyethylene wear has been the major mode of total knee replacement failure, said Dr. Dennis, of the Rocky Mountain Musculoskeletal Research Laboratory in Denver.

“We have seen in our laboratory better kinematics in gait with mobile bearings. They're more tolerant of condylar lift-off, which should reduce the potential for polyethylene wear, and I think they're more forgiving of component rotational mal-alignment—the bearing has the potential to self-correct,” he said.

In a 10-year study of total knee replacements, Dr. Dennis and his colleagues found that mobile-bearing knees allow for a wider range of axial rotation without creating excessive polyethylene stresses. “A fairly large number [of mobile-bearing knees] rotated greater than 20 degrees, which is beyond the rotational boundaries of most fixed-bearing designs,” he said.

Arlen D. Hanssen, M.D., argued that several studies have shown no difference in motion and no difference in patello-femoral mechanics between fixed and mobile-bearing knees. Early dislocation and instability continue to be a problem with the rotating-platform knee, and recently there have been reports of late dislocation.

“Late dislocation occurs in this knee because of advanced wear,” said Dr. Hanssen, of the Mayo Clinic in Rochester, Minn.

“One of the reasons to use the rotating-platform knee has been to avoid osteolysis wear … but osteolysis seems to be significantly higher [in patients with the mobile-bearing knee],” he said.

The rigid tibial trays that are required in the rotating platform design also contribute to stress shielding of the proximal tibia, he said.

“Why would you take a knee that [has only been studied] in the elderly, has no better motion, no better patello-femoral mechanics, has the unique complication of dislocation and instability, and now appears to have some wear and osteolysis problems and stress shielding problems?” Dr. Hanssen asked. “My answer is no thanks.”

Other panelists agreed. “The advertisements say [the mobile-bearing knee] is the best thing, that it's going to give us 20 years,” said Merrill A. Ritter, M.D., of the Center for Hip and Knee Surgery in Mooresville, Ind. “There [are] no data to support this, and there are too many things that do work.”

Leo A. Whiteside, M.D., of the Missouri Bone and Joint Center in St. Louis, said that theoretically, the mobile-bearing design should perform better. “What worries me [are] the multiple reports of higher wear,” he said.

Bearing surface is just one of several choices surgeons make when performing total knee arthroplasty. The type of fixation, the modularity of implants, and surgical technique are also controversial, Dr. Maloney added.

WASHINGTON — Mobile-bearing knee implants are hyped in advertisements and demanded by patients, but the jury is still out on whether the devices deliver what's promised.

During a panel discussion on “controversial issues and hot topics” in primary total knee replacement at the annual meeting of the American Academy of Orthopaedic Surgeons, several panelists objected to the idea that rotating platform knee implants are superior in many ways to fixed-bearing designs.

“There's certainly some skepticism here about whether mobile-bearing designs are really more forgiving [of rotational misalignment of the femoral and tibial components] and whether there truly is less wear,” said William J. Maloney, M.D., professor of orthopedic surgery at Stanford (Calif.) University, who moderated the discussion.

Rotating platform, or mobile-bearing, knee replacements are designed for potentially longer performance with less wear to parts of the prosthesis. The devices have been marketed and are recommended by some physicians, particularly for younger, active, or overweight patients.

The mobile-bearing knees use three components—just like fixed-bearing replacements—but have a different bearing surface. The metallic femoral component and the metallic tibial tray both move across a mobile polyethylene insert. The insert creates a dual-surface articulation, absorbing force across a greater contact surface and ensuring congruent contact between the femoral and tibial components.

These implants, said panelist Douglas A. Dennis, M.D., “allow increased conformity in both planes without dramatically increasing fixation stresses and the risk of component loosening.”

This, he said, reduces polyethylene wear—which should be the focus of “any total knee design.” Polyethylene wear has been the major mode of total knee replacement failure, said Dr. Dennis, of the Rocky Mountain Musculoskeletal Research Laboratory in Denver.

“We have seen in our laboratory better kinematics in gait with mobile bearings. They're more tolerant of condylar lift-off, which should reduce the potential for polyethylene wear, and I think they're more forgiving of component rotational mal-alignment—the bearing has the potential to self-correct,” he said.

In a 10-year study of total knee replacements, Dr. Dennis and his colleagues found that mobile-bearing knees allow for a wider range of axial rotation without creating excessive polyethylene stresses. “A fairly large number [of mobile-bearing knees] rotated greater than 20 degrees, which is beyond the rotational boundaries of most fixed-bearing designs,” he said.

Arlen D. Hanssen, M.D., argued that several studies have shown no difference in motion and no difference in patello-femoral mechanics between fixed and mobile-bearing knees. Early dislocation and instability continue to be a problem with the rotating-platform knee, and recently there have been reports of late dislocation.

“Late dislocation occurs in this knee because of advanced wear,” said Dr. Hanssen, of the Mayo Clinic in Rochester, Minn.

“One of the reasons to use the rotating-platform knee has been to avoid osteolysis wear … but osteolysis seems to be significantly higher [in patients with the mobile-bearing knee],” he said.

The rigid tibial trays that are required in the rotating platform design also contribute to stress shielding of the proximal tibia, he said.

“Why would you take a knee that [has only been studied] in the elderly, has no better motion, no better patello-femoral mechanics, has the unique complication of dislocation and instability, and now appears to have some wear and osteolysis problems and stress shielding problems?” Dr. Hanssen asked. “My answer is no thanks.”

Other panelists agreed. “The advertisements say [the mobile-bearing knee] is the best thing, that it's going to give us 20 years,” said Merrill A. Ritter, M.D., of the Center for Hip and Knee Surgery in Mooresville, Ind. “There [are] no data to support this, and there are too many things that do work.”

Leo A. Whiteside, M.D., of the Missouri Bone and Joint Center in St. Louis, said that theoretically, the mobile-bearing design should perform better. “What worries me [are] the multiple reports of higher wear,” he said.

Bearing surface is just one of several choices surgeons make when performing total knee arthroplasty. The type of fixation, the modularity of implants, and surgical technique are also controversial, Dr. Maloney added.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who have the disorder.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates reviewed the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA).

The investigators then analyzed functional outcomes data collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores from parent PODCI forms revealed significant relationships between lumbar spine BMD and upper extremity function, and an analysis of scores from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used for baseline measurements and monitoring of patients who have osteogenesis imperfecta, but in the future more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who have the disorder.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates reviewed the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA).

The investigators then analyzed functional outcomes data collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores from parent PODCI forms revealed significant relationships between lumbar spine BMD and upper extremity function, and an analysis of scores from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used for baseline measurements and monitoring of patients who have osteogenesis imperfecta, but in the future more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who have the disorder.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates reviewed the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA).

The investigators then analyzed functional outcomes data collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores from parent PODCI forms revealed significant relationships between lumbar spine BMD and upper extremity function, and an analysis of scores from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used for baseline measurements and monitoring of patients who have osteogenesis imperfecta, but in the future more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who are afflicted with osteogenesis imperfecta.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates conducted a review of the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA). He and his coinvestigators then analyzed functional outcomes data that were collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores obtained from parent PODCI forms revealed that there were significant relationships between lumbar spine BMD and upper extremity function. In addition, an analysis of scores that were obtained from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed that there were significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used as a means of obtaining baseline measurements and for monitoring patients with osteogenesis imperfecta, but more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who are afflicted with osteogenesis imperfecta.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates conducted a review of the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA). He and his coinvestigators then analyzed functional outcomes data that were collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores obtained from parent PODCI forms revealed that there were significant relationships between lumbar spine BMD and upper extremity function. In addition, an analysis of scores that were obtained from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed that there were significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used as a means of obtaining baseline measurements and for monitoring patients with osteogenesis imperfecta, but more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Bone mineral density is directly tied to functional outcome and ability in children with osteogenesis imperfecta, Robert Huang, M.D., reported at the annual meeting of the American Academy of Orthopaedic Surgeons.

The findings lend credence to a current focus in treatment on improving bone mineral density (BMD) in children who are afflicted with osteogenesis imperfecta.

“Bisphosphonates have come to the forefront of treatment for osteogenesis imperfecta, but [we haven't known] the relationship of BMD ultimately to function,” said Dr. Huang of Houston Shriners Hospital.

Dr. Huang and his associates conducted a review of the records of 29 consecutive patients with osteogenesis imperfecta (ages 4–17) who underwent BMD assessment (mostly of the lumbar spine and wrist) using dual-energy x-ray absorptiometry (DXA). He and his coinvestigators then analyzed functional outcomes data that were collected using the Pediatric Outcomes Data Collection Instrument (PODCI).

Their analysis of scores obtained from parent PODCI forms revealed that there were significant relationships between lumbar spine BMD and upper extremity function. In addition, an analysis of scores that were obtained from the child PODCI scores (15 children were old enough to complete the child PODCI forms) revealed that there were significant relationships between wrist BMD and upper extremity function.

The investigators also found relationships between BMD and other functional domains within PODCI. “Certainly, BMD is an indicator of physical function,” Dr. Huang said.

DXA scanning is increasingly being used as a means of obtaining baseline measurements and for monitoring patients with osteogenesis imperfecta, but more “BMD data for children with osteogenesis imperfecta will be required to establish specific guidelines for the treatment of children with [the disorder],” he said.

Physicians who urged conservative treatment for neck pain—including a waiting period for imaging studies—were peppered with questions at the annual meeting of the American Academy of Orthopaedic Surgeons about how to determine whether and when neck pain originates from the disk.

“Unfortunately, we have no clear guidelines on how to determine whether neck pain is coming from the disk,” said Raj Rao, M.D. “If it's worse with extension, I'm more inclined to believe that this may be [disk-related] pain. But number one is just my instinctive feel.”

Dr. Rao, director of spine surgery at the Medical College of Wisconsin, Milwaukee, and Jeffrey C. Wang, M.D., had both emphasized during a session on the cervical spine that neck pain—which 50%–70% of people experience at some point—most often resolves with conservative measures.

“If there are no urgent findings, no history of trauma, no suspicion of neoplasm or infection, and [the patient doesn't] have a worsening neurologic deficit, there is an appropriate period of time you can wait before obtaining any imaging studies whatsoever,” said Dr. Wang, chief of the spine service at the UCLA School of Medicine.

He recommended waiting at least 4 weeks before performing plain radiography of the cervical spine and evaluating radiographs as thoroughly as possible before considering MRI.

“The newer thinking is that [in addition to many other factors] we want to look at the amount of space available for the spinal cord and the neurologic elements,” Dr. Wang said. “And remember, the oblique views are important.”

Despite recent concerns about nonsteroidal anti-inflammatory drugs, the drugs are still a first line of treatment for patients who have neck pain, Dr. Wang said.

Corticosteroids “do not have a role in neck pain alone without any neurologic symptoms,” and narcotics and muscle relaxants are appropriate only for short-term use, he said.

“Physical therapy,” he emphasized, “is very, very valuable. We can now send patients in the acute phase—there are many more modalities to control pain.”

Dr. Wang and Dr. Rao responded to physicians who said they were frustrated with patients involved in legal actions who seek their opinion on whether motor vehicle accidents caused their neck pain—and specifically whether the accidents caused disk herniations.

The two physicians urged their colleagues to be cautious. “My party-line answer is that I can't make a determination of whether [their neck pain] is caused by the accident. … And I rarely see patients with an acute herniated disk from a car accident,” Dr. Wang said.

“We have to remember we're dealing with pain. There are so many inputs,” Dr. Rao said. “It's very difficult to quantify how much of the pain is coming from the patient's neck, the patient's disk, and elsewhere.”

Studies show that one-third of patients who suffer whiplash in motor vehicle accidents will have symptoms for 1 year, and 25% will have symptoms for up to 2 years, Dr. Wang said.

The physicians also responded cautiously to a question from the session moderator Jeffrey S. Fischgrund, M.D., about the role of diskograms in evaluating neck pain.

“I'm sure that within 2 years, cervical disk replacements will become available, and there's no question that people will be looking at this as a treatment for neck pain. And I'm sure we'll see a lot more diskograms. … Will this be an option for people with neck pain?” said Dr. Fischgrund, who practices in Southfield, Mich.

Some physicians who practice at UCLA order diskograms of the cervical spine as they do of the lumbar spine, but “I tend not to get diskograms,” Dr. Wang observed. “I'm not quite sure what to make of them.”

MRI helps identify severe narrowing of the spinal cord. The circles highlight swelling.

A lateral x-ray shows degenerative changes of the cervical spine. Photos courtesy Dr. Jeffrey C. Wang

Physicians who urged conservative treatment for neck pain—including a waiting period for imaging studies—were peppered with questions at the annual meeting of the American Academy of Orthopaedic Surgeons about how to determine whether and when neck pain originates from the disk.

“Unfortunately, we have no clear guidelines on how to determine whether neck pain is coming from the disk,” said Raj Rao, M.D. “If it's worse with extension, I'm more inclined to believe that this may be [disk-related] pain. But number one is just my instinctive feel.”

Dr. Rao, director of spine surgery at the Medical College of Wisconsin, Milwaukee, and Jeffrey C. Wang, M.D., had both emphasized during a session on the cervical spine that neck pain—which 50%–70% of people experience at some point—most often resolves with conservative measures.

“If there are no urgent findings, no history of trauma, no suspicion of neoplasm or infection, and [the patient doesn't] have a worsening neurologic deficit, there is an appropriate period of time you can wait before obtaining any imaging studies whatsoever,” said Dr. Wang, chief of the spine service at the UCLA School of Medicine.

He recommended waiting at least 4 weeks before performing plain radiography of the cervical spine and evaluating radiographs as thoroughly as possible before considering MRI.

“The newer thinking is that [in addition to many other factors] we want to look at the amount of space available for the spinal cord and the neurologic elements,” Dr. Wang said. “And remember, the oblique views are important.”

Despite recent concerns about nonsteroidal anti-inflammatory drugs, the drugs are still a first line of treatment for patients who have neck pain, Dr. Wang said.

Corticosteroids “do not have a role in neck pain alone without any neurologic symptoms,” and narcotics and muscle relaxants are appropriate only for short-term use, he said.

“Physical therapy,” he emphasized, “is very, very valuable. We can now send patients in the acute phase—there are many more modalities to control pain.”

Dr. Wang and Dr. Rao responded to physicians who said they were frustrated with patients involved in legal actions who seek their opinion on whether motor vehicle accidents caused their neck pain—and specifically whether the accidents caused disk herniations.

The two physicians urged their colleagues to be cautious. “My party-line answer is that I can't make a determination of whether [their neck pain] is caused by the accident. … And I rarely see patients with an acute herniated disk from a car accident,” Dr. Wang said.

“We have to remember we're dealing with pain. There are so many inputs,” Dr. Rao said. “It's very difficult to quantify how much of the pain is coming from the patient's neck, the patient's disk, and elsewhere.”

Studies show that one-third of patients who suffer whiplash in motor vehicle accidents will have symptoms for 1 year, and 25% will have symptoms for up to 2 years, Dr. Wang said.

The physicians also responded cautiously to a question from the session moderator Jeffrey S. Fischgrund, M.D., about the role of diskograms in evaluating neck pain.

“I'm sure that within 2 years, cervical disk replacements will become available, and there's no question that people will be looking at this as a treatment for neck pain. And I'm sure we'll see a lot more diskograms. … Will this be an option for people with neck pain?” said Dr. Fischgrund, who practices in Southfield, Mich.

Some physicians who practice at UCLA order diskograms of the cervical spine as they do of the lumbar spine, but “I tend not to get diskograms,” Dr. Wang observed. “I'm not quite sure what to make of them.”

MRI helps identify severe narrowing of the spinal cord. The circles highlight swelling.

A lateral x-ray shows degenerative changes of the cervical spine. Photos courtesy Dr. Jeffrey C. Wang

Physicians who urged conservative treatment for neck pain—including a waiting period for imaging studies—were peppered with questions at the annual meeting of the American Academy of Orthopaedic Surgeons about how to determine whether and when neck pain originates from the disk.

“Unfortunately, we have no clear guidelines on how to determine whether neck pain is coming from the disk,” said Raj Rao, M.D. “If it's worse with extension, I'm more inclined to believe that this may be [disk-related] pain. But number one is just my instinctive feel.”

Dr. Rao, director of spine surgery at the Medical College of Wisconsin, Milwaukee, and Jeffrey C. Wang, M.D., had both emphasized during a session on the cervical spine that neck pain—which 50%–70% of people experience at some point—most often resolves with conservative measures.

“If there are no urgent findings, no history of trauma, no suspicion of neoplasm or infection, and [the patient doesn't] have a worsening neurologic deficit, there is an appropriate period of time you can wait before obtaining any imaging studies whatsoever,” said Dr. Wang, chief of the spine service at the UCLA School of Medicine.

He recommended waiting at least 4 weeks before performing plain radiography of the cervical spine and evaluating radiographs as thoroughly as possible before considering MRI.

“The newer thinking is that [in addition to many other factors] we want to look at the amount of space available for the spinal cord and the neurologic elements,” Dr. Wang said. “And remember, the oblique views are important.”

Despite recent concerns about nonsteroidal anti-inflammatory drugs, the drugs are still a first line of treatment for patients who have neck pain, Dr. Wang said.

Corticosteroids “do not have a role in neck pain alone without any neurologic symptoms,” and narcotics and muscle relaxants are appropriate only for short-term use, he said.

“Physical therapy,” he emphasized, “is very, very valuable. We can now send patients in the acute phase—there are many more modalities to control pain.”

Dr. Wang and Dr. Rao responded to physicians who said they were frustrated with patients involved in legal actions who seek their opinion on whether motor vehicle accidents caused their neck pain—and specifically whether the accidents caused disk herniations.

The two physicians urged their colleagues to be cautious. “My party-line answer is that I can't make a determination of whether [their neck pain] is caused by the accident. … And I rarely see patients with an acute herniated disk from a car accident,” Dr. Wang said.

“We have to remember we're dealing with pain. There are so many inputs,” Dr. Rao said. “It's very difficult to quantify how much of the pain is coming from the patient's neck, the patient's disk, and elsewhere.”

Studies show that one-third of patients who suffer whiplash in motor vehicle accidents will have symptoms for 1 year, and 25% will have symptoms for up to 2 years, Dr. Wang said.

The physicians also responded cautiously to a question from the session moderator Jeffrey S. Fischgrund, M.D., about the role of diskograms in evaluating neck pain.

“I'm sure that within 2 years, cervical disk replacements will become available, and there's no question that people will be looking at this as a treatment for neck pain. And I'm sure we'll see a lot more diskograms. … Will this be an option for people with neck pain?” said Dr. Fischgrund, who practices in Southfield, Mich.

Some physicians who practice at UCLA order diskograms of the cervical spine as they do of the lumbar spine, but “I tend not to get diskograms,” Dr. Wang observed. “I'm not quite sure what to make of them.”

MRI helps identify severe narrowing of the spinal cord. The circles highlight swelling.

A lateral x-ray shows degenerative changes of the cervical spine. Photos courtesy Dr. Jeffrey C. Wang

Prenatal exposure to combustion-related air pollution may cause chromosomal abnormalities in fetal tissue, according to findings from a study of 60 New York City newborns.

In studies of other populations, such abnormalities have been linked to an increased risk of leukemia and other cancers, said Kirsti A. Bocskay of the department of environmental health sciences at Columbia University, New York, and her colleagues.

The investigators monitored exposure to polycyclic aromatic hydrocarbons (PAHs)—pollutants found in emissions from cars and other vehicles, residential heating, power generation, and tobacco smoking—among nonsmoking African American and Dominican mothers living in three low-income neighborhoods in the city.

The mothers filled out questionnaires and wore portable air monitors for 48 hours during the third trimester. Chromosomal abnormalities were measured in umbilical cord blood obtained at delivery.

The investigators found 4.7 chromosome abnormalities per 1,000 white blood cells in newborns from mothers with low exposure to PAHs and 7.2 abnormalities per 1,000 white blood cells in newborns from mothers with high exposure to PAHs.

(“Low” exposure meant air pollution levels below the average, while “high” exposure referred to above-average levels).

In particular, it was stable chromosomal aberrations—not unstable aberrations—that were increased. Stable aberrations are persistent, rather than transient, markers of cytogenetic damage.

“This study has demonstrated a significant association between prenatal environmental exposure to airborne carcinogenic PAHs and stable aberrations in cord blood at the relatively low environmental concentrations found in New York City,” the investigators said (Cancer Epidemiol. Biomarkers Prev. 2005;14:506–11).

Prenatal exposure to combustion-related air pollution may cause chromosomal abnormalities in fetal tissue, according to findings from a study of 60 New York City newborns.

In studies of other populations, such abnormalities have been linked to an increased risk of leukemia and other cancers, said Kirsti A. Bocskay of the department of environmental health sciences at Columbia University, New York, and her colleagues.

The investigators monitored exposure to polycyclic aromatic hydrocarbons (PAHs)—pollutants found in emissions from cars and other vehicles, residential heating, power generation, and tobacco smoking—among nonsmoking African American and Dominican mothers living in three low-income neighborhoods in the city.

The mothers filled out questionnaires and wore portable air monitors for 48 hours during the third trimester. Chromosomal abnormalities were measured in umbilical cord blood obtained at delivery.

The investigators found 4.7 chromosome abnormalities per 1,000 white blood cells in newborns from mothers with low exposure to PAHs and 7.2 abnormalities per 1,000 white blood cells in newborns from mothers with high exposure to PAHs.

(“Low” exposure meant air pollution levels below the average, while “high” exposure referred to above-average levels).

In particular, it was stable chromosomal aberrations—not unstable aberrations—that were increased. Stable aberrations are persistent, rather than transient, markers of cytogenetic damage.

“This study has demonstrated a significant association between prenatal environmental exposure to airborne carcinogenic PAHs and stable aberrations in cord blood at the relatively low environmental concentrations found in New York City,” the investigators said (Cancer Epidemiol. Biomarkers Prev. 2005;14:506–11).

Prenatal exposure to combustion-related air pollution may cause chromosomal abnormalities in fetal tissue, according to findings from a study of 60 New York City newborns.

In studies of other populations, such abnormalities have been linked to an increased risk of leukemia and other cancers, said Kirsti A. Bocskay of the department of environmental health sciences at Columbia University, New York, and her colleagues.

The investigators monitored exposure to polycyclic aromatic hydrocarbons (PAHs)—pollutants found in emissions from cars and other vehicles, residential heating, power generation, and tobacco smoking—among nonsmoking African American and Dominican mothers living in three low-income neighborhoods in the city.

The mothers filled out questionnaires and wore portable air monitors for 48 hours during the third trimester. Chromosomal abnormalities were measured in umbilical cord blood obtained at delivery.

The investigators found 4.7 chromosome abnormalities per 1,000 white blood cells in newborns from mothers with low exposure to PAHs and 7.2 abnormalities per 1,000 white blood cells in newborns from mothers with high exposure to PAHs.

(“Low” exposure meant air pollution levels below the average, while “high” exposure referred to above-average levels).

In particular, it was stable chromosomal aberrations—not unstable aberrations—that were increased. Stable aberrations are persistent, rather than transient, markers of cytogenetic damage.

“This study has demonstrated a significant association between prenatal environmental exposure to airborne carcinogenic PAHs and stable aberrations in cord blood at the relatively low environmental concentrations found in New York City,” the investigators said (Cancer Epidemiol. Biomarkers Prev. 2005;14:506–11).