Rheumatoid Arthritis

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, said Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, she said.

Dr. Lane, who was an investigator for Pfizer's anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may “bear fruit in the long term.”

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, said Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, she said.

Dr. Lane, who was an investigator for Pfizer's anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may “bear fruit in the long term.”

NEW YORK – Researchers will likely have to wait for months before they find out if they can continue studies on the use of nerve growth factor inhibitors in treating osteoarthritis pain, said Dr. Nancy E. Lane, Endowed Professor of Medicine and Rheumatology at the University of California, Davis, in Sacramento.

Over the past year, the Food and Drug Administration has put on clinical hold nearly all programs for nerve growth factor inhibitor (anti-NGF) development, particularly those related to treating knee pain in osteoarthritis. The agency requested that pharmaceutical manufacturers halt their trials because of reports that study subjects taking the drugs had developed rapidly progressive hip and knee osteoarthritis requiring total joint replacement. A few of those patients also were reported to have had osteonecrosis. The fate of those studies could be determined later this year, when the FDA meets with the pharmaceutical companies involved in developing NGF inhibitors to discuss the issue, she said.

Dr. Lane, who was an investigator for Pfizer's anti-NGF drug tanezumab, said the drug makers developing these compounds have been studying the possible causes of the adverse effects. The question remains whether the disease progression was due to reduced pain and increased activity, or if the inhibition of NGF compromised blood flow to the bone, resulting in osteonecrosis, she said. Regardless of whether the anti-NGF trials continue, Dr. Lane said understanding the NGF receptor TrkA and how to inhibit it may “bear fruit in the long term.”

A panel of 18 experts from 10 European countries had some difficulty in defining when the benefits sufficiently outweighed the potential adverse effects of various NSAIDs – with and without a proton pump inhibitor – for 144 profiles of patients with chronic rheumatic diseases.

Panelists generally gave patients with low gastrointestinal or cardiovascular risks the full range of NSAID options. Approximately one-third of the patient-drug matches labeled “inappropriate” by panelists applied to the use of a nonselective NSAID without a PPI (Ann. Rheum. Dis. 2011;70:818–22).

When scoring patient profiles, panelists took into account seven clinical variables: age of 65 years or older, history of upper gastrointestinal problems, use of anticoagulants, use of systemic corticosteroids, intermittent or continuous treatment pattern, cardiovascular risk, and the use of low-dose aspirin (for those patients with cardiovascular risk). Against these variables, panelists considered 10 treatment options: ibuprofen, diclofenac, naproxen, celecoxib, etoricoxib, and each of these drugs plus a PPI. They did not consider costs when making their treatment recommendations, according to Dr. G.R. Burmester of the department of rheumatology and clinical immunology, Charité Medical University Berlin, and his coauthors.

For patients with the lowest gastrointestinal and cardiovascular risks, a nonselective NSAID (ibuprofen, diclofenac, or naproxen) was deemed appropriate. As gastrointestinal risks increased, the cyclooxygenase-2 (COX-2) inhibitors celecoxib and etoricoxib alone or a nonselective NSAID plus PPI were considered appropriate. In cases of high gastrointestinal risk and low to average cardiovascular risk, panelists rated ibuprofen/diclofenac plus PPI, or a COX-2 inhibitor plus PPI, as the most appropriate options. For patients with both high gastrointestinal and cardiovascular risks, avoidance of all NSAIDs was recommended, with the use of diclofenac, naproxen, celecoxib, or etoricoxib plus PPI deemed acceptable if necessary.

In January 2008, the panel established the appropriateness rating of treatment options on a 1–9 scale, with 1 as “inappropriate” and 9 as “appropriate.” As defined by the RAND/UCLA appropriateness method, a “treatment had to be considered appropriate if the expected benefits exceeded the potential negative consequences by a sufficient margin.” However, the panel did not define “sufficient,” which led to most of the disagreement on scoring.

All panelists disclosed receiving honoraria from Pfizer, which supported the study with an unrestricted educational grant. Eleven panelists disclosed other relationships with pharmaceutical companies, including Pfizer.

A panel of 18 experts from 10 European countries had some difficulty in defining when the benefits sufficiently outweighed the potential adverse effects of various NSAIDs – with and without a proton pump inhibitor – for 144 profiles of patients with chronic rheumatic diseases.

Panelists generally gave patients with low gastrointestinal or cardiovascular risks the full range of NSAID options. Approximately one-third of the patient-drug matches labeled “inappropriate” by panelists applied to the use of a nonselective NSAID without a PPI (Ann. Rheum. Dis. 2011;70:818–22).

When scoring patient profiles, panelists took into account seven clinical variables: age of 65 years or older, history of upper gastrointestinal problems, use of anticoagulants, use of systemic corticosteroids, intermittent or continuous treatment pattern, cardiovascular risk, and the use of low-dose aspirin (for those patients with cardiovascular risk). Against these variables, panelists considered 10 treatment options: ibuprofen, diclofenac, naproxen, celecoxib, etoricoxib, and each of these drugs plus a PPI. They did not consider costs when making their treatment recommendations, according to Dr. G.R. Burmester of the department of rheumatology and clinical immunology, Charité Medical University Berlin, and his coauthors.

For patients with the lowest gastrointestinal and cardiovascular risks, a nonselective NSAID (ibuprofen, diclofenac, or naproxen) was deemed appropriate. As gastrointestinal risks increased, the cyclooxygenase-2 (COX-2) inhibitors celecoxib and etoricoxib alone or a nonselective NSAID plus PPI were considered appropriate. In cases of high gastrointestinal risk and low to average cardiovascular risk, panelists rated ibuprofen/diclofenac plus PPI, or a COX-2 inhibitor plus PPI, as the most appropriate options. For patients with both high gastrointestinal and cardiovascular risks, avoidance of all NSAIDs was recommended, with the use of diclofenac, naproxen, celecoxib, or etoricoxib plus PPI deemed acceptable if necessary.

In January 2008, the panel established the appropriateness rating of treatment options on a 1–9 scale, with 1 as “inappropriate” and 9 as “appropriate.” As defined by the RAND/UCLA appropriateness method, a “treatment had to be considered appropriate if the expected benefits exceeded the potential negative consequences by a sufficient margin.” However, the panel did not define “sufficient,” which led to most of the disagreement on scoring.

All panelists disclosed receiving honoraria from Pfizer, which supported the study with an unrestricted educational grant. Eleven panelists disclosed other relationships with pharmaceutical companies, including Pfizer.

A panel of 18 experts from 10 European countries had some difficulty in defining when the benefits sufficiently outweighed the potential adverse effects of various NSAIDs – with and without a proton pump inhibitor – for 144 profiles of patients with chronic rheumatic diseases.

Panelists generally gave patients with low gastrointestinal or cardiovascular risks the full range of NSAID options. Approximately one-third of the patient-drug matches labeled “inappropriate” by panelists applied to the use of a nonselective NSAID without a PPI (Ann. Rheum. Dis. 2011;70:818–22).

When scoring patient profiles, panelists took into account seven clinical variables: age of 65 years or older, history of upper gastrointestinal problems, use of anticoagulants, use of systemic corticosteroids, intermittent or continuous treatment pattern, cardiovascular risk, and the use of low-dose aspirin (for those patients with cardiovascular risk). Against these variables, panelists considered 10 treatment options: ibuprofen, diclofenac, naproxen, celecoxib, etoricoxib, and each of these drugs plus a PPI. They did not consider costs when making their treatment recommendations, according to Dr. G.R. Burmester of the department of rheumatology and clinical immunology, Charité Medical University Berlin, and his coauthors.

For patients with the lowest gastrointestinal and cardiovascular risks, a nonselective NSAID (ibuprofen, diclofenac, or naproxen) was deemed appropriate. As gastrointestinal risks increased, the cyclooxygenase-2 (COX-2) inhibitors celecoxib and etoricoxib alone or a nonselective NSAID plus PPI were considered appropriate. In cases of high gastrointestinal risk and low to average cardiovascular risk, panelists rated ibuprofen/diclofenac plus PPI, or a COX-2 inhibitor plus PPI, as the most appropriate options. For patients with both high gastrointestinal and cardiovascular risks, avoidance of all NSAIDs was recommended, with the use of diclofenac, naproxen, celecoxib, or etoricoxib plus PPI deemed acceptable if necessary.

In January 2008, the panel established the appropriateness rating of treatment options on a 1–9 scale, with 1 as “inappropriate” and 9 as “appropriate.” As defined by the RAND/UCLA appropriateness method, a “treatment had to be considered appropriate if the expected benefits exceeded the potential negative consequences by a sufficient margin.” However, the panel did not define “sufficient,” which led to most of the disagreement on scoring.

All panelists disclosed receiving honoraria from Pfizer, which supported the study with an unrestricted educational grant. Eleven panelists disclosed other relationships with pharmaceutical companies, including Pfizer.

NATIONAL HARBOR, MD. – Pharmaceutical companies are stepping up to address increasing opioid abuse and misuse by developing innovative abuse-deterrent formulations and drug delivery systems, Dr. Lynn R. Webster said.

Dr. Webster discussed several new opioid formulations that are currently available and some promising technologies in the pipeline. Dr. Webster is board certified in anesthesiology and pain medicine and is certified in addiction medicine. He is also the medical director and founder of the Lifetree Clinical Research and Pain Clinic in Salt Lake City.

New Opioids

In January 2011, the Food and Drug Administration approved Abstral (Prostrakan), a fentanyl transmucosal tablet indicated for the management of breakthrough cancer pain in adults. As an alternative to oral tablets or injections of fentanyl pain medications, the quick-dissolving tablet is placed under the tongue, providing very fast relief for cancer-related pain in patients already receiving opioids for pain treatment.

Approved in 2010, Exalgo is an extended-release formulation of hydromorphone indicated for once-daily administration for the management of moderate to severe pain in opioid-tolerant patients who require continuous, around-the-clock opioid analgesia for an extended period. Exalgo (Mallinckrodt) is not intended for use as an as-needed analgesic. The formulation utilizes a new osmotic, controlled-release oral delivery system in which osmosis attracts water in the body to the inside of the capsule to trigger release of hydromorphone. It takes about 6 hours for effective levels of hydromorphone to be released and 4–5 days for drug levels to reach a steady state in the body, Dr. Webster said.

There has been a resurgence of interest in buprenorphine. This drug has been around for several decades, but is now being used to treat chronic pain. Buprenorphine is a partial mu-opioid agonist, an antagonist at the kappa-opioid receptor, and a partial agonist at the ORL1/nociceptin and delta-opioid receptors. “There is a little bit of complexity with how the pharmacology of this drug works. We probably don't understand clinically what all of that means yet,” Dr. Webster said. Buprenorphine is the only opioid classified as a schedule III drug, making it an attractive choice for pain management. Buprenorphine also is associated with fewer of the side effects typical of opioids, such as respiratory depression.

In 2010, the FDA approved Butrans, an extended-release buprenorphine patch (Purdue Pharma), in 5-, 10- and 20-mcg/hour doses. The drug is indicated for the management of moderate to severe chronic pain in patients requiring continuous, around-the-clock opioid treatment for an extended period.

Notably, Subutex (buprenorphine monotherapy) and Suboxone (a buprenorphine/naloxone combination product) are approved for use in opioid addiction treatment, though other forms of the drug are not. However, other forms of buprenorphine are commonly used off-label for the management of addiction disorders, Dr. Webster said. Because buprenorphine is an opioid partial agonist, its maximal effects are less than those of full agonists (like heroin and methadone). At low doses, buprenorphine is thought to produce enough of an agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. Buprenorphine has poor oral bioavailability and only moderate sublingual bioavailability.

In the Pipeline

Acurox (Acura Pharmaceuticals and King Pharmaceuticals [now part of Pfizer]) is an oral immediate-release oxycodone tablet with a proposed indication for the relief of moderate to severe pain. Acurox is formulated so that if the tablets are dissolved in an attempt to extract the opioid for intravenous injection, the tablets turn into a viscous gel mixture with the active drug trapped in the gel. The Aversion technology used also causes burning and irritation of the nasal passages if the drug is crushed and snorted.

Last year, the FDA rejected an application for a version of the drug containing niacin, which was formulated so that the uncomfortable “niacin flush” would deter overuse of the drug. In February 2011, the FDA accepted a new drug application for Acurox (oxycodone) tablets without niacin.

MoxDuo (QRxPharma) is an immediate-release dual opioid intended for the acute management of moderate to severe pain. The drug is a combination of morphine and oxycodone that has been clinically shown to have a synergistic effect on pain with a significant reduction of total opioid dose and side effects.

“This formulation is built upon that thought that there are different receptor selectivities to an opioid,” Dr. Webster said. Because opioid receptors differ, “you can get enhanced analgesia with using overall less morphine equivalents, or you could get fewer side effects with the same level of analgesia, when you combine two different opioids.”

Collegium Pharmaceuticals is developing an abuse-deterrent, sustained-release oral oxycodone formulation (COL-003). The DETERx delivery technology consists of a multiparticulate matrix formulation in a capsule designed to be less susceptible to common forms of tampering, such as crushing or chewing prior to ingestion. Company studies showed that the plasma profile for the new-formulation pill was bioequivalent whether it was chewed or taken whole as intended. “It's an abuse-resistant formulation in that they can't extract more than is intended for its delivery,” Dr. Webster said.

Remoxy (Pain Therapeutics and King Pharmaceuticals) is a long-acting oral oxycodone for the treatment of moderate to severe chronic pain. “This is what I consider an opioid-resistant formulation, meaning it's got a barrier that is hard to crush, hard to manipulate; and it's hard to extract” the oxycodone, Dr. Webster said. “It can't be chewed, snorted, or injected very easily.”

A new transmucosal buprenorphine patch is also in the trial phase. According to PharmacoFore, the delivery system's developer, the novel Bio-Activated Molecular Delivery (Bio-MD) technology deters prescription drug abuse at a molecular level.

“This technology does not involve the reformulation of existing opioid drugs in physical matrices that are easily circumvented by simple extraction methods. Our opioid Bio-MD systems are 'activated' to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested),” the company noted on its Web site.

Essentially, an opioid molecule – any opioid – is attached to the delivery compound. “It's kind of like a clock. The intrinsic trypsin in our GI tract will activate that clock, which will … allow that drug to be released,” Dr. Webster said. The clock determines how much time it takes for the active compound to be released.

“It's very early on,” he cautioned. The delivery system is in phase I trials. Still, “it looks very interesting that they have the technology now to address multipill abuse. There are ways to design the same technologies so that the triggering system will only allow a certain number of pills or milligrams of medication to be absorbed.” Thus, regardless of how many pills an individual takes, no more than the prescribed dose is bioavailable.

Dr. Webster reported that he has significant financial relationships with a number of pharmaceutical companies, including King Pharmaceuticals and Collegium Pharmaceutical.

NATIONAL HARBOR, MD. – Pharmaceutical companies are stepping up to address increasing opioid abuse and misuse by developing innovative abuse-deterrent formulations and drug delivery systems, Dr. Lynn R. Webster said.

Dr. Webster discussed several new opioid formulations that are currently available and some promising technologies in the pipeline. Dr. Webster is board certified in anesthesiology and pain medicine and is certified in addiction medicine. He is also the medical director and founder of the Lifetree Clinical Research and Pain Clinic in Salt Lake City.

New Opioids

In January 2011, the Food and Drug Administration approved Abstral (Prostrakan), a fentanyl transmucosal tablet indicated for the management of breakthrough cancer pain in adults. As an alternative to oral tablets or injections of fentanyl pain medications, the quick-dissolving tablet is placed under the tongue, providing very fast relief for cancer-related pain in patients already receiving opioids for pain treatment.

Approved in 2010, Exalgo is an extended-release formulation of hydromorphone indicated for once-daily administration for the management of moderate to severe pain in opioid-tolerant patients who require continuous, around-the-clock opioid analgesia for an extended period. Exalgo (Mallinckrodt) is not intended for use as an as-needed analgesic. The formulation utilizes a new osmotic, controlled-release oral delivery system in which osmosis attracts water in the body to the inside of the capsule to trigger release of hydromorphone. It takes about 6 hours for effective levels of hydromorphone to be released and 4–5 days for drug levels to reach a steady state in the body, Dr. Webster said.

There has been a resurgence of interest in buprenorphine. This drug has been around for several decades, but is now being used to treat chronic pain. Buprenorphine is a partial mu-opioid agonist, an antagonist at the kappa-opioid receptor, and a partial agonist at the ORL1/nociceptin and delta-opioid receptors. “There is a little bit of complexity with how the pharmacology of this drug works. We probably don't understand clinically what all of that means yet,” Dr. Webster said. Buprenorphine is the only opioid classified as a schedule III drug, making it an attractive choice for pain management. Buprenorphine also is associated with fewer of the side effects typical of opioids, such as respiratory depression.

In 2010, the FDA approved Butrans, an extended-release buprenorphine patch (Purdue Pharma), in 5-, 10- and 20-mcg/hour doses. The drug is indicated for the management of moderate to severe chronic pain in patients requiring continuous, around-the-clock opioid treatment for an extended period.

Notably, Subutex (buprenorphine monotherapy) and Suboxone (a buprenorphine/naloxone combination product) are approved for use in opioid addiction treatment, though other forms of the drug are not. However, other forms of buprenorphine are commonly used off-label for the management of addiction disorders, Dr. Webster said. Because buprenorphine is an opioid partial agonist, its maximal effects are less than those of full agonists (like heroin and methadone). At low doses, buprenorphine is thought to produce enough of an agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. Buprenorphine has poor oral bioavailability and only moderate sublingual bioavailability.

In the Pipeline

Acurox (Acura Pharmaceuticals and King Pharmaceuticals [now part of Pfizer]) is an oral immediate-release oxycodone tablet with a proposed indication for the relief of moderate to severe pain. Acurox is formulated so that if the tablets are dissolved in an attempt to extract the opioid for intravenous injection, the tablets turn into a viscous gel mixture with the active drug trapped in the gel. The Aversion technology used also causes burning and irritation of the nasal passages if the drug is crushed and snorted.

Last year, the FDA rejected an application for a version of the drug containing niacin, which was formulated so that the uncomfortable “niacin flush” would deter overuse of the drug. In February 2011, the FDA accepted a new drug application for Acurox (oxycodone) tablets without niacin.

MoxDuo (QRxPharma) is an immediate-release dual opioid intended for the acute management of moderate to severe pain. The drug is a combination of morphine and oxycodone that has been clinically shown to have a synergistic effect on pain with a significant reduction of total opioid dose and side effects.

“This formulation is built upon that thought that there are different receptor selectivities to an opioid,” Dr. Webster said. Because opioid receptors differ, “you can get enhanced analgesia with using overall less morphine equivalents, or you could get fewer side effects with the same level of analgesia, when you combine two different opioids.”

Collegium Pharmaceuticals is developing an abuse-deterrent, sustained-release oral oxycodone formulation (COL-003). The DETERx delivery technology consists of a multiparticulate matrix formulation in a capsule designed to be less susceptible to common forms of tampering, such as crushing or chewing prior to ingestion. Company studies showed that the plasma profile for the new-formulation pill was bioequivalent whether it was chewed or taken whole as intended. “It's an abuse-resistant formulation in that they can't extract more than is intended for its delivery,” Dr. Webster said.

Remoxy (Pain Therapeutics and King Pharmaceuticals) is a long-acting oral oxycodone for the treatment of moderate to severe chronic pain. “This is what I consider an opioid-resistant formulation, meaning it's got a barrier that is hard to crush, hard to manipulate; and it's hard to extract” the oxycodone, Dr. Webster said. “It can't be chewed, snorted, or injected very easily.”

A new transmucosal buprenorphine patch is also in the trial phase. According to PharmacoFore, the delivery system's developer, the novel Bio-Activated Molecular Delivery (Bio-MD) technology deters prescription drug abuse at a molecular level.

“This technology does not involve the reformulation of existing opioid drugs in physical matrices that are easily circumvented by simple extraction methods. Our opioid Bio-MD systems are 'activated' to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested),” the company noted on its Web site.

Essentially, an opioid molecule – any opioid – is attached to the delivery compound. “It's kind of like a clock. The intrinsic trypsin in our GI tract will activate that clock, which will … allow that drug to be released,” Dr. Webster said. The clock determines how much time it takes for the active compound to be released.

“It's very early on,” he cautioned. The delivery system is in phase I trials. Still, “it looks very interesting that they have the technology now to address multipill abuse. There are ways to design the same technologies so that the triggering system will only allow a certain number of pills or milligrams of medication to be absorbed.” Thus, regardless of how many pills an individual takes, no more than the prescribed dose is bioavailable.

Dr. Webster reported that he has significant financial relationships with a number of pharmaceutical companies, including King Pharmaceuticals and Collegium Pharmaceutical.

NATIONAL HARBOR, MD. – Pharmaceutical companies are stepping up to address increasing opioid abuse and misuse by developing innovative abuse-deterrent formulations and drug delivery systems, Dr. Lynn R. Webster said.

Dr. Webster discussed several new opioid formulations that are currently available and some promising technologies in the pipeline. Dr. Webster is board certified in anesthesiology and pain medicine and is certified in addiction medicine. He is also the medical director and founder of the Lifetree Clinical Research and Pain Clinic in Salt Lake City.

New Opioids

In January 2011, the Food and Drug Administration approved Abstral (Prostrakan), a fentanyl transmucosal tablet indicated for the management of breakthrough cancer pain in adults. As an alternative to oral tablets or injections of fentanyl pain medications, the quick-dissolving tablet is placed under the tongue, providing very fast relief for cancer-related pain in patients already receiving opioids for pain treatment.

Approved in 2010, Exalgo is an extended-release formulation of hydromorphone indicated for once-daily administration for the management of moderate to severe pain in opioid-tolerant patients who require continuous, around-the-clock opioid analgesia for an extended period. Exalgo (Mallinckrodt) is not intended for use as an as-needed analgesic. The formulation utilizes a new osmotic, controlled-release oral delivery system in which osmosis attracts water in the body to the inside of the capsule to trigger release of hydromorphone. It takes about 6 hours for effective levels of hydromorphone to be released and 4–5 days for drug levels to reach a steady state in the body, Dr. Webster said.

There has been a resurgence of interest in buprenorphine. This drug has been around for several decades, but is now being used to treat chronic pain. Buprenorphine is a partial mu-opioid agonist, an antagonist at the kappa-opioid receptor, and a partial agonist at the ORL1/nociceptin and delta-opioid receptors. “There is a little bit of complexity with how the pharmacology of this drug works. We probably don't understand clinically what all of that means yet,” Dr. Webster said. Buprenorphine is the only opioid classified as a schedule III drug, making it an attractive choice for pain management. Buprenorphine also is associated with fewer of the side effects typical of opioids, such as respiratory depression.

In 2010, the FDA approved Butrans, an extended-release buprenorphine patch (Purdue Pharma), in 5-, 10- and 20-mcg/hour doses. The drug is indicated for the management of moderate to severe chronic pain in patients requiring continuous, around-the-clock opioid treatment for an extended period.

Notably, Subutex (buprenorphine monotherapy) and Suboxone (a buprenorphine/naloxone combination product) are approved for use in opioid addiction treatment, though other forms of the drug are not. However, other forms of buprenorphine are commonly used off-label for the management of addiction disorders, Dr. Webster said. Because buprenorphine is an opioid partial agonist, its maximal effects are less than those of full agonists (like heroin and methadone). At low doses, buprenorphine is thought to produce enough of an agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. Buprenorphine has poor oral bioavailability and only moderate sublingual bioavailability.

In the Pipeline

Acurox (Acura Pharmaceuticals and King Pharmaceuticals [now part of Pfizer]) is an oral immediate-release oxycodone tablet with a proposed indication for the relief of moderate to severe pain. Acurox is formulated so that if the tablets are dissolved in an attempt to extract the opioid for intravenous injection, the tablets turn into a viscous gel mixture with the active drug trapped in the gel. The Aversion technology used also causes burning and irritation of the nasal passages if the drug is crushed and snorted.

Last year, the FDA rejected an application for a version of the drug containing niacin, which was formulated so that the uncomfortable “niacin flush” would deter overuse of the drug. In February 2011, the FDA accepted a new drug application for Acurox (oxycodone) tablets without niacin.

MoxDuo (QRxPharma) is an immediate-release dual opioid intended for the acute management of moderate to severe pain. The drug is a combination of morphine and oxycodone that has been clinically shown to have a synergistic effect on pain with a significant reduction of total opioid dose and side effects.

“This formulation is built upon that thought that there are different receptor selectivities to an opioid,” Dr. Webster said. Because opioid receptors differ, “you can get enhanced analgesia with using overall less morphine equivalents, or you could get fewer side effects with the same level of analgesia, when you combine two different opioids.”

Collegium Pharmaceuticals is developing an abuse-deterrent, sustained-release oral oxycodone formulation (COL-003). The DETERx delivery technology consists of a multiparticulate matrix formulation in a capsule designed to be less susceptible to common forms of tampering, such as crushing or chewing prior to ingestion. Company studies showed that the plasma profile for the new-formulation pill was bioequivalent whether it was chewed or taken whole as intended. “It's an abuse-resistant formulation in that they can't extract more than is intended for its delivery,” Dr. Webster said.

Remoxy (Pain Therapeutics and King Pharmaceuticals) is a long-acting oral oxycodone for the treatment of moderate to severe chronic pain. “This is what I consider an opioid-resistant formulation, meaning it's got a barrier that is hard to crush, hard to manipulate; and it's hard to extract” the oxycodone, Dr. Webster said. “It can't be chewed, snorted, or injected very easily.”

A new transmucosal buprenorphine patch is also in the trial phase. According to PharmacoFore, the delivery system's developer, the novel Bio-Activated Molecular Delivery (Bio-MD) technology deters prescription drug abuse at a molecular level.

“This technology does not involve the reformulation of existing opioid drugs in physical matrices that are easily circumvented by simple extraction methods. Our opioid Bio-MD systems are 'activated' to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested),” the company noted on its Web site.

Essentially, an opioid molecule – any opioid – is attached to the delivery compound. “It's kind of like a clock. The intrinsic trypsin in our GI tract will activate that clock, which will … allow that drug to be released,” Dr. Webster said. The clock determines how much time it takes for the active compound to be released.

“It's very early on,” he cautioned. The delivery system is in phase I trials. Still, “it looks very interesting that they have the technology now to address multipill abuse. There are ways to design the same technologies so that the triggering system will only allow a certain number of pills or milligrams of medication to be absorbed.” Thus, regardless of how many pills an individual takes, no more than the prescribed dose is bioavailable.

Dr. Webster reported that he has significant financial relationships with a number of pharmaceutical companies, including King Pharmaceuticals and Collegium Pharmaceutical.

CHICAGO – The prevalence of ankylosing spondylitis is greatly underestimated, and diagnosis is typically delayed, according to Dr. Michael Weisman.

A 1998 report by the National Arthritis Data Workgroup stated that there are an estimated 2.1 cases of ankylosing spondylitis (AS) per 1,000 individuals older than age 15 years. But this widely cited estimate that 0.21% of the U.S. population has AS was based on classification criteria that required radiographic evidence of AS, said Dr. Weisman, who is director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center in Los Angeles.

“This was not a real epidemiologic survey. This was a grossly underestimated prevalence of AS” in the United States, he said, explaining that the researchers relied on the modified New York criteria for AS, which requires not only clinical features, but radiographic changes.

The problem is that radiographic changes take time, and there is a long preradiographic stage in AS during which patients have symptoms for years before developing x-ray changes in sacroiliac joints.

“So when you use modified New York criteria for classification, and you misuse it for diagnosis, you're going to grossly underestimate the frequency of this disease in the population,” he said.

Additionally, studies consistently show that there is an average delay in diagnosis of at least 7–9 years for AS, he said, noting that this is because AS is hidden from obvious view, imaging techniques are needed to make the diagnosis, and the disease is often not suspected because of “the whole ubiquitous idea of low back pain in the population” (Curr. Opin. Rheumatol. 2000;12:239–47).

Also, that study showed that diagnosis in women is delayed even more than in men, and other studies indicate that women have largely been underdiagnosed, Dr. Weisman said, noting that he was taught during training that AS occurs in a 10:1 male:female ratio. The latest data show that it is more like 3:1.

So how many people really have AS? There have been very few prevalence studies, but the latest compilation of data shows that newer prevalence estimates for AS and spondyloarthritis in general vary widely, from 0.52% to 1.3% in the United States, which suggests that the prevalence may be higher than the current estimated 0.6% prevalence of rheumatoid arthritis in the United States. The estimates of AS/spondyloarthritis in other parts of the world are even higher. The estimated prevalence in Norway, for example, ranges up to 6.7%.

A marked north/south gradient also exists in prevalence, and it mirrors the north/south gradient of HLA (human leukocyte antigen)–B27 gene prevalence in the indigenous populations worldwide, which is “tremendously variable.” HLA-B27 positivity is very high in northern areas, along with a higher prevalence of AS in northern areas.

These findings can be helpful for improving diagnosis, he said.

To make a correct – and earlier – diagnosis, use your perspective on inflammatory back pain, Dr. Weisman advised.

“Inflammatory back pain will be, for you, the greatest clue to be able to hone in on this diagnosis,” he said.

Onset at a young age, relatively long duration of pain, associated morning stiffness, awakening in the middle of the night, and no improvement with rest are classic signs of inflammatory back pain. In fact, at least one study has shown that among those with chronic back pain, about 5% will have AS; but in those with inflammatory back pain the probability is tripled to about 14%-15%. Adding other features can further improve diagnosis.

An emerging understanding of genetic influences, for example, is proving helpful for diagnosis. Heritability for AS is greater than 90%, with HLA-B serving as the major disease-associated locus. The HLA-B27 gene marker is present in about 90% of AS cases, although only about 5% of HLA-B27–positive individuals develop AS.

“So the current model is that AS is largely a monogenic disease with multiple modifying genes,” Dr. Weisman said at the meeting.

The ERAP1 and IL23R genes are other players.

If a frequency of a low AS prevalence estimate of 0.4% is assumed, HLA-B27 confers a probability of having AS of 3.6%. HLA-B27 along with ERAP1 increases that to about 10%, and the addition of both ERAP1 and IL23R increases it further to about 23%, Dr. Weisman said.

If patients with inflammatory back pain are considered, and a lower bound estimate of AS of about 10% is assumed in that population, the addition of B27 positivity increases AS likelihood to about 50%. The addition of ERAP1 and IL23R positivity increases AS likelihood to 80%-90%, he said.

However, these genes add only a small amount to the frequency of the genetic association in this disease, and there are certain caveats that must be considered, Dr. Weisman said. For example, the ERAP1 association with AS is not seen in the Chinese population, and the ERAP1 association is only found in those with HLA-B27 positivity, which implies a gene-gene interaction.

There remains a great deal of work to be done to define the genetic bases of AS, he said.

In the meantime, efforts to better determine AS prevalence based on newer classification criteria are underway.

Unlike the modified New York criteria, which used clear-cut radiographic sacroiliitis, new classification criteria for axial spondyloarthritis developed by the Assessments in Ankylosing Spondylitis Working Group uses additional features to increase sensitivity. One set of criteria uses HLA-B27 plus two additional features of spondyloarthritis for AS classification, and one uses sacroiliitis on imaging plus one spondyloarthritis feature to make a diagnosis. This increases sensitivity of screening to over 80%, he said (Ann. Rheum. Dis. 2009;68:777–83).

Furthermore, a screening questionnaire developed and published last year by Cedars-Sinai Medical Center to help improve diagnosis and to identify more patients on a population basis using various clinical features will be applied to National Health and Nutrition Examination Survey data for 2009–2010, which included a new survey on inflammatory back pain and spondyloarthritis. Together these seek to provide the first U.S. national inflammatory back pain estimate, and the first national U.S. study of HLA-B27 prevalence, Dr. Weisman said.

“With these two, we'll be able to find the lower bound of the true prevalence of ankylosing spondylitis in the United States,” he said.

Dr. Weisman had no financial disclosures to report.

CHICAGO – The prevalence of ankylosing spondylitis is greatly underestimated, and diagnosis is typically delayed, according to Dr. Michael Weisman.

A 1998 report by the National Arthritis Data Workgroup stated that there are an estimated 2.1 cases of ankylosing spondylitis (AS) per 1,000 individuals older than age 15 years. But this widely cited estimate that 0.21% of the U.S. population has AS was based on classification criteria that required radiographic evidence of AS, said Dr. Weisman, who is director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center in Los Angeles.

“This was not a real epidemiologic survey. This was a grossly underestimated prevalence of AS” in the United States, he said, explaining that the researchers relied on the modified New York criteria for AS, which requires not only clinical features, but radiographic changes.

The problem is that radiographic changes take time, and there is a long preradiographic stage in AS during which patients have symptoms for years before developing x-ray changes in sacroiliac joints.

“So when you use modified New York criteria for classification, and you misuse it for diagnosis, you're going to grossly underestimate the frequency of this disease in the population,” he said.

Additionally, studies consistently show that there is an average delay in diagnosis of at least 7–9 years for AS, he said, noting that this is because AS is hidden from obvious view, imaging techniques are needed to make the diagnosis, and the disease is often not suspected because of “the whole ubiquitous idea of low back pain in the population” (Curr. Opin. Rheumatol. 2000;12:239–47).

Also, that study showed that diagnosis in women is delayed even more than in men, and other studies indicate that women have largely been underdiagnosed, Dr. Weisman said, noting that he was taught during training that AS occurs in a 10:1 male:female ratio. The latest data show that it is more like 3:1.

So how many people really have AS? There have been very few prevalence studies, but the latest compilation of data shows that newer prevalence estimates for AS and spondyloarthritis in general vary widely, from 0.52% to 1.3% in the United States, which suggests that the prevalence may be higher than the current estimated 0.6% prevalence of rheumatoid arthritis in the United States. The estimates of AS/spondyloarthritis in other parts of the world are even higher. The estimated prevalence in Norway, for example, ranges up to 6.7%.

A marked north/south gradient also exists in prevalence, and it mirrors the north/south gradient of HLA (human leukocyte antigen)–B27 gene prevalence in the indigenous populations worldwide, which is “tremendously variable.” HLA-B27 positivity is very high in northern areas, along with a higher prevalence of AS in northern areas.

These findings can be helpful for improving diagnosis, he said.

To make a correct – and earlier – diagnosis, use your perspective on inflammatory back pain, Dr. Weisman advised.

“Inflammatory back pain will be, for you, the greatest clue to be able to hone in on this diagnosis,” he said.

Onset at a young age, relatively long duration of pain, associated morning stiffness, awakening in the middle of the night, and no improvement with rest are classic signs of inflammatory back pain. In fact, at least one study has shown that among those with chronic back pain, about 5% will have AS; but in those with inflammatory back pain the probability is tripled to about 14%-15%. Adding other features can further improve diagnosis.

An emerging understanding of genetic influences, for example, is proving helpful for diagnosis. Heritability for AS is greater than 90%, with HLA-B serving as the major disease-associated locus. The HLA-B27 gene marker is present in about 90% of AS cases, although only about 5% of HLA-B27–positive individuals develop AS.

“So the current model is that AS is largely a monogenic disease with multiple modifying genes,” Dr. Weisman said at the meeting.

The ERAP1 and IL23R genes are other players.

If a frequency of a low AS prevalence estimate of 0.4% is assumed, HLA-B27 confers a probability of having AS of 3.6%. HLA-B27 along with ERAP1 increases that to about 10%, and the addition of both ERAP1 and IL23R increases it further to about 23%, Dr. Weisman said.

If patients with inflammatory back pain are considered, and a lower bound estimate of AS of about 10% is assumed in that population, the addition of B27 positivity increases AS likelihood to about 50%. The addition of ERAP1 and IL23R positivity increases AS likelihood to 80%-90%, he said.

However, these genes add only a small amount to the frequency of the genetic association in this disease, and there are certain caveats that must be considered, Dr. Weisman said. For example, the ERAP1 association with AS is not seen in the Chinese population, and the ERAP1 association is only found in those with HLA-B27 positivity, which implies a gene-gene interaction.

There remains a great deal of work to be done to define the genetic bases of AS, he said.

In the meantime, efforts to better determine AS prevalence based on newer classification criteria are underway.

Unlike the modified New York criteria, which used clear-cut radiographic sacroiliitis, new classification criteria for axial spondyloarthritis developed by the Assessments in Ankylosing Spondylitis Working Group uses additional features to increase sensitivity. One set of criteria uses HLA-B27 plus two additional features of spondyloarthritis for AS classification, and one uses sacroiliitis on imaging plus one spondyloarthritis feature to make a diagnosis. This increases sensitivity of screening to over 80%, he said (Ann. Rheum. Dis. 2009;68:777–83).

Furthermore, a screening questionnaire developed and published last year by Cedars-Sinai Medical Center to help improve diagnosis and to identify more patients on a population basis using various clinical features will be applied to National Health and Nutrition Examination Survey data for 2009–2010, which included a new survey on inflammatory back pain and spondyloarthritis. Together these seek to provide the first U.S. national inflammatory back pain estimate, and the first national U.S. study of HLA-B27 prevalence, Dr. Weisman said.

“With these two, we'll be able to find the lower bound of the true prevalence of ankylosing spondylitis in the United States,” he said.

Dr. Weisman had no financial disclosures to report.

CHICAGO – The prevalence of ankylosing spondylitis is greatly underestimated, and diagnosis is typically delayed, according to Dr. Michael Weisman.

A 1998 report by the National Arthritis Data Workgroup stated that there are an estimated 2.1 cases of ankylosing spondylitis (AS) per 1,000 individuals older than age 15 years. But this widely cited estimate that 0.21% of the U.S. population has AS was based on classification criteria that required radiographic evidence of AS, said Dr. Weisman, who is director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center in Los Angeles.

“This was not a real epidemiologic survey. This was a grossly underestimated prevalence of AS” in the United States, he said, explaining that the researchers relied on the modified New York criteria for AS, which requires not only clinical features, but radiographic changes.

The problem is that radiographic changes take time, and there is a long preradiographic stage in AS during which patients have symptoms for years before developing x-ray changes in sacroiliac joints.

“So when you use modified New York criteria for classification, and you misuse it for diagnosis, you're going to grossly underestimate the frequency of this disease in the population,” he said.

Additionally, studies consistently show that there is an average delay in diagnosis of at least 7–9 years for AS, he said, noting that this is because AS is hidden from obvious view, imaging techniques are needed to make the diagnosis, and the disease is often not suspected because of “the whole ubiquitous idea of low back pain in the population” (Curr. Opin. Rheumatol. 2000;12:239–47).

Also, that study showed that diagnosis in women is delayed even more than in men, and other studies indicate that women have largely been underdiagnosed, Dr. Weisman said, noting that he was taught during training that AS occurs in a 10:1 male:female ratio. The latest data show that it is more like 3:1.

So how many people really have AS? There have been very few prevalence studies, but the latest compilation of data shows that newer prevalence estimates for AS and spondyloarthritis in general vary widely, from 0.52% to 1.3% in the United States, which suggests that the prevalence may be higher than the current estimated 0.6% prevalence of rheumatoid arthritis in the United States. The estimates of AS/spondyloarthritis in other parts of the world are even higher. The estimated prevalence in Norway, for example, ranges up to 6.7%.

A marked north/south gradient also exists in prevalence, and it mirrors the north/south gradient of HLA (human leukocyte antigen)–B27 gene prevalence in the indigenous populations worldwide, which is “tremendously variable.” HLA-B27 positivity is very high in northern areas, along with a higher prevalence of AS in northern areas.

These findings can be helpful for improving diagnosis, he said.

To make a correct – and earlier – diagnosis, use your perspective on inflammatory back pain, Dr. Weisman advised.

“Inflammatory back pain will be, for you, the greatest clue to be able to hone in on this diagnosis,” he said.

Onset at a young age, relatively long duration of pain, associated morning stiffness, awakening in the middle of the night, and no improvement with rest are classic signs of inflammatory back pain. In fact, at least one study has shown that among those with chronic back pain, about 5% will have AS; but in those with inflammatory back pain the probability is tripled to about 14%-15%. Adding other features can further improve diagnosis.

An emerging understanding of genetic influences, for example, is proving helpful for diagnosis. Heritability for AS is greater than 90%, with HLA-B serving as the major disease-associated locus. The HLA-B27 gene marker is present in about 90% of AS cases, although only about 5% of HLA-B27–positive individuals develop AS.

“So the current model is that AS is largely a monogenic disease with multiple modifying genes,” Dr. Weisman said at the meeting.

The ERAP1 and IL23R genes are other players.

If a frequency of a low AS prevalence estimate of 0.4% is assumed, HLA-B27 confers a probability of having AS of 3.6%. HLA-B27 along with ERAP1 increases that to about 10%, and the addition of both ERAP1 and IL23R increases it further to about 23%, Dr. Weisman said.

If patients with inflammatory back pain are considered, and a lower bound estimate of AS of about 10% is assumed in that population, the addition of B27 positivity increases AS likelihood to about 50%. The addition of ERAP1 and IL23R positivity increases AS likelihood to 80%-90%, he said.

However, these genes add only a small amount to the frequency of the genetic association in this disease, and there are certain caveats that must be considered, Dr. Weisman said. For example, the ERAP1 association with AS is not seen in the Chinese population, and the ERAP1 association is only found in those with HLA-B27 positivity, which implies a gene-gene interaction.

There remains a great deal of work to be done to define the genetic bases of AS, he said.

In the meantime, efforts to better determine AS prevalence based on newer classification criteria are underway.

Unlike the modified New York criteria, which used clear-cut radiographic sacroiliitis, new classification criteria for axial spondyloarthritis developed by the Assessments in Ankylosing Spondylitis Working Group uses additional features to increase sensitivity. One set of criteria uses HLA-B27 plus two additional features of spondyloarthritis for AS classification, and one uses sacroiliitis on imaging plus one spondyloarthritis feature to make a diagnosis. This increases sensitivity of screening to over 80%, he said (Ann. Rheum. Dis. 2009;68:777–83).

Furthermore, a screening questionnaire developed and published last year by Cedars-Sinai Medical Center to help improve diagnosis and to identify more patients on a population basis using various clinical features will be applied to National Health and Nutrition Examination Survey data for 2009–2010, which included a new survey on inflammatory back pain and spondyloarthritis. Together these seek to provide the first U.S. national inflammatory back pain estimate, and the first national U.S. study of HLA-B27 prevalence, Dr. Weisman said.

“With these two, we'll be able to find the lower bound of the true prevalence of ankylosing spondylitis in the United States,” he said.

Dr. Weisman had no financial disclosures to report.

Vitals: The diagnostic accuracy for spondyloarthritis was 70% when MRI is used.

Data Source: A long-term prospective follow-up of 708 patients with early, inflammatory back pain who were part of the French DESIR cohort.

Disclosures: Dr. Dougados has received grants for research projects and/or honorarium fees for participation at advisory boards/symposiums from Abbott, Bristol-Myers Squibb, Merck, Pfizer, Sanofi, and UCB.

NEW YORK – When magnetic resonance imaging is used instead of plain x-rays in patients with early inflammatory back pain, the diagnostic accuracy for spondyloarthritis jumps from 25% to 70%, according to Dr. Maxime Dougados.

“Seventy-five percent of the time, you cannot make the diagnosis with plain x-rays,” said Dr. Dougados, who is professor of rheumatology at the Paris-Descartes University/Cochin Hospital in Paris and the president-elect of EULAR. He presented the Ira Goldstein Memorial Lecture at the meeting, focusing on spondyloarthritis (SpA).

Dr. Dougados presented the as yet unpublished results from the DESIR cohort, a large French national multicenter database of long-term follow-up of 708 patients presenting with early inflammatory back pain that was initiated by the French Society of Rheumatology.

Patients were recruited between December 2007 and April 2010 if they had inflammatory back pain lasting more than 3 months and less than 3 years. The group will be followed for 10 years in the ongoing study.

At baseline, the mean age of the study population was 35 years, 54% were female and 57% were HLA-B27 positive (Joint Bone Spine 2011 March 30 [doi: 10.1016/j.jbspin.2011.01.013]).

With use of radiological sacroiliac changes, the diagnosis was “obvious” for 26% of the cohort, “doubtful” for 21%, and “normal” for 53%.

“These results indicate that at the first clinical visit, the interview is very important to pick up other clinical symptoms,” said Dr. Dougados. In fact, about 80% were found to have nonaxial clinical manifestations, including articular peripheral involvement, enthesopathy, dactylitis, anterior chest wall pain, uveitis, or psoriasis.

With MRI, 70% of the cohort were determined to have “obvious” sacroiliitis, about 20% had a “doubtful” diagnosis and about 10% were thought to be “normal.”

“These results indicate that you can detect early abnormalities of the sacroiliac joint on MRI even if x-rays are normal,” he said.

According to Dr. Dougados, these imaging findings fit well with recent results from the DECLIC study, in which 163 rheumatologists were asked to diagnose 472 patients with early inflammatory back pain, including 161 patients with spondyloarthritis, according to four different sets of criteria.

The specificity of the modified New York criteria, which relies on radiographic signs of sacroiliitis (unilateral grade III or bilateral grade II), fell well below that of the modified Amor criteria, the modified ESSG (European Spondyloarthropathy Study Group) criteria, and the ASAS (Assessment of Spondyloarthritis International Society) criteria.

The latter three criteria include the option of diagnosing sacroiliitis with MRI.

In the new classification criteria from the ASAS, separate criteria are listed for patients with axial SpA with and without peripheral manifestations and patients with peripheral manifestations only.

For axial SpA, one diagnostic pathway requires sacroiliitis on imaging plus one or more SpA feature. Sacroiliitis on MRI is given as much weight as is sacroiliitis on radiographs (Best Pract. Res. Clin. Rheumatol. 2010;24:589–604).

The other pathway requires HLA-B27 positivity plus two or more SpA features.

In patients who have peripheral manifestations only, the requirements include peripheral arthritis, enthesitis or dactylitis plus one or more spondyloarthritis features, including sacroiliitis on imaging.

Dr. Dougados also spoke about recent findings showing that patients with SpA were more likely to have distinct noninflammatory spinal MRI lesions (known as Fatty Romanus lesions) than were patients with degenerative arthritis or spinal malignancy (Ann. Rheum. Dis. 2010;69:891–94).

“As MRI is becoming more important, rheumatologists should be trained to interpret MRIs,” he said. “You don't need to be a specialist in radiology.”

Vitals

Source Elsevier Global Medical News

Vitals: The diagnostic accuracy for spondyloarthritis was 70% when MRI is used.

Data Source: A long-term prospective follow-up of 708 patients with early, inflammatory back pain who were part of the French DESIR cohort.

Disclosures: Dr. Dougados has received grants for research projects and/or honorarium fees for participation at advisory boards/symposiums from Abbott, Bristol-Myers Squibb, Merck, Pfizer, Sanofi, and UCB.

NEW YORK – When magnetic resonance imaging is used instead of plain x-rays in patients with early inflammatory back pain, the diagnostic accuracy for spondyloarthritis jumps from 25% to 70%, according to Dr. Maxime Dougados.

“Seventy-five percent of the time, you cannot make the diagnosis with plain x-rays,” said Dr. Dougados, who is professor of rheumatology at the Paris-Descartes University/Cochin Hospital in Paris and the president-elect of EULAR. He presented the Ira Goldstein Memorial Lecture at the meeting, focusing on spondyloarthritis (SpA).

Dr. Dougados presented the as yet unpublished results from the DESIR cohort, a large French national multicenter database of long-term follow-up of 708 patients presenting with early inflammatory back pain that was initiated by the French Society of Rheumatology.

Patients were recruited between December 2007 and April 2010 if they had inflammatory back pain lasting more than 3 months and less than 3 years. The group will be followed for 10 years in the ongoing study.

At baseline, the mean age of the study population was 35 years, 54% were female and 57% were HLA-B27 positive (Joint Bone Spine 2011 March 30 [doi: 10.1016/j.jbspin.2011.01.013]).

With use of radiological sacroiliac changes, the diagnosis was “obvious” for 26% of the cohort, “doubtful” for 21%, and “normal” for 53%.

“These results indicate that at the first clinical visit, the interview is very important to pick up other clinical symptoms,” said Dr. Dougados. In fact, about 80% were found to have nonaxial clinical manifestations, including articular peripheral involvement, enthesopathy, dactylitis, anterior chest wall pain, uveitis, or psoriasis.

With MRI, 70% of the cohort were determined to have “obvious” sacroiliitis, about 20% had a “doubtful” diagnosis and about 10% were thought to be “normal.”

“These results indicate that you can detect early abnormalities of the sacroiliac joint on MRI even if x-rays are normal,” he said.

According to Dr. Dougados, these imaging findings fit well with recent results from the DECLIC study, in which 163 rheumatologists were asked to diagnose 472 patients with early inflammatory back pain, including 161 patients with spondyloarthritis, according to four different sets of criteria.

The specificity of the modified New York criteria, which relies on radiographic signs of sacroiliitis (unilateral grade III or bilateral grade II), fell well below that of the modified Amor criteria, the modified ESSG (European Spondyloarthropathy Study Group) criteria, and the ASAS (Assessment of Spondyloarthritis International Society) criteria.

The latter three criteria include the option of diagnosing sacroiliitis with MRI.

In the new classification criteria from the ASAS, separate criteria are listed for patients with axial SpA with and without peripheral manifestations and patients with peripheral manifestations only.

For axial SpA, one diagnostic pathway requires sacroiliitis on imaging plus one or more SpA feature. Sacroiliitis on MRI is given as much weight as is sacroiliitis on radiographs (Best Pract. Res. Clin. Rheumatol. 2010;24:589–604).

The other pathway requires HLA-B27 positivity plus two or more SpA features.

In patients who have peripheral manifestations only, the requirements include peripheral arthritis, enthesitis or dactylitis plus one or more spondyloarthritis features, including sacroiliitis on imaging.

Dr. Dougados also spoke about recent findings showing that patients with SpA were more likely to have distinct noninflammatory spinal MRI lesions (known as Fatty Romanus lesions) than were patients with degenerative arthritis or spinal malignancy (Ann. Rheum. Dis. 2010;69:891–94).

“As MRI is becoming more important, rheumatologists should be trained to interpret MRIs,” he said. “You don't need to be a specialist in radiology.”

Vitals

Source Elsevier Global Medical News

Vitals: The diagnostic accuracy for spondyloarthritis was 70% when MRI is used.

Data Source: A long-term prospective follow-up of 708 patients with early, inflammatory back pain who were part of the French DESIR cohort.

Disclosures: Dr. Dougados has received grants for research projects and/or honorarium fees for participation at advisory boards/symposiums from Abbott, Bristol-Myers Squibb, Merck, Pfizer, Sanofi, and UCB.

NEW YORK – When magnetic resonance imaging is used instead of plain x-rays in patients with early inflammatory back pain, the diagnostic accuracy for spondyloarthritis jumps from 25% to 70%, according to Dr. Maxime Dougados.

“Seventy-five percent of the time, you cannot make the diagnosis with plain x-rays,” said Dr. Dougados, who is professor of rheumatology at the Paris-Descartes University/Cochin Hospital in Paris and the president-elect of EULAR. He presented the Ira Goldstein Memorial Lecture at the meeting, focusing on spondyloarthritis (SpA).

Dr. Dougados presented the as yet unpublished results from the DESIR cohort, a large French national multicenter database of long-term follow-up of 708 patients presenting with early inflammatory back pain that was initiated by the French Society of Rheumatology.

Patients were recruited between December 2007 and April 2010 if they had inflammatory back pain lasting more than 3 months and less than 3 years. The group will be followed for 10 years in the ongoing study.

At baseline, the mean age of the study population was 35 years, 54% were female and 57% were HLA-B27 positive (Joint Bone Spine 2011 March 30 [doi: 10.1016/j.jbspin.2011.01.013]).

With use of radiological sacroiliac changes, the diagnosis was “obvious” for 26% of the cohort, “doubtful” for 21%, and “normal” for 53%.

“These results indicate that at the first clinical visit, the interview is very important to pick up other clinical symptoms,” said Dr. Dougados. In fact, about 80% were found to have nonaxial clinical manifestations, including articular peripheral involvement, enthesopathy, dactylitis, anterior chest wall pain, uveitis, or psoriasis.

With MRI, 70% of the cohort were determined to have “obvious” sacroiliitis, about 20% had a “doubtful” diagnosis and about 10% were thought to be “normal.”

“These results indicate that you can detect early abnormalities of the sacroiliac joint on MRI even if x-rays are normal,” he said.

According to Dr. Dougados, these imaging findings fit well with recent results from the DECLIC study, in which 163 rheumatologists were asked to diagnose 472 patients with early inflammatory back pain, including 161 patients with spondyloarthritis, according to four different sets of criteria.

The specificity of the modified New York criteria, which relies on radiographic signs of sacroiliitis (unilateral grade III or bilateral grade II), fell well below that of the modified Amor criteria, the modified ESSG (European Spondyloarthropathy Study Group) criteria, and the ASAS (Assessment of Spondyloarthritis International Society) criteria.

The latter three criteria include the option of diagnosing sacroiliitis with MRI.

In the new classification criteria from the ASAS, separate criteria are listed for patients with axial SpA with and without peripheral manifestations and patients with peripheral manifestations only.

For axial SpA, one diagnostic pathway requires sacroiliitis on imaging plus one or more SpA feature. Sacroiliitis on MRI is given as much weight as is sacroiliitis on radiographs (Best Pract. Res. Clin. Rheumatol. 2010;24:589–604).

The other pathway requires HLA-B27 positivity plus two or more SpA features.

In patients who have peripheral manifestations only, the requirements include peripheral arthritis, enthesitis or dactylitis plus one or more spondyloarthritis features, including sacroiliitis on imaging.

Dr. Dougados also spoke about recent findings showing that patients with SpA were more likely to have distinct noninflammatory spinal MRI lesions (known as Fatty Romanus lesions) than were patients with degenerative arthritis or spinal malignancy (Ann. Rheum. Dis. 2010;69:891–94).

“As MRI is becoming more important, rheumatologists should be trained to interpret MRIs,” he said. “You don't need to be a specialist in radiology.”

Vitals

Source Elsevier Global Medical News

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data were culled from the British Society for Rheumatology Biologics Register.

Despite its relatively large size, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, the authors said.

“[W]ithout further evidence, guidelines that suggest these drugs should be avoided at the time of conception must remain” in place, recommended Dr. Suzanne M.M. Verstappen of the University of Manchester's Arthritis Research UK Epidemiology Unit, and her associates.

The investigators looked at women in the register who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception.

A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a “known risk of adverse pregnancy outcomes,” according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use but rather received nonbiologic disease-modifying antirheumatic drugs, excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies.

They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%), and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: The 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%).

There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were 0 terminations and 1 spontaneous abortion (10%).

The baseline disease activity score–28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University's Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, “The default choice would be to avoid these drugs during pregnancy. Starting their use in a women contemplating conception should be delayed based on the data on hand.”

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Roche, Shering-Plough, and Wyeth Pharmaceuticals.

They added that they had no personal competing interests in relation to this study.

View on the News

What I Tell My Pregnant Patients

The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P.M. Symmons.

There are, however, a few problems with that strategy. “Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!” she joked.

“Beyond that, we have to wait for anecdotal evidence to accumulate.”

In the meantime, she said, “We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment. There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug.”

According to Dr. Symmons, when treating a female patient of child-bearing age, “I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.

“This study is reassuring for us to continue our current practice.”

DR. SYMMONS is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, England. She had no financial interests to disclose.

Vitals

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data were culled from the British Society for Rheumatology Biologics Register.

Despite its relatively large size, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, the authors said.

“[W]ithout further evidence, guidelines that suggest these drugs should be avoided at the time of conception must remain” in place, recommended Dr. Suzanne M.M. Verstappen of the University of Manchester's Arthritis Research UK Epidemiology Unit, and her associates.

The investigators looked at women in the register who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception.

A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a “known risk of adverse pregnancy outcomes,” according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use but rather received nonbiologic disease-modifying antirheumatic drugs, excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies.

They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%), and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: The 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%).

There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were 0 terminations and 1 spontaneous abortion (10%).

The baseline disease activity score–28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University's Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, “The default choice would be to avoid these drugs during pregnancy. Starting their use in a women contemplating conception should be delayed based on the data on hand.”

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Roche, Shering-Plough, and Wyeth Pharmaceuticals.

They added that they had no personal competing interests in relation to this study.

View on the News

What I Tell My Pregnant Patients

The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P.M. Symmons.

There are, however, a few problems with that strategy. “Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!” she joked.

“Beyond that, we have to wait for anecdotal evidence to accumulate.”

In the meantime, she said, “We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment. There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug.”

According to Dr. Symmons, when treating a female patient of child-bearing age, “I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.

“This study is reassuring for us to continue our current practice.”

DR. SYMMONS is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, England. She had no financial interests to disclose.

Vitals

Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data were culled from the British Society for Rheumatology Biologics Register.

Despite its relatively large size, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, the authors said.

“[W]ithout further evidence, guidelines that suggest these drugs should be avoided at the time of conception must remain” in place, recommended Dr. Suzanne M.M. Verstappen of the University of Manchester's Arthritis Research UK Epidemiology Unit, and her associates.

The investigators looked at women in the register who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception.

A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a “known risk of adverse pregnancy outcomes,” according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use but rather received nonbiologic disease-modifying antirheumatic drugs, excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies.

They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%), and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: The 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%).

There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were 0 terminations and 1 spontaneous abortion (10%).

The baseline disease activity score–28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University's Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, “The default choice would be to avoid these drugs during pregnancy. Starting their use in a women contemplating conception should be delayed based on the data on hand.”

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Roche, Shering-Plough, and Wyeth Pharmaceuticals.

They added that they had no personal competing interests in relation to this study.

View on the News

What I Tell My Pregnant Patients

The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P.M. Symmons.

There are, however, a few problems with that strategy. “Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!” she joked.

“Beyond that, we have to wait for anecdotal evidence to accumulate.”

In the meantime, she said, “We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment. There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug.”

According to Dr. Symmons, when treating a female patient of child-bearing age, “I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.

“This study is reassuring for us to continue our current practice.”

DR. SYMMONS is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, England. She had no financial interests to disclose.

Vitals

Major finding: Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduced risk (HR 0.83, 95% CI 0.44–1.57) of the primary composite CV end point of myocardial infarction, stroke, and CV-related death in patients with rheumatoid arthritis. Patients using a TNF inhibitor had a 61% reduced risk (HR 0.39, 95% CI 0.18–0.74) of the end point.

Data source: Longitudinal cohort study of the CORRONA registry.

Disclosures: Dr. Greenberg has done consulting for Centocor, CORRONA, Novartis Pharmaceuticals, Roche Laboratories, and UCB. He has received research and grant support from the Arthritis Foundation and the National Institutes of Health. He receives consulting fees from, or owns stock shares in, AstraZeneca, CORRONA, Genentech, Novartis, and Pfizer.

NEW YORK – Tumor necrosis factor inhibitors reduced the risk of myocardial infarction, stroke, and cardiovascular-related disease in patients with rheumatoid arthritis, according to Dr. Jeffrey D. Greenberg, who presented the findings at the meeting. Methotrexate was not associated with a reduced risk of cardiovascular events, and prednisone use was associated with a dose-dependent increased risk.

The findings come from CORRONA (Consortium of Rheumatology Researchers of North America), a registry of patients with RA or psoriatic arthritis. The study population involved 10,156 patients followed for a median of 23 months. A subset analysis was performed and 88 patients were identified who had experienced nonfatal myocardial infarction (n = 26), transient ischemic attack or stroke (n = 45), or CV-related death (n = 17) (Ann. Rheum. Dis. 2011;70:576–82).

In an editorial accompanying Dr. Greenberg's report (Ann. Rheum. Dis. 2011 70:561–2), Dr. Johan Askling of Karolinska University Hospital, Stockholm, and Dr. Will Dixon of the University of Manchester (England) praised the study's methodology and transparency. But they noted that other studies, like those published by the British Society for Rheumatology Biologics Register (BSRBR), do not support a CV protective effect for TNF inhibitors.

Nonbiologic disease-modifying antirheumatic drugs (DMARDs) other than methotrexate served as the reference cohort for all comparisons. Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduction in risk (hazard ratio 0.83, 95% confidence interval C0.44–1.57). In contrast, patients using a TNF inhibitor had a 61% lower risk of the primary composite CV end point (HR 0.39, 95% CI 0.18–0.74).

Dr. Greenberg also showed significant reductions in risk for those taking TNF inhibitors compared with those taking nonbiological DMARDs, as measured by a composite end point that included CV deaths (HR 0.39, 95% CI 0.19–0.82) and a composite end point that excluded CV deaths (HR 0.35, 95% CI 0.16–0.74), and nonfatal MI (HR 0.24, 95% CI 0.06–0.95). There was a trend toward reduced risk for nonfatal TIA/stroke (HR 0.44, 95% CI 0.18–1.09). “These data indicate that TNF antagonists may represent a therapeutic strategy to attenuate the heightened CV risk experienced by RA patients,” Dr. Greenberg said.

“As expected, there was a dose-dependent increased risk of CV events with steroids,” said Dr. Greenberg of New York University. Prednisone dosesbof 1–2.5 mg and 3–7 mg almost doubled the risk (HR 1.90 and 1.89, respectively) while doses greater than 7 mg tripled the risk (HR 3.00, 95% CI 1.44–6.25) (p = 0.04).

Dr. Greenberg advocates a three-step strategy to decrease CV risk in RA. The first is to adhere to recommended CV disease prevention, screening, and guidelines. This includes management of “traditional” CV risk factors such as blood pressure, diabetes, lipids, smoking, and obesity, he said. The second component – as supported by his study's results – is to minimize use of NSAIDs and steroids, and to utilize steroid-sparing options if possible. The third component is to aim for tighter control of RA disease activity.

For patients at increased CV risk, “I would treat RA aggressively,” said Dr. Greenberg. Even so, he acknowledged that it has not been proved that the strategy would alter the natural course of developing CV disease. Measures that should be targeted might include a specific disease activity score, C-reactive protein levels, or other inflammatory biomarkers, he said.

Major finding: Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduced risk (HR 0.83, 95% CI 0.44–1.57) of the primary composite CV end point of myocardial infarction, stroke, and CV-related death in patients with rheumatoid arthritis. Patients using a TNF inhibitor had a 61% reduced risk (HR 0.39, 95% CI 0.18–0.74) of the end point.

Data source: Longitudinal cohort study of the CORRONA registry.

Disclosures: Dr. Greenberg has done consulting for Centocor, CORRONA, Novartis Pharmaceuticals, Roche Laboratories, and UCB. He has received research and grant support from the Arthritis Foundation and the National Institutes of Health. He receives consulting fees from, or owns stock shares in, AstraZeneca, CORRONA, Genentech, Novartis, and Pfizer.

NEW YORK – Tumor necrosis factor inhibitors reduced the risk of myocardial infarction, stroke, and cardiovascular-related disease in patients with rheumatoid arthritis, according to Dr. Jeffrey D. Greenberg, who presented the findings at the meeting. Methotrexate was not associated with a reduced risk of cardiovascular events, and prednisone use was associated with a dose-dependent increased risk.

The findings come from CORRONA (Consortium of Rheumatology Researchers of North America), a registry of patients with RA or psoriatic arthritis. The study population involved 10,156 patients followed for a median of 23 months. A subset analysis was performed and 88 patients were identified who had experienced nonfatal myocardial infarction (n = 26), transient ischemic attack or stroke (n = 45), or CV-related death (n = 17) (Ann. Rheum. Dis. 2011;70:576–82).

In an editorial accompanying Dr. Greenberg's report (Ann. Rheum. Dis. 2011 70:561–2), Dr. Johan Askling of Karolinska University Hospital, Stockholm, and Dr. Will Dixon of the University of Manchester (England) praised the study's methodology and transparency. But they noted that other studies, like those published by the British Society for Rheumatology Biologics Register (BSRBR), do not support a CV protective effect for TNF inhibitors.

Nonbiologic disease-modifying antirheumatic drugs (DMARDs) other than methotrexate served as the reference cohort for all comparisons. Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduction in risk (hazard ratio 0.83, 95% confidence interval C0.44–1.57). In contrast, patients using a TNF inhibitor had a 61% lower risk of the primary composite CV end point (HR 0.39, 95% CI 0.18–0.74).

Dr. Greenberg also showed significant reductions in risk for those taking TNF inhibitors compared with those taking nonbiological DMARDs, as measured by a composite end point that included CV deaths (HR 0.39, 95% CI 0.19–0.82) and a composite end point that excluded CV deaths (HR 0.35, 95% CI 0.16–0.74), and nonfatal MI (HR 0.24, 95% CI 0.06–0.95). There was a trend toward reduced risk for nonfatal TIA/stroke (HR 0.44, 95% CI 0.18–1.09). “These data indicate that TNF antagonists may represent a therapeutic strategy to attenuate the heightened CV risk experienced by RA patients,” Dr. Greenberg said.

“As expected, there was a dose-dependent increased risk of CV events with steroids,” said Dr. Greenberg of New York University. Prednisone dosesbof 1–2.5 mg and 3–7 mg almost doubled the risk (HR 1.90 and 1.89, respectively) while doses greater than 7 mg tripled the risk (HR 3.00, 95% CI 1.44–6.25) (p = 0.04).

Dr. Greenberg advocates a three-step strategy to decrease CV risk in RA. The first is to adhere to recommended CV disease prevention, screening, and guidelines. This includes management of “traditional” CV risk factors such as blood pressure, diabetes, lipids, smoking, and obesity, he said. The second component – as supported by his study's results – is to minimize use of NSAIDs and steroids, and to utilize steroid-sparing options if possible. The third component is to aim for tighter control of RA disease activity.

For patients at increased CV risk, “I would treat RA aggressively,” said Dr. Greenberg. Even so, he acknowledged that it has not been proved that the strategy would alter the natural course of developing CV disease. Measures that should be targeted might include a specific disease activity score, C-reactive protein levels, or other inflammatory biomarkers, he said.

Major finding: Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduced risk (HR 0.83, 95% CI 0.44–1.57) of the primary composite CV end point of myocardial infarction, stroke, and CV-related death in patients with rheumatoid arthritis. Patients using a TNF inhibitor had a 61% reduced risk (HR 0.39, 95% CI 0.18–0.74) of the end point.

Data source: Longitudinal cohort study of the CORRONA registry.

Disclosures: Dr. Greenberg has done consulting for Centocor, CORRONA, Novartis Pharmaceuticals, Roche Laboratories, and UCB. He has received research and grant support from the Arthritis Foundation and the National Institutes of Health. He receives consulting fees from, or owns stock shares in, AstraZeneca, CORRONA, Genentech, Novartis, and Pfizer.

NEW YORK – Tumor necrosis factor inhibitors reduced the risk of myocardial infarction, stroke, and cardiovascular-related disease in patients with rheumatoid arthritis, according to Dr. Jeffrey D. Greenberg, who presented the findings at the meeting. Methotrexate was not associated with a reduced risk of cardiovascular events, and prednisone use was associated with a dose-dependent increased risk.

The findings come from CORRONA (Consortium of Rheumatology Researchers of North America), a registry of patients with RA or psoriatic arthritis. The study population involved 10,156 patients followed for a median of 23 months. A subset analysis was performed and 88 patients were identified who had experienced nonfatal myocardial infarction (n = 26), transient ischemic attack or stroke (n = 45), or CV-related death (n = 17) (Ann. Rheum. Dis. 2011;70:576–82).

In an editorial accompanying Dr. Greenberg's report (Ann. Rheum. Dis. 2011 70:561–2), Dr. Johan Askling of Karolinska University Hospital, Stockholm, and Dr. Will Dixon of the University of Manchester (England) praised the study's methodology and transparency. But they noted that other studies, like those published by the British Society for Rheumatology Biologics Register (BSRBR), do not support a CV protective effect for TNF inhibitors.

Nonbiologic disease-modifying antirheumatic drugs (DMARDs) other than methotrexate served as the reference cohort for all comparisons. Relative to nonbiologic DMARDs, methotrexate use was associated with a nonsignificant reduction in risk (hazard ratio 0.83, 95% confidence interval C0.44–1.57). In contrast, patients using a TNF inhibitor had a 61% lower risk of the primary composite CV end point (HR 0.39, 95% CI 0.18–0.74).

Dr. Greenberg also showed significant reductions in risk for those taking TNF inhibitors compared with those taking nonbiological DMARDs, as measured by a composite end point that included CV deaths (HR 0.39, 95% CI 0.19–0.82) and a composite end point that excluded CV deaths (HR 0.35, 95% CI 0.16–0.74), and nonfatal MI (HR 0.24, 95% CI 0.06–0.95). There was a trend toward reduced risk for nonfatal TIA/stroke (HR 0.44, 95% CI 0.18–1.09). “These data indicate that TNF antagonists may represent a therapeutic strategy to attenuate the heightened CV risk experienced by RA patients,” Dr. Greenberg said.

“As expected, there was a dose-dependent increased risk of CV events with steroids,” said Dr. Greenberg of New York University. Prednisone dosesbof 1–2.5 mg and 3–7 mg almost doubled the risk (HR 1.90 and 1.89, respectively) while doses greater than 7 mg tripled the risk (HR 3.00, 95% CI 1.44–6.25) (p = 0.04).

Dr. Greenberg advocates a three-step strategy to decrease CV risk in RA. The first is to adhere to recommended CV disease prevention, screening, and guidelines. This includes management of “traditional” CV risk factors such as blood pressure, diabetes, lipids, smoking, and obesity, he said. The second component – as supported by his study's results – is to minimize use of NSAIDs and steroids, and to utilize steroid-sparing options if possible. The third component is to aim for tighter control of RA disease activity.

For patients at increased CV risk, “I would treat RA aggressively,” said Dr. Greenberg. Even so, he acknowledged that it has not been proved that the strategy would alter the natural course of developing CV disease. Measures that should be targeted might include a specific disease activity score, C-reactive protein levels, or other inflammatory biomarkers, he said.

Major Finding: Joint space narrowing significantly corresponded with increasing disability in patients with rheumatoid arthritis.

Data Source: Pooled data from several clinical trials of patients in remission from rheumatoid arthritis.

Disclosures: Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis, and Wyeth (later acquired by Pfizer). None of the authors disclosed financial conflicts of interest in relation to this study.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce patients' disability should focus on cartilage preservation, “since even relatively little cartilage degradation can lead to significant impairment of physical functioning,” wrote Dr. Daniel Aletaha of the division of rheumatology at the Medical University of Vienna and his colleagues.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide.

“To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component],” Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733–9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis.

Patient data were assessed at the first visit in which a patient was in remission, and that visit's corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as “the best estimate of the patient's irreversible functional disability” for the current study, the investigators wrote.

The HAQ-DI scale has a 0–3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO).

As was expected, in the univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as the JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

“Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased,” wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

“In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability,” such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered “prototypic for RA,” whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, “in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone,” Dr. Aletaha and his coauthors wrote.

“The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA,” they concluded.

Major Finding: Joint space narrowing significantly corresponded with increasing disability in patients with rheumatoid arthritis.

Data Source: Pooled data from several clinical trials of patients in remission from rheumatoid arthritis.

Disclosures: Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis, and Wyeth (later acquired by Pfizer). None of the authors disclosed financial conflicts of interest in relation to this study.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce patients' disability should focus on cartilage preservation, “since even relatively little cartilage degradation can lead to significant impairment of physical functioning,” wrote Dr. Daniel Aletaha of the division of rheumatology at the Medical University of Vienna and his colleagues.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide.

“To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component],” Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733–9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis.

Patient data were assessed at the first visit in which a patient was in remission, and that visit's corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as “the best estimate of the patient's irreversible functional disability” for the current study, the investigators wrote.

The HAQ-DI scale has a 0–3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO).

As was expected, in the univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as the JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

“Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased,” wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

“In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability,” such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered “prototypic for RA,” whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, “in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone,” Dr. Aletaha and his coauthors wrote.

“The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA,” they concluded.

Major Finding: Joint space narrowing significantly corresponded with increasing disability in patients with rheumatoid arthritis.

Data Source: Pooled data from several clinical trials of patients in remission from rheumatoid arthritis.

Disclosures: Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis, and Wyeth (later acquired by Pfizer). None of the authors disclosed financial conflicts of interest in relation to this study.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce patients' disability should focus on cartilage preservation, “since even relatively little cartilage degradation can lead to significant impairment of physical functioning,” wrote Dr. Daniel Aletaha of the division of rheumatology at the Medical University of Vienna and his colleagues.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide.

“To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component],” Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733–9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis.

Patient data were assessed at the first visit in which a patient was in remission, and that visit's corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as “the best estimate of the patient's irreversible functional disability” for the current study, the investigators wrote.

The HAQ-DI scale has a 0–3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO).

As was expected, in the univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as the JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

“Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased,” wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

“In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability,” such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered “prototypic for RA,” whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, “in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone,” Dr. Aletaha and his coauthors wrote.

“The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA,” they concluded.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

“We'd like to believe we're actually doing something substantial for our patients in addition to actually relieving symptoms,” said Dr. Michael H. Weisman, adding that this is an area of “hot, current controversy.”

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rheum. Engl. Ed. 1995;62:10–5), Dr. Weisman said.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205–15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52[6];1756–65) h most experts “take this particular study with a grain of salt,” Dr. Weisman said.

That's in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It's very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010;69:1756–61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

“We really don't know why syndesmophytes form in this disease,” he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

“We'd like to believe we're actually doing something substantial for our patients in addition to actually relieving symptoms,” said Dr. Michael H. Weisman, adding that this is an area of “hot, current controversy.”

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rheum. Engl. Ed. 1995;62:10–5), Dr. Weisman said.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205–15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52[6];1756–65) h most experts “take this particular study with a grain of salt,” Dr. Weisman said.

That's in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It's very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010;69:1756–61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

“We really don't know why syndesmophytes form in this disease,” he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

“We'd like to believe we're actually doing something substantial for our patients in addition to actually relieving symptoms,” said Dr. Michael H. Weisman, adding that this is an area of “hot, current controversy.”

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rheum. Engl. Ed. 1995;62:10–5), Dr. Weisman said.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205–15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52[6];1756–65) h most experts “take this particular study with a grain of salt,” Dr. Weisman said.

That's in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It's very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010;69:1756–61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

“We really don't know why syndesmophytes form in this disease,” he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

Major Finding: For every 0.6-point increase on the DAS28, there was a corresponding 4% increase in outpatient infections; for every 5 points on the CDAI, there was a 14% increase, for all CDAI scores less than 10.

Data Source: More than 2,000 infections that were registered through the CORRONA database between March 2002 and December 2007.

Disclosures: Several of the authors reported contracts and professional affiliations with the CORRONA database. Several also reported financial relationships with multiple pharmaceutical companies, including Amgen, Centocor, Pfizer, Roche/Genentech, and UCB.

Increasing disease activity in rheumatoid arthritis is associated with a higher risk for both outpatient infections and more serious infections requiring hospitalization in patients receiving stable therapy.

Moreover, this finding was true even among patients with mild disease activity, according to Dr. Karen Au of the division of rheumatology at the University of California, Los Angeles.

Dr. Au and her colleagues looked at 6,246 patients with RA who were listed on the CORRONA (Consortium of Rheumatology Researchers of North America) registry, which includes data contributed by 80 academic and private practices across the United States.

The patients' mean age was 60 years; 75% were women. CDAI (Clinical Disease Activity Index) scores were available for 6,020 patients. DAS28 (disease activity score based on a 28-joint count) was calculated throughout the study period for 3,666 patients (Ann. Rheum. Dis. 2011;70:785–91).

“To minimize confounding related to recent changes in disease-modifying medications on the rate of infections, we limited the study to RA patients on stable therapy” (defined as no change in the dose of either methotrexate, TNF (tumor necrosis factor) inhibitor, corticosteroid, or any other disease-modifying anti rheumatic drug over three consecutive visits spanning at least 6 months), they said.

Overall, 2,282 infections were reported during the study period, from March 2002 to December 2007; 1,382 patients had one or more outpatient infections and 50 patients had serious infections that required hospitalization.

Most of the infections tallied (2,223 of the total 2,282) were outpatient.

When outpatient infections alone were considered, researchers found that for all patients with CDAI scores less than 10 of a possible 76 (corresponding to the mildest class of disease), there was a 14% increase in outpatient infections for each 5-point increase in score, after the researchers controlled for covariates including body mass index, smoking, disease duration, therapy, and coexisting cardiovascular disease (incidence rate ratio, 1.14; P = .003).

And although no further linear relationship was noted, patients with moderate (CDAI scores of 10–22) and high (CDAI scores greater than 22) disease activity had increased infections, compared with patients with mild disease activity, although only the moderate category was statistically significant (IRR for moderate activity compared with low activity, 1.19; 95% confidence interval, 1.06–1.34; IRR for high activity, 1.07; 95% CI 0.90–1.27).

Among patients for whom DAS28 data were available, there was a 4% increase in outpatient infections for each 0.6-point increase in the score, which persisted throughout the entire DAS28 spectrum (IRR, 1.04; P = .03).

A history of infections increased the likelihood of having an outpatient infection (IRR, 2.84–3.15; P less than .001), as did use of methotrexate, use of TNF inhibitors, and poorer functional class.

Although infections requiring hospitalization were much less frequent among the study participants, the authors were able to identify that for every 0.6-point increase in the DAS28, there was a corresponding significant 25% increase in the rate of infections that required hospitalization.

On the CDAI scale, there was no significant trend between an increasing score and inpatient infections on multivariate analysis, likely because of the small number of inpatient infections observed, according to the authors.

Prednisone use of 7.5 mg daily or more was also independently associated with infections that required hospitalization, as was a history of infection. Previous studies have shown that RA patients have a twofold increased risk of developing infections, compared with patients who do not have RA, and they are also at higher risk of serious infections requiring hospitalization, they said.

Indeed, they added, the “continued increased mortality observed in RA patients compared with the general population can be explained partly by a higher susceptibility to infections.”

The strength of this study, they pointed out, lies in the size and quality of the prospectively collected clinical data in the CORRONA database.

Major Finding: For every 0.6-point increase on the DAS28, there was a corresponding 4% increase in outpatient infections; for every 5 points on the CDAI, there was a 14% increase, for all CDAI scores less than 10.

Data Source: More than 2,000 infections that were registered through the CORRONA database between March 2002 and December 2007.

Disclosures: Several of the authors reported contracts and professional affiliations with the CORRONA database. Several also reported financial relationships with multiple pharmaceutical companies, including Amgen, Centocor, Pfizer, Roche/Genentech, and UCB.

Increasing disease activity in rheumatoid arthritis is associated with a higher risk for both outpatient infections and more serious infections requiring hospitalization in patients receiving stable therapy.

Moreover, this finding was true even among patients with mild disease activity, according to Dr. Karen Au of the division of rheumatology at the University of California, Los Angeles.

Dr. Au and her colleagues looked at 6,246 patients with RA who were listed on the CORRONA (Consortium of Rheumatology Researchers of North America) registry, which includes data contributed by 80 academic and private practices across the United States.

The patients' mean age was 60 years; 75% were women. CDAI (Clinical Disease Activity Index) scores were available for 6,020 patients. DAS28 (disease activity score based on a 28-joint count) was calculated throughout the study period for 3,666 patients (Ann. Rheum. Dis. 2011;70:785–91).

“To minimize confounding related to recent changes in disease-modifying medications on the rate of infections, we limited the study to RA patients on stable therapy” (defined as no change in the dose of either methotrexate, TNF (tumor necrosis factor) inhibitor, corticosteroid, or any other disease-modifying anti rheumatic drug over three consecutive visits spanning at least 6 months), they said.

Overall, 2,282 infections were reported during the study period, from March 2002 to December 2007; 1,382 patients had one or more outpatient infections and 50 patients had serious infections that required hospitalization.

Most of the infections tallied (2,223 of the total 2,282) were outpatient.

When outpatient infections alone were considered, researchers found that for all patients with CDAI scores less than 10 of a possible 76 (corresponding to the mildest class of disease), there was a 14% increase in outpatient infections for each 5-point increase in score, after the researchers controlled for covariates including body mass index, smoking, disease duration, therapy, and coexisting cardiovascular disease (incidence rate ratio, 1.14; P = .003).

And although no further linear relationship was noted, patients with moderate (CDAI scores of 10–22) and high (CDAI scores greater than 22) disease activity had increased infections, compared with patients with mild disease activity, although only the moderate category was statistically significant (IRR for moderate activity compared with low activity, 1.19; 95% confidence interval, 1.06–1.34; IRR for high activity, 1.07; 95% CI 0.90–1.27).

Among patients for whom DAS28 data were available, there was a 4% increase in outpatient infections for each 0.6-point increase in the score, which persisted throughout the entire DAS28 spectrum (IRR, 1.04; P = .03).

A history of infections increased the likelihood of having an outpatient infection (IRR, 2.84–3.15; P less than .001), as did use of methotrexate, use of TNF inhibitors, and poorer functional class.

Although infections requiring hospitalization were much less frequent among the study participants, the authors were able to identify that for every 0.6-point increase in the DAS28, there was a corresponding significant 25% increase in the rate of infections that required hospitalization.

On the CDAI scale, there was no significant trend between an increasing score and inpatient infections on multivariate analysis, likely because of the small number of inpatient infections observed, according to the authors.

Prednisone use of 7.5 mg daily or more was also independently associated with infections that required hospitalization, as was a history of infection. Previous studies have shown that RA patients have a twofold increased risk of developing infections, compared with patients who do not have RA, and they are also at higher risk of serious infections requiring hospitalization, they said.

Indeed, they added, the “continued increased mortality observed in RA patients compared with the general population can be explained partly by a higher susceptibility to infections.”

The strength of this study, they pointed out, lies in the size and quality of the prospectively collected clinical data in the CORRONA database.

Major Finding: For every 0.6-point increase on the DAS28, there was a corresponding 4% increase in outpatient infections; for every 5 points on the CDAI, there was a 14% increase, for all CDAI scores less than 10.

Data Source: More than 2,000 infections that were registered through the CORRONA database between March 2002 and December 2007.

Disclosures: Several of the authors reported contracts and professional affiliations with the CORRONA database. Several also reported financial relationships with multiple pharmaceutical companies, including Amgen, Centocor, Pfizer, Roche/Genentech, and UCB.

Increasing disease activity in rheumatoid arthritis is associated with a higher risk for both outpatient infections and more serious infections requiring hospitalization in patients receiving stable therapy.

Moreover, this finding was true even among patients with mild disease activity, according to Dr. Karen Au of the division of rheumatology at the University of California, Los Angeles.

Dr. Au and her colleagues looked at 6,246 patients with RA who were listed on the CORRONA (Consortium of Rheumatology Researchers of North America) registry, which includes data contributed by 80 academic and private practices across the United States.

The patients' mean age was 60 years; 75% were women. CDAI (Clinical Disease Activity Index) scores were available for 6,020 patients. DAS28 (disease activity score based on a 28-joint count) was calculated throughout the study period for 3,666 patients (Ann. Rheum. Dis. 2011;70:785–91).

“To minimize confounding related to recent changes in disease-modifying medications on the rate of infections, we limited the study to RA patients on stable therapy” (defined as no change in the dose of either methotrexate, TNF (tumor necrosis factor) inhibitor, corticosteroid, or any other disease-modifying anti rheumatic drug over three consecutive visits spanning at least 6 months), they said.

Overall, 2,282 infections were reported during the study period, from March 2002 to December 2007; 1,382 patients had one or more outpatient infections and 50 patients had serious infections that required hospitalization.

Most of the infections tallied (2,223 of the total 2,282) were outpatient.

When outpatient infections alone were considered, researchers found that for all patients with CDAI scores less than 10 of a possible 76 (corresponding to the mildest class of disease), there was a 14% increase in outpatient infections for each 5-point increase in score, after the researchers controlled for covariates including body mass index, smoking, disease duration, therapy, and coexisting cardiovascular disease (incidence rate ratio, 1.14; P = .003).

And although no further linear relationship was noted, patients with moderate (CDAI scores of 10–22) and high (CDAI scores greater than 22) disease activity had increased infections, compared with patients with mild disease activity, although only the moderate category was statistically significant (IRR for moderate activity compared with low activity, 1.19; 95% confidence interval, 1.06–1.34; IRR for high activity, 1.07; 95% CI 0.90–1.27).

Among patients for whom DAS28 data were available, there was a 4% increase in outpatient infections for each 0.6-point increase in the score, which persisted throughout the entire DAS28 spectrum (IRR, 1.04; P = .03).

A history of infections increased the likelihood of having an outpatient infection (IRR, 2.84–3.15; P less than .001), as did use of methotrexate, use of TNF inhibitors, and poorer functional class.

Although infections requiring hospitalization were much less frequent among the study participants, the authors were able to identify that for every 0.6-point increase in the DAS28, there was a corresponding significant 25% increase in the rate of infections that required hospitalization.

On the CDAI scale, there was no significant trend between an increasing score and inpatient infections on multivariate analysis, likely because of the small number of inpatient infections observed, according to the authors.

Prednisone use of 7.5 mg daily or more was also independently associated with infections that required hospitalization, as was a history of infection. Previous studies have shown that RA patients have a twofold increased risk of developing infections, compared with patients who do not have RA, and they are also at higher risk of serious infections requiring hospitalization, they said.

Indeed, they added, the “continued increased mortality observed in RA patients compared with the general population can be explained partly by a higher susceptibility to infections.”

The strength of this study, they pointed out, lies in the size and quality of the prospectively collected clinical data in the CORRONA database.