Rheumatoid Arthritis

KANANASKIS, ALTA. — The finding that the monoclonal antibody tocilizumab provided rapid and sustained improvement in the signs and symptoms of rheumatoid arthritis, regardless of patients' prior therapy, is not compelling enough to abandon methotrexate.

Dr. Robert McKendry said he was not convinced that he would turn to tocilizumab before methotrexate in rheumatoid arthritis patients.

“The difference between tocilizumab's efficacy and methotrexate's is real, but not necessarily dramatic,” according to Dr. McKendry, professor of medicine at the University of Ottawa.

“Moreover, most of these products—tocilizumab and others—work about 30% better when given with a background of methotrexate.

“So I think we're going to continue to do that until there's a reason not to,” Dr. McKendry said at the annual meeting of the Canadian Rheumatology Association.

Dr. McKendry made these remarks while presenting an analysis of data from more than 3,000 patients who used tocilizumab as monotherapy or in combination with disease modifying antirheumatic drugs (DMARDs) or methotrexate. The patients participated in any one of four phase III trials: TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), RADIATE (Research on Actemra [tocilizumab] Determining Efficacy After Anti-TNF [tumor necrosis factor] Failures), and AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), he said.

“This product has a unique mechanism of action in that it blocks the [interleukin-6] receptor, which is very important in many aspects of inflammation,” he said.

Each of the trials was randomized and double-blinded, and consisted of a 24-week study period in patients with moderate to severe active rheumatoid arthritis; each patient received a standardized tocilizumab IV dose of 8 mg/kg.

In TOWARD, patients with inadequate prior response to DMARDs received tocilizumab or placebo in combination with DMARDs. OPTION included methotrexate patients who received tocilizumab or placebo plus 10–25 mg/wk methotrexate.

In RADIATE, patients with moderate to severe RA who had an inadequate response to at least one anti-TNF agent received either tocilizumab or placebo plus 10–25 mg/wk methotrexate.

Finally, AMBITION assessed the effects of tocilizumab monotherapy every 4 weeks or methotrexate monotherapy (escalating dosage, 7.5–20 mg/wk) in patients who had not failed previous methotrexate or biologic treatment.

It was found that in all four studies, differences between the tocilizumab and control groups became apparent by the first scheduled assessment at week 2, regardless of prior therapy.

“I emphasize that [tocilizumab] works quickly, compared with other biologics,” Dr. McKendry said in an interview. “You get a significant response within the first 2 weeks, the first time you see the patient.” The studies showed that 17%–25% of patients on tocilizumab achieved an ACR 20 response in the first 2 weeks, compared with 7%–10% of controls.

ACR 50 and ACR 70 responses were observed in a greater percentage of tocilizumab patients than controls from weeks 4 and 8 onward. Patients treated with tocilizumab also demonstrated greater DAS28 improvements from baseline than did controls; DAS28 remission rates were also greater in tocilizumab patients by week 2.

Dr. McKendry had no disclosures to report.

KANANASKIS, ALTA. — The finding that the monoclonal antibody tocilizumab provided rapid and sustained improvement in the signs and symptoms of rheumatoid arthritis, regardless of patients' prior therapy, is not compelling enough to abandon methotrexate.

Dr. Robert McKendry said he was not convinced that he would turn to tocilizumab before methotrexate in rheumatoid arthritis patients.

“The difference between tocilizumab's efficacy and methotrexate's is real, but not necessarily dramatic,” according to Dr. McKendry, professor of medicine at the University of Ottawa.

“Moreover, most of these products—tocilizumab and others—work about 30% better when given with a background of methotrexate.

“So I think we're going to continue to do that until there's a reason not to,” Dr. McKendry said at the annual meeting of the Canadian Rheumatology Association.

Dr. McKendry made these remarks while presenting an analysis of data from more than 3,000 patients who used tocilizumab as monotherapy or in combination with disease modifying antirheumatic drugs (DMARDs) or methotrexate. The patients participated in any one of four phase III trials: TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), RADIATE (Research on Actemra [tocilizumab] Determining Efficacy After Anti-TNF [tumor necrosis factor] Failures), and AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), he said.

“This product has a unique mechanism of action in that it blocks the [interleukin-6] receptor, which is very important in many aspects of inflammation,” he said.

Each of the trials was randomized and double-blinded, and consisted of a 24-week study period in patients with moderate to severe active rheumatoid arthritis; each patient received a standardized tocilizumab IV dose of 8 mg/kg.

In TOWARD, patients with inadequate prior response to DMARDs received tocilizumab or placebo in combination with DMARDs. OPTION included methotrexate patients who received tocilizumab or placebo plus 10–25 mg/wk methotrexate.

In RADIATE, patients with moderate to severe RA who had an inadequate response to at least one anti-TNF agent received either tocilizumab or placebo plus 10–25 mg/wk methotrexate.

Finally, AMBITION assessed the effects of tocilizumab monotherapy every 4 weeks or methotrexate monotherapy (escalating dosage, 7.5–20 mg/wk) in patients who had not failed previous methotrexate or biologic treatment.

It was found that in all four studies, differences between the tocilizumab and control groups became apparent by the first scheduled assessment at week 2, regardless of prior therapy.

“I emphasize that [tocilizumab] works quickly, compared with other biologics,” Dr. McKendry said in an interview. “You get a significant response within the first 2 weeks, the first time you see the patient.” The studies showed that 17%–25% of patients on tocilizumab achieved an ACR 20 response in the first 2 weeks, compared with 7%–10% of controls.

ACR 50 and ACR 70 responses were observed in a greater percentage of tocilizumab patients than controls from weeks 4 and 8 onward. Patients treated with tocilizumab also demonstrated greater DAS28 improvements from baseline than did controls; DAS28 remission rates were also greater in tocilizumab patients by week 2.

Dr. McKendry had no disclosures to report.

KANANASKIS, ALTA. — The finding that the monoclonal antibody tocilizumab provided rapid and sustained improvement in the signs and symptoms of rheumatoid arthritis, regardless of patients' prior therapy, is not compelling enough to abandon methotrexate.

Dr. Robert McKendry said he was not convinced that he would turn to tocilizumab before methotrexate in rheumatoid arthritis patients.

“The difference between tocilizumab's efficacy and methotrexate's is real, but not necessarily dramatic,” according to Dr. McKendry, professor of medicine at the University of Ottawa.

“Moreover, most of these products—tocilizumab and others—work about 30% better when given with a background of methotrexate.

“So I think we're going to continue to do that until there's a reason not to,” Dr. McKendry said at the annual meeting of the Canadian Rheumatology Association.

Dr. McKendry made these remarks while presenting an analysis of data from more than 3,000 patients who used tocilizumab as monotherapy or in combination with disease modifying antirheumatic drugs (DMARDs) or methotrexate. The patients participated in any one of four phase III trials: TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), RADIATE (Research on Actemra [tocilizumab] Determining Efficacy After Anti-TNF [tumor necrosis factor] Failures), and AMBITION (Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy), he said.

“This product has a unique mechanism of action in that it blocks the [interleukin-6] receptor, which is very important in many aspects of inflammation,” he said.

Each of the trials was randomized and double-blinded, and consisted of a 24-week study period in patients with moderate to severe active rheumatoid arthritis; each patient received a standardized tocilizumab IV dose of 8 mg/kg.

In TOWARD, patients with inadequate prior response to DMARDs received tocilizumab or placebo in combination with DMARDs. OPTION included methotrexate patients who received tocilizumab or placebo plus 10–25 mg/wk methotrexate.

In RADIATE, patients with moderate to severe RA who had an inadequate response to at least one anti-TNF agent received either tocilizumab or placebo plus 10–25 mg/wk methotrexate.

Finally, AMBITION assessed the effects of tocilizumab monotherapy every 4 weeks or methotrexate monotherapy (escalating dosage, 7.5–20 mg/wk) in patients who had not failed previous methotrexate or biologic treatment.

It was found that in all four studies, differences between the tocilizumab and control groups became apparent by the first scheduled assessment at week 2, regardless of prior therapy.

“I emphasize that [tocilizumab] works quickly, compared with other biologics,” Dr. McKendry said in an interview. “You get a significant response within the first 2 weeks, the first time you see the patient.” The studies showed that 17%–25% of patients on tocilizumab achieved an ACR 20 response in the first 2 weeks, compared with 7%–10% of controls.

ACR 50 and ACR 70 responses were observed in a greater percentage of tocilizumab patients than controls from weeks 4 and 8 onward. Patients treated with tocilizumab also demonstrated greater DAS28 improvements from baseline than did controls; DAS28 remission rates were also greater in tocilizumab patients by week 2.

Dr. McKendry had no disclosures to report.

Despite having clinically well-controlled disease, more than half of patients with rheumatoid arthritis experience moderate to severe pain, and few take the medications necessary to control it, according to findings from a prospective study.

Patients and rheumatologists share the responsibility for inadequate pain control, Dr. Mary-Ann Fitzcharles and her colleagues found. Rheumatologists tend to ignore pain in favor of focusing on disease control, whereas patients are afraid of the very medications that could help control pain, wrote Dr. Fitzcharles of McGill University in Montreal (J. Pain 2009;10:300–5).

“Both rheumatologists and patients have been lulled into believing that pain is simply part of the condition,” she said in an interview. “Our patients were very, very cautious about pain medication. They are scared of addiction, they dislike taking even more pills, and they worry about drug interactions, side effects and masking disease progression. We rheumatologists, on the other hand, focus predominately on trying to control the inflammatory disease. We have not appreciated the importance of pain to these patients and simply don't ask about it.”

The study comprised 60 patients with RA who attended a specialist rheumatology practice. In all, 54 (90%) were women; their mean age was 57 years. They had been diagnosed with RA for a mean of 14 years. Most (54, or 90%) were taking disease-modifying antirheumatic drugs.

Patients were asked to complete several questionnaires about pain and quality of life, including the Health Assessment Questionnaire, McGill Pain Questionnaire, and a visual analogue pain scale. They were also asked about potential barriers to pain control with medications.

A seeming contradiction appeared almost immediately, Dr. Fitzcharles said. Despite 39 (65%) patients' reporting satisfaction with their pain control, 28 (47%) reported a desire for additional pain relief, and 32 (53%) reported experiencing moderate to severe pain. Almost half (45%) reported that the pain caused them moderate to severe distress, and the same percentage reported that pain exerted a moderate to severe interference with their daily activities.

“This was most striking,” she said. “They believed their pain was controlled, yet they were still having pain. And most were not using any modality to reduce the pain. Of the 60 patients, only 4 were taking anything stronger than acetaminophen.”

Patients expressed a high degree of concern about taking pain medications. More than half of the group (55%) expressed at least three barriers to taking such drugs. In all, 48 (80%) were worried about the side effects; 38 (63%) disliked taking even more pills; 34 (57%) worried about drug interactions; 21 (35%) had concerns about addiction; and 16 (27%) thought that controlling pain might mask disease progression. The higher the patient's pain level, the more barriers the patient felt toward controlling that pain.

Patients with RA seem to believe that pain is “an inevitable symptom,” and that little can be done about it, Dr. Fitzcharles and her colleagues wrote. “The importance of pain may also take second place to other effects of RA, including the impact on self-esteem due to deformity, the systemic effects of fatigue and depression, and functional limitations due to mechanical joint dysfunction.”

Rheumatologists can—and should—do more to investigate pain in their RA patients, the authors said. Patients should be specifically questioned about pain, because many will not volunteer this information. It's also a good idea to explore their worries about pain medication.

Despite having clinically well-controlled disease, more than half of patients with rheumatoid arthritis experience moderate to severe pain, and few take the medications necessary to control it, according to findings from a prospective study.

Patients and rheumatologists share the responsibility for inadequate pain control, Dr. Mary-Ann Fitzcharles and her colleagues found. Rheumatologists tend to ignore pain in favor of focusing on disease control, whereas patients are afraid of the very medications that could help control pain, wrote Dr. Fitzcharles of McGill University in Montreal (J. Pain 2009;10:300–5).

“Both rheumatologists and patients have been lulled into believing that pain is simply part of the condition,” she said in an interview. “Our patients were very, very cautious about pain medication. They are scared of addiction, they dislike taking even more pills, and they worry about drug interactions, side effects and masking disease progression. We rheumatologists, on the other hand, focus predominately on trying to control the inflammatory disease. We have not appreciated the importance of pain to these patients and simply don't ask about it.”

The study comprised 60 patients with RA who attended a specialist rheumatology practice. In all, 54 (90%) were women; their mean age was 57 years. They had been diagnosed with RA for a mean of 14 years. Most (54, or 90%) were taking disease-modifying antirheumatic drugs.

Patients were asked to complete several questionnaires about pain and quality of life, including the Health Assessment Questionnaire, McGill Pain Questionnaire, and a visual analogue pain scale. They were also asked about potential barriers to pain control with medications.

A seeming contradiction appeared almost immediately, Dr. Fitzcharles said. Despite 39 (65%) patients' reporting satisfaction with their pain control, 28 (47%) reported a desire for additional pain relief, and 32 (53%) reported experiencing moderate to severe pain. Almost half (45%) reported that the pain caused them moderate to severe distress, and the same percentage reported that pain exerted a moderate to severe interference with their daily activities.

“This was most striking,” she said. “They believed their pain was controlled, yet they were still having pain. And most were not using any modality to reduce the pain. Of the 60 patients, only 4 were taking anything stronger than acetaminophen.”

Patients expressed a high degree of concern about taking pain medications. More than half of the group (55%) expressed at least three barriers to taking such drugs. In all, 48 (80%) were worried about the side effects; 38 (63%) disliked taking even more pills; 34 (57%) worried about drug interactions; 21 (35%) had concerns about addiction; and 16 (27%) thought that controlling pain might mask disease progression. The higher the patient's pain level, the more barriers the patient felt toward controlling that pain.

Patients with RA seem to believe that pain is “an inevitable symptom,” and that little can be done about it, Dr. Fitzcharles and her colleagues wrote. “The importance of pain may also take second place to other effects of RA, including the impact on self-esteem due to deformity, the systemic effects of fatigue and depression, and functional limitations due to mechanical joint dysfunction.”

Rheumatologists can—and should—do more to investigate pain in their RA patients, the authors said. Patients should be specifically questioned about pain, because many will not volunteer this information. It's also a good idea to explore their worries about pain medication.

Despite having clinically well-controlled disease, more than half of patients with rheumatoid arthritis experience moderate to severe pain, and few take the medications necessary to control it, according to findings from a prospective study.

Patients and rheumatologists share the responsibility for inadequate pain control, Dr. Mary-Ann Fitzcharles and her colleagues found. Rheumatologists tend to ignore pain in favor of focusing on disease control, whereas patients are afraid of the very medications that could help control pain, wrote Dr. Fitzcharles of McGill University in Montreal (J. Pain 2009;10:300–5).

“Both rheumatologists and patients have been lulled into believing that pain is simply part of the condition,” she said in an interview. “Our patients were very, very cautious about pain medication. They are scared of addiction, they dislike taking even more pills, and they worry about drug interactions, side effects and masking disease progression. We rheumatologists, on the other hand, focus predominately on trying to control the inflammatory disease. We have not appreciated the importance of pain to these patients and simply don't ask about it.”

The study comprised 60 patients with RA who attended a specialist rheumatology practice. In all, 54 (90%) were women; their mean age was 57 years. They had been diagnosed with RA for a mean of 14 years. Most (54, or 90%) were taking disease-modifying antirheumatic drugs.

Patients were asked to complete several questionnaires about pain and quality of life, including the Health Assessment Questionnaire, McGill Pain Questionnaire, and a visual analogue pain scale. They were also asked about potential barriers to pain control with medications.

A seeming contradiction appeared almost immediately, Dr. Fitzcharles said. Despite 39 (65%) patients' reporting satisfaction with their pain control, 28 (47%) reported a desire for additional pain relief, and 32 (53%) reported experiencing moderate to severe pain. Almost half (45%) reported that the pain caused them moderate to severe distress, and the same percentage reported that pain exerted a moderate to severe interference with their daily activities.

“This was most striking,” she said. “They believed their pain was controlled, yet they were still having pain. And most were not using any modality to reduce the pain. Of the 60 patients, only 4 were taking anything stronger than acetaminophen.”

Patients expressed a high degree of concern about taking pain medications. More than half of the group (55%) expressed at least three barriers to taking such drugs. In all, 48 (80%) were worried about the side effects; 38 (63%) disliked taking even more pills; 34 (57%) worried about drug interactions; 21 (35%) had concerns about addiction; and 16 (27%) thought that controlling pain might mask disease progression. The higher the patient's pain level, the more barriers the patient felt toward controlling that pain.

Patients with RA seem to believe that pain is “an inevitable symptom,” and that little can be done about it, Dr. Fitzcharles and her colleagues wrote. “The importance of pain may also take second place to other effects of RA, including the impact on self-esteem due to deformity, the systemic effects of fatigue and depression, and functional limitations due to mechanical joint dysfunction.”

Rheumatologists can—and should—do more to investigate pain in their RA patients, the authors said. Patients should be specifically questioned about pain, because many will not volunteer this information. It's also a good idea to explore their worries about pain medication.

KANANASKIS, ALTA. — Rheumatologists' best hope for dealing with the coming deluge of joint disease is to use physician extenders to triage patients and oversee their physical therapy.

A report by the American College of Rheumatology has anticipated a significant shortage of rheumatologists that will begin after 2010 and continue for at least 20 years. In 2006, when the report was published, fellows of the ACR averaged 56 years of age. Rheumatology is one of many specialties with projected shortfalls of physicians that may reach 200,000 by 2025, according to the ACR (Arthritis Rheum. 2007;56:722–9).

“The challenge is in determining who is going to do what. Fortunately, we now have some evidence to show that doing things differently can help facilitate the delivery of these interventions to more people in a more timely manner,” Linda Li, Ph.D., said at the annual meeting of the Canadian Rheumatology Association.

Dr. Li and her associates developed an integrated framework for rheumatoid arthritis treatment to shorten the delays between various levels of care, based on a review of the literature (Arthritis Rheum. 2008;59:1171–83).

The framework begins at the community level, where health care services should provide information to patients during the interval between symptom onset and the first visit to a primary care physician. “Some interventions involve using community therapists, pharmacists, and nurses to facilitate the transition from community to primary care,” noted Dr. Li, the Harold Robinson/Arthritis Society Chair in Arthritic Diseases at the University of British Columbia, Vancouver.

One study looked at the use of community pharmacists to disseminate information about the relationship between knee pain and osteoarthritis (Arthritis Rheum. 2007;57:1238–44). A simple screening questionnaire found that 190 (98%) of 194 patients who indicated knee pain met ACR clinical criteria for knee osteoarthritis.

At the primary care level, where specially trained nurses triaged rheumatology referrals using standardized guidelines, the rate of appropriate referrals increased from 50% to 90% within 2 years (Rheumatology [Oxford] 2003;42:763–8).

Another study found that specially trained physical therapists reduced referrals to orthopedists by 17% and to rheumatologists by 8%, compared with the conventional model of direct referral from general practitioners to hospital departments (Am. J. Phys. Med. Rehabil. 2005;84:702–11).

Secondary care focuses on self-management and follow-up assessments, yet another area where nonphysicians can play a role in effective clinical care, Dr. Li said. This frees up rheumatologists to see the sickest people, she added.

Dr. Linda Li is supported by the Harold Robinson/Arthritis Society Chair in Arthritic Diseases, a Canadian Institutes of Health Research (CIHR) New Investigator Award, and an American College of Rheumatology Research & Education Foundation Health Professional New Investigator Award.

KANANASKIS, ALTA. — Rheumatologists' best hope for dealing with the coming deluge of joint disease is to use physician extenders to triage patients and oversee their physical therapy.

A report by the American College of Rheumatology has anticipated a significant shortage of rheumatologists that will begin after 2010 and continue for at least 20 years. In 2006, when the report was published, fellows of the ACR averaged 56 years of age. Rheumatology is one of many specialties with projected shortfalls of physicians that may reach 200,000 by 2025, according to the ACR (Arthritis Rheum. 2007;56:722–9).

“The challenge is in determining who is going to do what. Fortunately, we now have some evidence to show that doing things differently can help facilitate the delivery of these interventions to more people in a more timely manner,” Linda Li, Ph.D., said at the annual meeting of the Canadian Rheumatology Association.

Dr. Li and her associates developed an integrated framework for rheumatoid arthritis treatment to shorten the delays between various levels of care, based on a review of the literature (Arthritis Rheum. 2008;59:1171–83).

The framework begins at the community level, where health care services should provide information to patients during the interval between symptom onset and the first visit to a primary care physician. “Some interventions involve using community therapists, pharmacists, and nurses to facilitate the transition from community to primary care,” noted Dr. Li, the Harold Robinson/Arthritis Society Chair in Arthritic Diseases at the University of British Columbia, Vancouver.

One study looked at the use of community pharmacists to disseminate information about the relationship between knee pain and osteoarthritis (Arthritis Rheum. 2007;57:1238–44). A simple screening questionnaire found that 190 (98%) of 194 patients who indicated knee pain met ACR clinical criteria for knee osteoarthritis.

At the primary care level, where specially trained nurses triaged rheumatology referrals using standardized guidelines, the rate of appropriate referrals increased from 50% to 90% within 2 years (Rheumatology [Oxford] 2003;42:763–8).

Another study found that specially trained physical therapists reduced referrals to orthopedists by 17% and to rheumatologists by 8%, compared with the conventional model of direct referral from general practitioners to hospital departments (Am. J. Phys. Med. Rehabil. 2005;84:702–11).

Secondary care focuses on self-management and follow-up assessments, yet another area where nonphysicians can play a role in effective clinical care, Dr. Li said. This frees up rheumatologists to see the sickest people, she added.

Dr. Linda Li is supported by the Harold Robinson/Arthritis Society Chair in Arthritic Diseases, a Canadian Institutes of Health Research (CIHR) New Investigator Award, and an American College of Rheumatology Research & Education Foundation Health Professional New Investigator Award.

KANANASKIS, ALTA. — Rheumatologists' best hope for dealing with the coming deluge of joint disease is to use physician extenders to triage patients and oversee their physical therapy.

A report by the American College of Rheumatology has anticipated a significant shortage of rheumatologists that will begin after 2010 and continue for at least 20 years. In 2006, when the report was published, fellows of the ACR averaged 56 years of age. Rheumatology is one of many specialties with projected shortfalls of physicians that may reach 200,000 by 2025, according to the ACR (Arthritis Rheum. 2007;56:722–9).

“The challenge is in determining who is going to do what. Fortunately, we now have some evidence to show that doing things differently can help facilitate the delivery of these interventions to more people in a more timely manner,” Linda Li, Ph.D., said at the annual meeting of the Canadian Rheumatology Association.

Dr. Li and her associates developed an integrated framework for rheumatoid arthritis treatment to shorten the delays between various levels of care, based on a review of the literature (Arthritis Rheum. 2008;59:1171–83).

The framework begins at the community level, where health care services should provide information to patients during the interval between symptom onset and the first visit to a primary care physician. “Some interventions involve using community therapists, pharmacists, and nurses to facilitate the transition from community to primary care,” noted Dr. Li, the Harold Robinson/Arthritis Society Chair in Arthritic Diseases at the University of British Columbia, Vancouver.

One study looked at the use of community pharmacists to disseminate information about the relationship between knee pain and osteoarthritis (Arthritis Rheum. 2007;57:1238–44). A simple screening questionnaire found that 190 (98%) of 194 patients who indicated knee pain met ACR clinical criteria for knee osteoarthritis.

At the primary care level, where specially trained nurses triaged rheumatology referrals using standardized guidelines, the rate of appropriate referrals increased from 50% to 90% within 2 years (Rheumatology [Oxford] 2003;42:763–8).

Another study found that specially trained physical therapists reduced referrals to orthopedists by 17% and to rheumatologists by 8%, compared with the conventional model of direct referral from general practitioners to hospital departments (Am. J. Phys. Med. Rehabil. 2005;84:702–11).

Secondary care focuses on self-management and follow-up assessments, yet another area where nonphysicians can play a role in effective clinical care, Dr. Li said. This frees up rheumatologists to see the sickest people, she added.

Dr. Linda Li is supported by the Harold Robinson/Arthritis Society Chair in Arthritic Diseases, a Canadian Institutes of Health Research (CIHR) New Investigator Award, and an American College of Rheumatology Research & Education Foundation Health Professional New Investigator Award.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

FORT LAUDERDALE, FLA. — The use of magnetic resonance imaging has provided a keyhole view into the early pathological events of rheumatoid arthritis, long before structural damage becomes evident on conventional radiography, according to recent research.

MRI has yet to be as fully embraced by rheumatologists as it has been in other specialties, according to Dr. Norman B. Gaylis. “I believe that we are going to catch up, however, and our approach to management of rheumatoid arthritis will be more like that used for other systemic diseases such as lymphoma,” Dr. Gaylis said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Conventional radiography cannot visualize bone marrow edema in rheumatoid arthritis (RA). “Bone marrow edema may be the best biomarker that we haven't been using in the management of rheumatoid arthritis,” said Dr. Gaylis, who is in private practice in Aventura, Fla.

Bone marrow edema in RA was first recognized in a cohort of patients from New Zealand who had MRI scans of the wrist at the time of diagnosis (Ann. Rheum. Dis. 1998;57:350–6).

The lymphocyte and osteoclast infiltration in the subchondral bone seen in bone marrow edema suggests that this might be the site for important pathological events driving the rheumatologic joint damage in RA.

Bone marrow edema also is more predictive of later MRI-detected erosions than is any other clinical feature, including disease activity score, C-reactive protein, or anticyclic citrullinated peptide antibody, and it predicts functional disability at 6 years more closely than does other MRI features such as synovitis and tendinitis (Ann. Rheum. Dis. 2004;63:555–61).

Dr. Gaylis stated that he had no conflicts of interest. SDEF and this news organization are owned by Elsevier.

To view a video interview of Dr. Gaylis, go to http://www.youtube.com/watch?v=IObehXizRQg

Bone marrow edema on MRI predicts both joint damage and disability better than clinical features. DR. GAYLIS

FORT LAUDERDALE, FLA. — The use of magnetic resonance imaging has provided a keyhole view into the early pathological events of rheumatoid arthritis, long before structural damage becomes evident on conventional radiography, according to recent research.

MRI has yet to be as fully embraced by rheumatologists as it has been in other specialties, according to Dr. Norman B. Gaylis. “I believe that we are going to catch up, however, and our approach to management of rheumatoid arthritis will be more like that used for other systemic diseases such as lymphoma,” Dr. Gaylis said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Conventional radiography cannot visualize bone marrow edema in rheumatoid arthritis (RA). “Bone marrow edema may be the best biomarker that we haven't been using in the management of rheumatoid arthritis,” said Dr. Gaylis, who is in private practice in Aventura, Fla.

Bone marrow edema in RA was first recognized in a cohort of patients from New Zealand who had MRI scans of the wrist at the time of diagnosis (Ann. Rheum. Dis. 1998;57:350–6).

The lymphocyte and osteoclast infiltration in the subchondral bone seen in bone marrow edema suggests that this might be the site for important pathological events driving the rheumatologic joint damage in RA.

Bone marrow edema also is more predictive of later MRI-detected erosions than is any other clinical feature, including disease activity score, C-reactive protein, or anticyclic citrullinated peptide antibody, and it predicts functional disability at 6 years more closely than does other MRI features such as synovitis and tendinitis (Ann. Rheum. Dis. 2004;63:555–61).

Dr. Gaylis stated that he had no conflicts of interest. SDEF and this news organization are owned by Elsevier.

To view a video interview of Dr. Gaylis, go to http://www.youtube.com/watch?v=IObehXizRQg

Bone marrow edema on MRI predicts both joint damage and disability better than clinical features. DR. GAYLIS

FORT LAUDERDALE, FLA. — The use of magnetic resonance imaging has provided a keyhole view into the early pathological events of rheumatoid arthritis, long before structural damage becomes evident on conventional radiography, according to recent research.

MRI has yet to be as fully embraced by rheumatologists as it has been in other specialties, according to Dr. Norman B. Gaylis. “I believe that we are going to catch up, however, and our approach to management of rheumatoid arthritis will be more like that used for other systemic diseases such as lymphoma,” Dr. Gaylis said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Conventional radiography cannot visualize bone marrow edema in rheumatoid arthritis (RA). “Bone marrow edema may be the best biomarker that we haven't been using in the management of rheumatoid arthritis,” said Dr. Gaylis, who is in private practice in Aventura, Fla.

Bone marrow edema in RA was first recognized in a cohort of patients from New Zealand who had MRI scans of the wrist at the time of diagnosis (Ann. Rheum. Dis. 1998;57:350–6).

The lymphocyte and osteoclast infiltration in the subchondral bone seen in bone marrow edema suggests that this might be the site for important pathological events driving the rheumatologic joint damage in RA.

Bone marrow edema also is more predictive of later MRI-detected erosions than is any other clinical feature, including disease activity score, C-reactive protein, or anticyclic citrullinated peptide antibody, and it predicts functional disability at 6 years more closely than does other MRI features such as synovitis and tendinitis (Ann. Rheum. Dis. 2004;63:555–61).

Dr. Gaylis stated that he had no conflicts of interest. SDEF and this news organization are owned by Elsevier.

To view a video interview of Dr. Gaylis, go to http://www.youtube.com/watch?v=IObehXizRQg

Bone marrow edema on MRI predicts both joint damage and disability better than clinical features. DR. GAYLIS

Rheumatoid arthritis patients with comorbid depression and/or cardiovascular disease accumulated thousands more dollars in annual health care costs than did their peers with RA alone.

This finding is based on a study of over 10,000 people with rheumatoid arthritis conducted by Amie T. Joyce of Pharmetrics Inc., Watertown, Mass., and her associates.

In an interview, Edward H. Yelin, Ph.D., an expert on the economic impacts of chronic diseases who was asked by this publication to comment on this research, said “We are seeing increasingly that inflammation [is present in] many chronic diseases and, thus, it is impossible to separate out specific illness costs perfectly.”

Rheumatologists can help bring down utilization costs for these patients “by treating the whole person, rather than just the single most pressing condition,” said Dr. Yelin, who was not involved in the study. He is professor in residence of medicine and health policy in the division of rheumatology at the University of California, San Francisco.

Dr. Joyce's study looked at 10,298 RA patients culled from PharMetrics Inc.'s patient-centric database from 2001 to 2005. The database contains medical and pharmaceutical claims from 92 health plans across the United States. Of the sample, 8,916 patients (87%) had RA alone, 608 (6%) had RA with CVD, 716 (7%) had RA with depression, and 58 (0.6%) patients had all three conditions.

The annual cost for patients with RA alone was $14,257 vs. $21,410 for patients with RA plus depression, $24,444 for patients with RA plus CVD, and $35,246 for all three conditions.

Patients with RA plus depression had higher annual RA-specific costs than did patients with RA alone ($9,940 vs. $9,322; P = .014), and the RA-specific costs increased even more in patients with all three conditions, to $12,318 (P = .012). That effect was not seen in the RA plus CVD group (J. Rheumatol. 2009 Feb. 15 [doi:10.3899/jrheum.080670]).

Hospitalization contributed to the increased costs. Just 8% of patients with RA alone had a hospital stay in the 12 months prior to their index date (the date of the patient's first claim with an RA diagnosis). In the RA plus CVD cohort, this jumped to 35%. In the RA plus depression cohort, it was 19%, and among the patients who had all three diagnoses, 60% were hospitalized during that 12-month period. (For all rates, P was less than .001.)

The average number of prescriptions filled also increased with increasing comorbidities. RA-only patients filled an average of 46.8 prescriptions in the 12 months following RA diagnosis, compared with 69.2 in the RA plus CVD group, 71.3 in the RA plus depression group, and 114.3 in the RA plus depression plus CVD group.

The authors disclosed funding from Wyeth Research. Three of the authors are also Wyeth Research employees.

Rheumatoid arthritis patients with comorbid depression and/or cardiovascular disease accumulated thousands more dollars in annual health care costs than did their peers with RA alone.

This finding is based on a study of over 10,000 people with rheumatoid arthritis conducted by Amie T. Joyce of Pharmetrics Inc., Watertown, Mass., and her associates.

In an interview, Edward H. Yelin, Ph.D., an expert on the economic impacts of chronic diseases who was asked by this publication to comment on this research, said “We are seeing increasingly that inflammation [is present in] many chronic diseases and, thus, it is impossible to separate out specific illness costs perfectly.”

Rheumatologists can help bring down utilization costs for these patients “by treating the whole person, rather than just the single most pressing condition,” said Dr. Yelin, who was not involved in the study. He is professor in residence of medicine and health policy in the division of rheumatology at the University of California, San Francisco.

Dr. Joyce's study looked at 10,298 RA patients culled from PharMetrics Inc.'s patient-centric database from 2001 to 2005. The database contains medical and pharmaceutical claims from 92 health plans across the United States. Of the sample, 8,916 patients (87%) had RA alone, 608 (6%) had RA with CVD, 716 (7%) had RA with depression, and 58 (0.6%) patients had all three conditions.

The annual cost for patients with RA alone was $14,257 vs. $21,410 for patients with RA plus depression, $24,444 for patients with RA plus CVD, and $35,246 for all three conditions.

Patients with RA plus depression had higher annual RA-specific costs than did patients with RA alone ($9,940 vs. $9,322; P = .014), and the RA-specific costs increased even more in patients with all three conditions, to $12,318 (P = .012). That effect was not seen in the RA plus CVD group (J. Rheumatol. 2009 Feb. 15 [doi:10.3899/jrheum.080670]).

Hospitalization contributed to the increased costs. Just 8% of patients with RA alone had a hospital stay in the 12 months prior to their index date (the date of the patient's first claim with an RA diagnosis). In the RA plus CVD cohort, this jumped to 35%. In the RA plus depression cohort, it was 19%, and among the patients who had all three diagnoses, 60% were hospitalized during that 12-month period. (For all rates, P was less than .001.)

The average number of prescriptions filled also increased with increasing comorbidities. RA-only patients filled an average of 46.8 prescriptions in the 12 months following RA diagnosis, compared with 69.2 in the RA plus CVD group, 71.3 in the RA plus depression group, and 114.3 in the RA plus depression plus CVD group.

The authors disclosed funding from Wyeth Research. Three of the authors are also Wyeth Research employees.

Rheumatoid arthritis patients with comorbid depression and/or cardiovascular disease accumulated thousands more dollars in annual health care costs than did their peers with RA alone.

This finding is based on a study of over 10,000 people with rheumatoid arthritis conducted by Amie T. Joyce of Pharmetrics Inc., Watertown, Mass., and her associates.

In an interview, Edward H. Yelin, Ph.D., an expert on the economic impacts of chronic diseases who was asked by this publication to comment on this research, said “We are seeing increasingly that inflammation [is present in] many chronic diseases and, thus, it is impossible to separate out specific illness costs perfectly.”

Rheumatologists can help bring down utilization costs for these patients “by treating the whole person, rather than just the single most pressing condition,” said Dr. Yelin, who was not involved in the study. He is professor in residence of medicine and health policy in the division of rheumatology at the University of California, San Francisco.

Dr. Joyce's study looked at 10,298 RA patients culled from PharMetrics Inc.'s patient-centric database from 2001 to 2005. The database contains medical and pharmaceutical claims from 92 health plans across the United States. Of the sample, 8,916 patients (87%) had RA alone, 608 (6%) had RA with CVD, 716 (7%) had RA with depression, and 58 (0.6%) patients had all three conditions.

The annual cost for patients with RA alone was $14,257 vs. $21,410 for patients with RA plus depression, $24,444 for patients with RA plus CVD, and $35,246 for all three conditions.

Patients with RA plus depression had higher annual RA-specific costs than did patients with RA alone ($9,940 vs. $9,322; P = .014), and the RA-specific costs increased even more in patients with all three conditions, to $12,318 (P = .012). That effect was not seen in the RA plus CVD group (J. Rheumatol. 2009 Feb. 15 [doi:10.3899/jrheum.080670]).

Hospitalization contributed to the increased costs. Just 8% of patients with RA alone had a hospital stay in the 12 months prior to their index date (the date of the patient's first claim with an RA diagnosis). In the RA plus CVD cohort, this jumped to 35%. In the RA plus depression cohort, it was 19%, and among the patients who had all three diagnoses, 60% were hospitalized during that 12-month period. (For all rates, P was less than .001.)

The average number of prescriptions filled also increased with increasing comorbidities. RA-only patients filled an average of 46.8 prescriptions in the 12 months following RA diagnosis, compared with 69.2 in the RA plus CVD group, 71.3 in the RA plus depression group, and 114.3 in the RA plus depression plus CVD group.

The authors disclosed funding from Wyeth Research. Three of the authors are also Wyeth Research employees.

FORT LAUDERDALE, FLA. — The treatment of ankylosing spondylitis should include both pharmacologic and nonpharmacologic modalities tailored to the current manifestations of the disease, and should reflect the wishes and expectations of the patient, according to Dr. Tore K. Kvien.

All domains of health status are affected by the disease, from bodily pain to social functioning, according to findings from a survey of patients with ankylosing spondylitis (AS). Interrupted sleep was the most frequently reported problem, surpassing difficulties in climbing stairs and getting out of bed.

“A way of addressing the complexity of this disease and prioritizing our treatment is by asking not only how the patient feels and is doing, but also asking about their priorities in treatment and what issues are most important to them,” said Dr. Kvien, professor of rheumatology, University of Oslo, and past president of EULAR as well as editor of the Annals of the Rheumatic Diseases.

“The optimal management of AS requires a combination of nonpharmacologic and pharmacologic modalities, with nonpharmacologic strategies possibly being more important than in many of the other diseases we treat,” Dr. Kvien said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Exercise is crucial for these patients and is most beneficial in a formalized program. An updated Cochrane review of physiotherapy in AS recently concluded that individual home-based exercise is better than no exercise, that supervised group physiotherapy is preferable to home exercise, and that pool exercise followed by group physiotherapy is better than group exercise alone (Cochrane Database Syst. Rev. 2008 Jan. 23;CD002822).

The most effective medical treatments in AS differ from those for rheumatoid arthritis (RA), clinicians have learned. For example, the Assessment in Ankylosing Spondylitis International Working Group recommends nonsteroidal anti-inflammatory drugs as first-line treatment for pain and stiffness, and, as such, NSAIDs represent a more prominent component of treatment in AS than in RA. Corticosteroid injections also are recommended, but evidence does not support the use of systemic steroids for axial disease, said Dr. Kvien, also head of rheumatology, Diakonhjemmet Hospital, Oslo.

Conventional disease-modifying antirheumatic drugs (DMARDs) play a less prominent role in AS, with evidence of their efficacy being much weaker than in RA. Some recent studies, however, have suggested that sulfasalazine or methotrexate may be useful for patients with peripheral arthritis, Dr. Kvien said.

A further difference in treatment strategy compared with RA is that there is no requirement for a prior trial of DMARDs before initiating anti-tumor necrosis factor (TNF) therapy in the patient with a persistently high level of AS disease activity. There also is no evidence that combination therapy with a TNF inhibitor and a DMARD is better than the biologic alone.

All three of the available TNF inhibitors have demonstrated efficacy, and there has been no suggestion from the clinical trials that there are any differences in efficacy among them. One special circumstance is for the patient with acute anterior uveitis, however. “Some data suggest that in a patient with ongoing uveitis, the antibodies [infliximab and adalimumab] may be more effective than etanercept, but if the patient just has a history of one attack, you can use whatever you like,” Dr. Kvien said. The same general safety concerns exist for the use of these drugs in AS as in RA, he added.

Increasing experience with TNF inhibitors in AS also has shown that they are associated with greater improvements in health-related quality of life than in RA. “Our data from observational studies have shown that the improvements on all dimensions of the [Short Form Health Survey] SF-36 were greater in patients with AS than in those with RA,” he said. Differences were most notable on scores for emotional role, physical functioning, physical role, and vitality (Arthritis Rheum. 2005;52:2506–12).

Drug retention rates for the TNF inhibitors also are better for AS than for either RA or psoriatic arthritis, said Dr. Kvien. In another observational study, unadjusted 1-year retention rates were 77.5%, 77.3%, and 65.4%, in the AS, psoriatic arthritis, and RA groups, respectively, while adjusted hazard ratios for treatment termination were 0.76 for psoriatic arthritis versus RA and 0.66 for AS versus RA (Arthritis Rheum. 2008;59:234–40).

Dr. Kvien disclosed that he receives grant research support from, and acts as a consultant to, several companies, including Abbott Laboratories, Hoffmann-La Roche Inc., and Wyeth.

SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — The treatment of ankylosing spondylitis should include both pharmacologic and nonpharmacologic modalities tailored to the current manifestations of the disease, and should reflect the wishes and expectations of the patient, according to Dr. Tore K. Kvien.

All domains of health status are affected by the disease, from bodily pain to social functioning, according to findings from a survey of patients with ankylosing spondylitis (AS). Interrupted sleep was the most frequently reported problem, surpassing difficulties in climbing stairs and getting out of bed.

“A way of addressing the complexity of this disease and prioritizing our treatment is by asking not only how the patient feels and is doing, but also asking about their priorities in treatment and what issues are most important to them,” said Dr. Kvien, professor of rheumatology, University of Oslo, and past president of EULAR as well as editor of the Annals of the Rheumatic Diseases.

“The optimal management of AS requires a combination of nonpharmacologic and pharmacologic modalities, with nonpharmacologic strategies possibly being more important than in many of the other diseases we treat,” Dr. Kvien said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Exercise is crucial for these patients and is most beneficial in a formalized program. An updated Cochrane review of physiotherapy in AS recently concluded that individual home-based exercise is better than no exercise, that supervised group physiotherapy is preferable to home exercise, and that pool exercise followed by group physiotherapy is better than group exercise alone (Cochrane Database Syst. Rev. 2008 Jan. 23;CD002822).

The most effective medical treatments in AS differ from those for rheumatoid arthritis (RA), clinicians have learned. For example, the Assessment in Ankylosing Spondylitis International Working Group recommends nonsteroidal anti-inflammatory drugs as first-line treatment for pain and stiffness, and, as such, NSAIDs represent a more prominent component of treatment in AS than in RA. Corticosteroid injections also are recommended, but evidence does not support the use of systemic steroids for axial disease, said Dr. Kvien, also head of rheumatology, Diakonhjemmet Hospital, Oslo.

Conventional disease-modifying antirheumatic drugs (DMARDs) play a less prominent role in AS, with evidence of their efficacy being much weaker than in RA. Some recent studies, however, have suggested that sulfasalazine or methotrexate may be useful for patients with peripheral arthritis, Dr. Kvien said.

A further difference in treatment strategy compared with RA is that there is no requirement for a prior trial of DMARDs before initiating anti-tumor necrosis factor (TNF) therapy in the patient with a persistently high level of AS disease activity. There also is no evidence that combination therapy with a TNF inhibitor and a DMARD is better than the biologic alone.

All three of the available TNF inhibitors have demonstrated efficacy, and there has been no suggestion from the clinical trials that there are any differences in efficacy among them. One special circumstance is for the patient with acute anterior uveitis, however. “Some data suggest that in a patient with ongoing uveitis, the antibodies [infliximab and adalimumab] may be more effective than etanercept, but if the patient just has a history of one attack, you can use whatever you like,” Dr. Kvien said. The same general safety concerns exist for the use of these drugs in AS as in RA, he added.

Increasing experience with TNF inhibitors in AS also has shown that they are associated with greater improvements in health-related quality of life than in RA. “Our data from observational studies have shown that the improvements on all dimensions of the [Short Form Health Survey] SF-36 were greater in patients with AS than in those with RA,” he said. Differences were most notable on scores for emotional role, physical functioning, physical role, and vitality (Arthritis Rheum. 2005;52:2506–12).

Drug retention rates for the TNF inhibitors also are better for AS than for either RA or psoriatic arthritis, said Dr. Kvien. In another observational study, unadjusted 1-year retention rates were 77.5%, 77.3%, and 65.4%, in the AS, psoriatic arthritis, and RA groups, respectively, while adjusted hazard ratios for treatment termination were 0.76 for psoriatic arthritis versus RA and 0.66 for AS versus RA (Arthritis Rheum. 2008;59:234–40).

Dr. Kvien disclosed that he receives grant research support from, and acts as a consultant to, several companies, including Abbott Laboratories, Hoffmann-La Roche Inc., and Wyeth.

SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — The treatment of ankylosing spondylitis should include both pharmacologic and nonpharmacologic modalities tailored to the current manifestations of the disease, and should reflect the wishes and expectations of the patient, according to Dr. Tore K. Kvien.

All domains of health status are affected by the disease, from bodily pain to social functioning, according to findings from a survey of patients with ankylosing spondylitis (AS). Interrupted sleep was the most frequently reported problem, surpassing difficulties in climbing stairs and getting out of bed.

“A way of addressing the complexity of this disease and prioritizing our treatment is by asking not only how the patient feels and is doing, but also asking about their priorities in treatment and what issues are most important to them,” said Dr. Kvien, professor of rheumatology, University of Oslo, and past president of EULAR as well as editor of the Annals of the Rheumatic Diseases.

“The optimal management of AS requires a combination of nonpharmacologic and pharmacologic modalities, with nonpharmacologic strategies possibly being more important than in many of the other diseases we treat,” Dr. Kvien said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Exercise is crucial for these patients and is most beneficial in a formalized program. An updated Cochrane review of physiotherapy in AS recently concluded that individual home-based exercise is better than no exercise, that supervised group physiotherapy is preferable to home exercise, and that pool exercise followed by group physiotherapy is better than group exercise alone (Cochrane Database Syst. Rev. 2008 Jan. 23;CD002822).

The most effective medical treatments in AS differ from those for rheumatoid arthritis (RA), clinicians have learned. For example, the Assessment in Ankylosing Spondylitis International Working Group recommends nonsteroidal anti-inflammatory drugs as first-line treatment for pain and stiffness, and, as such, NSAIDs represent a more prominent component of treatment in AS than in RA. Corticosteroid injections also are recommended, but evidence does not support the use of systemic steroids for axial disease, said Dr. Kvien, also head of rheumatology, Diakonhjemmet Hospital, Oslo.

Conventional disease-modifying antirheumatic drugs (DMARDs) play a less prominent role in AS, with evidence of their efficacy being much weaker than in RA. Some recent studies, however, have suggested that sulfasalazine or methotrexate may be useful for patients with peripheral arthritis, Dr. Kvien said.

A further difference in treatment strategy compared with RA is that there is no requirement for a prior trial of DMARDs before initiating anti-tumor necrosis factor (TNF) therapy in the patient with a persistently high level of AS disease activity. There also is no evidence that combination therapy with a TNF inhibitor and a DMARD is better than the biologic alone.

All three of the available TNF inhibitors have demonstrated efficacy, and there has been no suggestion from the clinical trials that there are any differences in efficacy among them. One special circumstance is for the patient with acute anterior uveitis, however. “Some data suggest that in a patient with ongoing uveitis, the antibodies [infliximab and adalimumab] may be more effective than etanercept, but if the patient just has a history of one attack, you can use whatever you like,” Dr. Kvien said. The same general safety concerns exist for the use of these drugs in AS as in RA, he added.

Increasing experience with TNF inhibitors in AS also has shown that they are associated with greater improvements in health-related quality of life than in RA. “Our data from observational studies have shown that the improvements on all dimensions of the [Short Form Health Survey] SF-36 were greater in patients with AS than in those with RA,” he said. Differences were most notable on scores for emotional role, physical functioning, physical role, and vitality (Arthritis Rheum. 2005;52:2506–12).

Drug retention rates for the TNF inhibitors also are better for AS than for either RA or psoriatic arthritis, said Dr. Kvien. In another observational study, unadjusted 1-year retention rates were 77.5%, 77.3%, and 65.4%, in the AS, psoriatic arthritis, and RA groups, respectively, while adjusted hazard ratios for treatment termination were 0.76 for psoriatic arthritis versus RA and 0.66 for AS versus RA (Arthritis Rheum. 2008;59:234–40).

Dr. Kvien disclosed that he receives grant research support from, and acts as a consultant to, several companies, including Abbott Laboratories, Hoffmann-La Roche Inc., and Wyeth.

SDEF and this news organization are owned by Elsevier.

SAN FRANCISCO — The gentle martial art tai chi significantly lessened pain and improved physical function in a randomized, controlled trial in 40 patients with knee osteoarthritis.

Participants were randomly selected to attend hour-long classes twice a week for 12 weeks to learn and practice 10 modified forms of tai chi or to receive wellness education and engage in stretching in a control group. Patient characteristics were similar between groups, with baseline pain scores of 209 in the tai chi group and 220 in the control group on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, which was the main outcome measure.

After 12 weeks, scores decreased by 157 points in the tai chi group and 39 points in the control group, a significant difference (P = .004), Dr. Chenchen Wang reported at the annual meeting of the American College of Rheumatology.

Although the WOMAC pain scores remained significantly different between groups at 24 weeks, they did not at 48 weeks, as some patients stopped tai chi once the 12-week intervention had ended. Those who continued, however, showed significant improvements in pain and secondary measures of function, compared with controls, said Dr. Wang of Tufts University, Boston.

The tai chi group also showed significant improvements, compared with the control group, in the WOMAC physical function score; the patient and physician global assessment scores (on visual analog scales); a timed chair-stand test; an assessment of knee proprioception; and in depression scores on the Center for Epidemiologic Studies-Depression scale.

Sessions in the current trial included a warm-up, review of technique, and practice of the meditative movements, some of which were modified for the osteoarthritic cohort by incorporating chairs or other accommodations.

Patients were obese, with a baseline body mass index of 30 kg/m

All patients completed the 12-week trial, with 85% attendance in the tai chi sessions and 89% in the control sessions.

The Arthritis Foundation promotes a tai chi practice based on the Sun style that differs in some respects from the Yang style used in the study, she noted.

Tai chi uses an integrated mind-body approach to enhance muscle function, balance, and flexibility. ©Anne Clark/

SAN FRANCISCO — The gentle martial art tai chi significantly lessened pain and improved physical function in a randomized, controlled trial in 40 patients with knee osteoarthritis.

Participants were randomly selected to attend hour-long classes twice a week for 12 weeks to learn and practice 10 modified forms of tai chi or to receive wellness education and engage in stretching in a control group. Patient characteristics were similar between groups, with baseline pain scores of 209 in the tai chi group and 220 in the control group on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, which was the main outcome measure.

After 12 weeks, scores decreased by 157 points in the tai chi group and 39 points in the control group, a significant difference (P = .004), Dr. Chenchen Wang reported at the annual meeting of the American College of Rheumatology.

Although the WOMAC pain scores remained significantly different between groups at 24 weeks, they did not at 48 weeks, as some patients stopped tai chi once the 12-week intervention had ended. Those who continued, however, showed significant improvements in pain and secondary measures of function, compared with controls, said Dr. Wang of Tufts University, Boston.

The tai chi group also showed significant improvements, compared with the control group, in the WOMAC physical function score; the patient and physician global assessment scores (on visual analog scales); a timed chair-stand test; an assessment of knee proprioception; and in depression scores on the Center for Epidemiologic Studies-Depression scale.

Sessions in the current trial included a warm-up, review of technique, and practice of the meditative movements, some of which were modified for the osteoarthritic cohort by incorporating chairs or other accommodations.

Patients were obese, with a baseline body mass index of 30 kg/m

All patients completed the 12-week trial, with 85% attendance in the tai chi sessions and 89% in the control sessions.

The Arthritis Foundation promotes a tai chi practice based on the Sun style that differs in some respects from the Yang style used in the study, she noted.

Tai chi uses an integrated mind-body approach to enhance muscle function, balance, and flexibility. ©Anne Clark/

SAN FRANCISCO — The gentle martial art tai chi significantly lessened pain and improved physical function in a randomized, controlled trial in 40 patients with knee osteoarthritis.

Participants were randomly selected to attend hour-long classes twice a week for 12 weeks to learn and practice 10 modified forms of tai chi or to receive wellness education and engage in stretching in a control group. Patient characteristics were similar between groups, with baseline pain scores of 209 in the tai chi group and 220 in the control group on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, which was the main outcome measure.

After 12 weeks, scores decreased by 157 points in the tai chi group and 39 points in the control group, a significant difference (P = .004), Dr. Chenchen Wang reported at the annual meeting of the American College of Rheumatology.

Although the WOMAC pain scores remained significantly different between groups at 24 weeks, they did not at 48 weeks, as some patients stopped tai chi once the 12-week intervention had ended. Those who continued, however, showed significant improvements in pain and secondary measures of function, compared with controls, said Dr. Wang of Tufts University, Boston.

The tai chi group also showed significant improvements, compared with the control group, in the WOMAC physical function score; the patient and physician global assessment scores (on visual analog scales); a timed chair-stand test; an assessment of knee proprioception; and in depression scores on the Center for Epidemiologic Studies-Depression scale.

Sessions in the current trial included a warm-up, review of technique, and practice of the meditative movements, some of which were modified for the osteoarthritic cohort by incorporating chairs or other accommodations.

Patients were obese, with a baseline body mass index of 30 kg/m

All patients completed the 12-week trial, with 85% attendance in the tai chi sessions and 89% in the control sessions.

The Arthritis Foundation promotes a tai chi practice based on the Sun style that differs in some respects from the Yang style used in the study, she noted.

Tai chi uses an integrated mind-body approach to enhance muscle function, balance, and flexibility. ©Anne Clark/

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

A risk-management plan will be required to address the ongoing problems of misuse, abuse, inappropriate prescribing, and accidental overdoses of certain opioid medications, the Food and Drug Administration announced.

The agency said that letters had been sent to 16 manufacturers of 24 opioid products stating that a Risk Evaluation and Mitigation Strategy (REMS)—which is intended to address serious risks, including fatalities associated with the improper use of these drugs—will be required for their products. The FDA has addressed this problem in the past, with efforts that have included adding warnings to the product labels, direct communications to prescribers, and working with other federal agencies.

“Despite these efforts, the rates of misuse and abuse and of accidental overdosages of opiates have risen over the past decade,” Dr. John Jenkins, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research, said during a briefing. In 2007, 21 million prescriptions for these 24 products were dispensed to 3.7 million individual patients and were associated with “hundreds” of reports of deaths, he said.

Under legislation passed in 2007, the FDA can require a company to provide a REMS if the agency determines that such a plan is needed to ensure that the benefits of a drug outweigh its risks. The REMS may include a medication guide, provided to patients with each prescription filled; a patient package insert; and education of prescribers.

The opioid drugs on the FDA's list include fentanyl (Duragesic extended-release transdermal system), methadone (Dolophine tablets), oxycodone (OxyContin extended-release tablets), oxymorphone (Opana extended-release tablets), and several extended-release oral morphine products. These products are responsible for the greatest proportion of serious adverse events and deaths, according to Dr. Jenkins.

He emphasized that patients and physicians should follow the directions on the label. Although these products are intended only for people who experience moderate to severe pain, are opioid tolerant, and require around-the-clock pain relief, the FDA receives reports of adverse events in opioid-intolerant people who are inappropriately prescribed one of these products for conditions like a sprained ankle, he noted.

In an interview, Dr. Roy Altman, professor of rheumatology at the University of California, Los Angeles, noted that the majority of physicians tend not to use narcotics for chronic noncancer pain when indicated, because of legal ramifications, potential addiction risks, and other issues.

The agency will be holding several meetings to discuss the REMS plan for these products, and to obtain input from interested parties, including physicians, industry representatives, members of the pain- and addiction-treatment communities, and patient advocacy groups, beginning with a meeting on March 3 for manufacturers.

The full list of the drugs, along with the FDA's statement, is available at www.fda.gov/cder/drug/infopage/opioids/default.htmwww.fda.gov/MedWatch/report.htm

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

GAITHERSBURG, MD. — If the Food and Drug Administration agrees with an advisory panel's narrow recommendation to take Darvon and other products that contain propoxyphene off the market, the void may not make much difference to rheumatologists, who appear to be among the lowest prescribers of these products.

At a joint meeting of the FDA's Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee last month, the panelists voted 14–12 that the risk-benefit profile on these products did not support their continued marketing for the treatment of patients with mild to moderate pain. The majority of panelists agreed that there was “marginal” or “modest” evidence at best indicating that propoxyphene, an opioid analgesic, was effective as monotherapy, or that propoxyphene plus acetaminophen was more effective than acetaminophen alone. Several panel members said they did not believe there was any evidence of efficacy for propoxyphene, either alone or in combination with acetaminophen.

The FDA held the meeting to review the safety of these products, first approved in 1957, in response to a Citizen's Petition filed by Public Citizen's Health Research Group in February 2006, calling for a phased withdrawal of all propoxyphene-containing products from the market.

Darvon and Darvocet (propoxyphene plus acetaminophen) are the branded versions of propoxyphene, which is a schedule IV drug. There are multiple generic formulations available. In the petition, the group maintained that the risks of these products outweigh their benefits, citing insufficient evidence that propoxyphene alone effectively alleviates pain and offers little, if any, added benefit when combined with acetaminophen. The petition states that propoxyphene and its main metabolite are cardiotoxic, and that it has a narrow therapeutic index and was associated with 2,110 reports of accidental deaths in the United States from 1981 through 1999.

Based on data from U.S. outpatient retail pharmacies presented by the FDA, rheumatologists wrote about 525,000 prescriptions for propoxyphene-acetaminophen in 2007 (2.4% of the total).

Propoxyphene “just simply is not a very good drug,” and has become less popular over the past few years, said Dr. Roy Altman, professor of rheumatology and immunology at the University of California, Los Angeles.

In an interview, Dr. Altman said that he has not used propoxyphene in more than a decade, “mostly because it's such a weak analgesic.” Moreover, because of the side effects associated with propoxyphene, a more potent analgesic effect would be needed to justify its use, he added. In fact, when he was at the University of Miami several years ago, these products were contraindicated in elderly patients because of the multiple central nervous system side effects—such as depression, depersonalization, drowsiness, and unsteadiness—in this population, so the outcome of the FDA panel meeting does not surprise him, nor would it surprise others in the geriatric community, he said, adding that the main reason these products remain in use now is because of the critical need for more analgesic options.

At the FDA meeting, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, presented data from DAWN (Drug Abuse Warning Network), which received reports of 446 propoxyphene-related deaths from U.S. emergency departments in 2006, and 503 such reports in 2007. (DAWN, which collects data on drugs associated with emergency department visits or deaths, covers only a fraction of the U.S. population; during this time, the number of jurisdictions reporting to DAWN increased.)

Among the other data he presented were reports made to the medical examiner in Florida in 2007 (not included in the DAWN data), in which 314 deaths were related to propoxyphene; in 25% of the cases, the medical examiner concluded that the drug was the cause of death.

The panelists agreed there was no evidence that at therapeutic levels, propoxyphene has been associated with an increased risk for cardiotoxicity, largely because of an insufficient amount of data. However, the panel agreed that if propoxyphene remained on the market, the cardiotoxicity potential should be studied further—in studies that evaluate QT and EKG changes as well as in observational studies, including in elderly populations. The panel also recommended that the label should be changed to discourage chronic use, which has not been studied. The panel cited concerns over the lack of data on safety and efficacy in chronic use and use in the elderly.

Panelists were split on whether the lack of conclusive evidence on efficacy—most of which was from single-dose studies conducted in the 1970s—or on safety justified keeping these products available in the U.S. Sean Hennessy, Pharm.D., of the University of Pennsylvania, Philadelphia, said he voted no because in the “absence of benefit, no risk is acceptable.”

At the meeting, the FDA presented efficacy data from seven acute-pain, single-dose trials that compared propoxyphene alone with acetaminophen alone, with propoxyphene plus acetaminophen, and with placebo, as well as a review of the medical literature through December 2008. Based on a review of these data, the agency concluded that propoxy-phene had a weak analgesic effect in some of the acute-pain trials, and that the contribution of propoxyphene to the analgesic effects of acetaminophen was “variable across acute pain trials,” said Dr. Jin Chen, a medical officer in the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. There were no data on chronic pain submitted to the FDA, and there is insufficient information in the literature to make any conclusions about its analgesic effects with chronic use, he said.

Other data presented by FDA reviewers indicated that there are possible drug-drug interactions with CYP3A4 inhibitors, and that the pharmacokinetics of the drug are altered with hepatic and renal impairment and in the elderly. Animal data indicate that propoxyphene may affect cardiac conduction and toxicity, possibly through its effects on sodium and potassium channels. There also have been case reports of cardiac effects in humans, such as prolonged PR interval and QRS widening associated with drug concentrations that exceed the clinical therapeutic level.

But it is unclear whether the cardiac effects seen in nonclinical studies would be a risk in people who are taking therapeutic doses of propoxyphene-containing drugs, according to the FDA reviewers.

Of the 65 unduplicated adverse event reports associated with propoxyphene-containing products that were submitted to the FDA's Adverse Event Reporting System between 2006 and 2007, 17% (11 cases) were cardiac-related events—including 4 cases of bradycardia, 2 cases of cardiorespiratory arrest, and 2 cases of tachycardia—but 82% of the cardiac cases were confounded by other factors that made it difficult to attribute the report to the drug, according to the FDA. The other cases included accidental multiple drug overdoses in 14% (nine cases) and 18% that were psychiatry related, such as hallucinations or changes in mental status; 40% of the reports overall were in the elderly, and 18% overall were fatal accidental overdoses.

Panelist Dr. William Hiatt, professor of medicine at the University of Colorado, Denver, said that based on these efficacy data, it appears that acetaminophen and propoxyphene alone are more effective than placebo, but that the combination did not clearly exceed pain relief with either component alone in studies of a single dose in people with acute postoperative or postpartum pain.

He also cited preclinical evidence of possible cardiotoxicity, particularly its effect on sodium channels, and recommended that if the products remained on the market, clinical studies should be conducted to evaluate QT changes associated with the drug, and whether the drug increases the background risk of cardiac events in an elderly population.

The FDA usually follows the recommendations of its advisory panels, which are not binding.