Nancy Walsh

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and rheumatoid arthritis (RA) is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, Dr. Daniel Edmundowicz said.

“But in any case, the process is driven by dyslipidemia,” he said.

“We are born with LDL cholesterol levels around 35–40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble,” he said.

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral artery disease who have a high prevalence of CAD events such as fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol.

“In my opinion, patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs. With a 40-mg dose of simvastatin you can get almost a 40% reduction in LDL,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Benefits of exercise training in patients with RA and lupus include improvements in aerobic capacity, endurance, and strength, and can help decrease joint swelling and pain, increase social activity, and reduce depression and anxiety.

Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads in exercise training can be very beneficial, he said. “You can't forget these things,” he said. “Atherosclerosis is killing our patients. The charge to a community of physicians who take care of very-high-risk patients like yours is not to leave it to the other guy.”

Dr. Edmundowicz disclosed that he is a consultant to GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and rheumatoid arthritis (RA) is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, Dr. Daniel Edmundowicz said.

“But in any case, the process is driven by dyslipidemia,” he said.

“We are born with LDL cholesterol levels around 35–40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble,” he said.

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral artery disease who have a high prevalence of CAD events such as fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol.

“In my opinion, patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs. With a 40-mg dose of simvastatin you can get almost a 40% reduction in LDL,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Benefits of exercise training in patients with RA and lupus include improvements in aerobic capacity, endurance, and strength, and can help decrease joint swelling and pain, increase social activity, and reduce depression and anxiety.

Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads in exercise training can be very beneficial, he said. “You can't forget these things,” he said. “Atherosclerosis is killing our patients. The charge to a community of physicians who take care of very-high-risk patients like yours is not to leave it to the other guy.”

Dr. Edmundowicz disclosed that he is a consultant to GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Patients with systemic lupus erythematosus and rheumatoid arthritis should be considered in a cardiovascular risk category equivalent to that of patients with diabetes, with aggressive management of risk factors, particularly dyslipidemia, according to experts.

It is not yet clear whether the increased incidence of coronary artery disease (CAD) in patients with lupus and rheumatoid arthritis (RA) is a result of rheumatic factors that drive the atherosclerotic process, or if risk factors in the milieu of rheumatic disease cause patients to be more vulnerable, Dr. Daniel Edmundowicz said.

“But in any case, the process is driven by dyslipidemia,” he said.

“We are born with LDL cholesterol levels around 35–40 mg/dL, and a lab result that says you are normal at 130 mg/dL is wrong—that's average but it's abnormal for homo sapiens, and if you are vulnerable you are in trouble,” he said.

Because of this vulnerability, “many of us feel that patients with rheumatologic diseases should be considered CHD [coronary heart disease] risk equivalents,” said Dr. Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute.

“CHD risk equivalent” is the designation given by the National Cholesterol Education Program (NCEP) to people with diabetes and conditions such as peripheral artery disease who have a high prevalence of CAD events such as fatal and nonfatal myocardial infarction.

Currently, NCEP practice guidelines suggest that patients who are CHD risk equivalents be treated aggressively with regard to their risk factors such as cholesterol.

“In my opinion, patients with rheumatologic diseases should be reaching the same aggressive risk factor goals, which would mean non-HDL cholesterol less than 130 mg/dL or less than 100 mg/dL for patients who already have CAD, and LDL cholesterol of less than 100 mg/dL or less than 70 mg/dL if they already have CAD,” he said.

For many patients, meeting these goals will require statins, Dr. Edmundowicz said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

“Over the past 20 years, we have demonstrated that statin therapy is safe, and there now are effective and inexpensive generic lipid-lowering drugs. With a 40-mg dose of simvastatin you can get almost a 40% reduction in LDL,” he said.

But with aggressive statin therapy it is important to realize that titration of the drugs provides minimal additive benefits and can increase toxicity. “If you start your patient on 40 mg of simvastatin and then raise it to 80 mg you are probably only going to get an additional 5% of lowering of lipoproteins but you are much more likely to get myalgias,” he said.

Additive or combination lipid therapy is now becoming much more popular, utilizing agents that have different mechanisms of action. For example, blocking cholesterol uptake with ezetimibe and absorbing biliary cholesterol with bile acid sequestrants can provide very effective lowering of LDL, he said.

Attention also must be paid to lowering blood pressure, smoking cessation, and increasing physical activity. Benefits of exercise training in patients with RA and lupus include improvements in aerobic capacity, endurance, and strength, and can help decrease joint swelling and pain, increase social activity, and reduce depression and anxiety.

Of course, these patients have considerable limitations, with restricted joint range of motion and deconditioning, but even small inroads in exercise training can be very beneficial, he said. “You can't forget these things,” he said. “Atherosclerosis is killing our patients. The charge to a community of physicians who take care of very-high-risk patients like yours is not to leave it to the other guy.”

Dr. Edmundowicz disclosed that he is a consultant to GNC, Merck & Co., Schering Plough, and Takeda. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for a condition with such protean manifestations and inconsistent course, for which there has not been a new drug approved for 50 years.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes NSAIDs, cyclophosphamide, azathioprine, and cyclosporine, there has been considerable enthusiasm in the lupus community for the newer immunosuppressants and biologic agents that have revolutionized treatment of other rheumatic diseases. Unfortunately, results thus far have been somewhat disappointing, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered to be effective—if toxic—by the lupus community, although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. More than half of patients in the trial were black, and a subanalysis determined that the nonwhite patients were those who responded best.

The safety profile also was better in the MMF group, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“Most people said MMF might be a good drug for patients without rapidly progressive disease, particularly if you are concerned about infertility or infection,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, the largest industry-sponsored randomized trial, presented as a late-breaking abstract at the American College of Rheumatology (ACR) meeting in 2007. This trial was required by the FDA to be a superiority study, randomizing 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events, which was “a double whammy,” Dr. Manzi said.

“If they had shown a much better safety profile, the company might have had a chance to go back to the FDA and see if they could move forward, but there was no difference in safety,” she said.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is that it isn't good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo, which has been a stumbling block for our trials. So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved,” she said.

Other agents also are being tested, again with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. “They may have been enrolling the wrong patients,” she said, noting that a phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between rituximab and placebo on any clinical end points, although a subgroup analysis found significant improvements in black and Hispanic patients.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was a negative trial, Dr. Manzi said, with 79% and 82% of patients in the abatacept and placebo groups experiencing flares when the steroids were tapered. Patients whose primary complaint was arthritis seemed to respond the best.

“So lupus is still a complex disease and measuring response remains incredibly challenging. We're also challenged by the fact that we have to do superiority studies, and we have to be careful about who we enter into trials,” she said.

Dr. Manzi disclosed that she receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., the manufacturer of MMF. SDEF and this news organization are owned by Elsevier.

'We all got very excited about [mycophenylate mofetil] when the first study came out in 2000.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for a condition with such protean manifestations and inconsistent course, for which there has not been a new drug approved for 50 years.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes NSAIDs, cyclophosphamide, azathioprine, and cyclosporine, there has been considerable enthusiasm in the lupus community for the newer immunosuppressants and biologic agents that have revolutionized treatment of other rheumatic diseases. Unfortunately, results thus far have been somewhat disappointing, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered to be effective—if toxic—by the lupus community, although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. More than half of patients in the trial were black, and a subanalysis determined that the nonwhite patients were those who responded best.

The safety profile also was better in the MMF group, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“Most people said MMF might be a good drug for patients without rapidly progressive disease, particularly if you are concerned about infertility or infection,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, the largest industry-sponsored randomized trial, presented as a late-breaking abstract at the American College of Rheumatology (ACR) meeting in 2007. This trial was required by the FDA to be a superiority study, randomizing 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events, which was “a double whammy,” Dr. Manzi said.

“If they had shown a much better safety profile, the company might have had a chance to go back to the FDA and see if they could move forward, but there was no difference in safety,” she said.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is that it isn't good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo, which has been a stumbling block for our trials. So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved,” she said.

Other agents also are being tested, again with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. “They may have been enrolling the wrong patients,” she said, noting that a phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between rituximab and placebo on any clinical end points, although a subgroup analysis found significant improvements in black and Hispanic patients.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was a negative trial, Dr. Manzi said, with 79% and 82% of patients in the abatacept and placebo groups experiencing flares when the steroids were tapered. Patients whose primary complaint was arthritis seemed to respond the best.

“So lupus is still a complex disease and measuring response remains incredibly challenging. We're also challenged by the fact that we have to do superiority studies, and we have to be careful about who we enter into trials,” she said.

Dr. Manzi disclosed that she receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., the manufacturer of MMF. SDEF and this news organization are owned by Elsevier.

'We all got very excited about [mycophenylate mofetil] when the first study came out in 2000.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for a condition with such protean manifestations and inconsistent course, for which there has not been a new drug approved for 50 years.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes NSAIDs, cyclophosphamide, azathioprine, and cyclosporine, there has been considerable enthusiasm in the lupus community for the newer immunosuppressants and biologic agents that have revolutionized treatment of other rheumatic diseases. Unfortunately, results thus far have been somewhat disappointing, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered to be effective—if toxic—by the lupus community, although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. More than half of patients in the trial were black, and a subanalysis determined that the nonwhite patients were those who responded best.

The safety profile also was better in the MMF group, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“Most people said MMF might be a good drug for patients without rapidly progressive disease, particularly if you are concerned about infertility or infection,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, the largest industry-sponsored randomized trial, presented as a late-breaking abstract at the American College of Rheumatology (ACR) meeting in 2007. This trial was required by the FDA to be a superiority study, randomizing 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events, which was “a double whammy,” Dr. Manzi said.

“If they had shown a much better safety profile, the company might have had a chance to go back to the FDA and see if they could move forward, but there was no difference in safety,” she said.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is that it isn't good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo, which has been a stumbling block for our trials. So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved,” she said.

Other agents also are being tested, again with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. “They may have been enrolling the wrong patients,” she said, noting that a phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between rituximab and placebo on any clinical end points, although a subgroup analysis found significant improvements in black and Hispanic patients.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was a negative trial, Dr. Manzi said, with 79% and 82% of patients in the abatacept and placebo groups experiencing flares when the steroids were tapered. Patients whose primary complaint was arthritis seemed to respond the best.

“So lupus is still a complex disease and measuring response remains incredibly challenging. We're also challenged by the fact that we have to do superiority studies, and we have to be careful about who we enter into trials,” she said.

Dr. Manzi disclosed that she receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., the manufacturer of MMF. SDEF and this news organization are owned by Elsevier.

'We all got very excited about [mycophenylate mofetil] when the first study came out in 2000.' DR. MANZI

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

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

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

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

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

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

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

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

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

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

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

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

SDEF and this news organization are owned by Elsevier.

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

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

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

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

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

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

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

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

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

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

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

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

SDEF and this news organization are owned by Elsevier.

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

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

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

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

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

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

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

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

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

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

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

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

SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West, it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement. The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who practices in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is lower. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction. A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

Pain due to vulvar lesions in Behçet's disease may respond to lidocaine. Courtesy Dr. Andrew T. Goldstein

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West, it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement. The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who practices in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is lower. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction. A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

Pain due to vulvar lesions in Behçet's disease may respond to lidocaine. Courtesy Dr. Andrew T. Goldstein

LAKE BUENA VISTA, FLA. — The diagnosis of Behçet's disease must be considered in any patient with recurrent oral and vulvar aphthous ulcers, even if the deep, full-thickness ulcers in the mouth and vulva develop at different times.

Behçet's disease is a chronic inflammatory vasculitis most commonly seen along the ancient silk route from Japan and across Korea, Turkey, and Greece, according to Dr. Andrew T. Goldstein. In the West, it occurs most often among young women of Asian or Mediterranean descent.

“This is a bad vasculitis, with complications including dissection of the aorta, blindness, and stroke,” he said.

Aside from the aphthous ulcers, patients with Behçet's disease may have acnelike skin lesions or erythema nodosum as well as ocular, central nervous system, and bowel involvement. The ocular manifestations can be varied and severe, and include iritis, uveitis, and retinal vasculitis. Behçet's disease also can be associated with arthritis and meningitis, and any evidence of this disorder should prompt consultations with ophthalmologists, rheumatologists, and gastroenterologists as symptoms dictate.

“One of the easiest ways of diagnosing Behçet's is the pathergy test,” said Dr. Goldstein, who practices in Washington.

The pathergy test, in which a 5- to 7-gauge needle is inserted into the forearm, has a very high predictive value, although its negative predictive value is lower. If induration develops 24–48 hours later at the site of needle insertion, the test is positive, he said at the annual meeting of the International Pelvic Pain Society.

Although a positive pathergy test is helpful in the diagnosis of Behçet's disease, only a minority of Behçet's patients demonstrate the pathergy phenomenon, according to the Vasculitis Foundation. Patients from the Mediterranean region are more likely to show a positive response, with only 50% of patients in Middle Eastern countries and Japan showing the reaction. A positive reaction is even less common in the United States, and other conditions can occasionally mimic the results (www.vasculitisfoundation.org/pathergytest

Treatments that have been tried for Behçet's disease include conventional immunosuppressives such as azathioprine and corticosteroids; and anti-tumor necrosis factor therapy, particularly with infliximab, according to Dr. Goldstein, who also practices at George Washington University Hospital, Washington.

A recent international expert panel suggested that anti-TNF therapy might be suitable for patients with severe, organ-threatening disease—patients with two or more relapses of posterior uveitis per year—low visual acuity resulting from chronic cystoid macular edema, or active central nervous system disease (Rheumatology 2007;46:736–41).

Aphthous ulcers not caused by Behçet's disease occasionally can be associated with Epstein-Barr virus or cytomegalovirus, but most commonly they are a manifestation of stress.

“These can be seen in adolescents who are sexually naive and are accused of having herpes and are repeatedly tested and cultured,” Dr. Goldstein said.

Treatment for these ulcers involves managing pain with lidocaine and systemic pain medications, intralesional triamcinolone, and amoxicillin-clavulanate and fluconazole for superinfection.

Pain due to vulvar lesions in Behçet's disease may respond to lidocaine. Courtesy Dr. Andrew T. Goldstein

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease” and move toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype, said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and nonsteroidal anti-inflammatory drugs, she said.

There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, make sure they use drugs other than NSAIDs, she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Unfortunately, even with the newer immunosuppressive medications, rates of surgery for Crohn's disease have not decreased.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc.

SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease” and move toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype, said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and nonsteroidal anti-inflammatory drugs, she said.

There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, make sure they use drugs other than NSAIDs, she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Unfortunately, even with the newer immunosuppressive medications, rates of surgery for Crohn's disease have not decreased.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc.

SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease” and move toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype, said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and nonsteroidal anti-inflammatory drugs, she said.

There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, make sure they use drugs other than NSAIDs, she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Unfortunately, even with the newer immunosuppressive medications, rates of surgery for Crohn's disease have not decreased.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc.

SDEF and this news organization are owned by Elsevier.

A related video is at www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said. For example, although the mucosal disease in ulcerative colitis is generally superficial, if the ulcers are deep, the patient can have more pain than would be expected.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease and move more toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype,” said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12. This gene's product is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and NSAIDs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions … make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Meanwhile, surgery rates for Crohn's disease have not declined. In a retrospective study of 2,573 patients treated over 25 years in a French center, the cumulative probability of receiving immunosuppressants rose from 0 in 1978 to 0.56 in 2002. But the cumulative risk of intestinal resection within 5 years remained steady, from 0.35 to 0.34 (Gut 2005;54:237-41).

Sometimes luminal inflammation is the least of the patient's problems. “With potential complications including primary sclerosing cholangitis, pyoderma gangrenosum, and anterior uveitis, a little diarrhea isn't always such a big deal,” she said.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

A related video is at www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said. For example, although the mucosal disease in ulcerative colitis is generally superficial, if the ulcers are deep, the patient can have more pain than would be expected.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease and move more toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype,” said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12. This gene's product is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and NSAIDs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions … make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Meanwhile, surgery rates for Crohn's disease have not declined. In a retrospective study of 2,573 patients treated over 25 years in a French center, the cumulative probability of receiving immunosuppressants rose from 0 in 1978 to 0.56 in 2002. But the cumulative risk of intestinal resection within 5 years remained steady, from 0.35 to 0.34 (Gut 2005;54:237-41).

Sometimes luminal inflammation is the least of the patient's problems. “With potential complications including primary sclerosing cholangitis, pyoderma gangrenosum, and anterior uveitis, a little diarrhea isn't always such a big deal,” she said.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

A related video is at www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” Dr. Sunanda Kane said. For example, although the mucosal disease in ulcerative colitis is generally superficial, if the ulcers are deep, the patient can have more pain than would be expected.

“So we are trying to move away from the black-and-white categories of ulcerative colitis and Crohn's disease and move more toward thinking about the mechanisms of the inflammatory response and the individual patient's phenotype,” said Dr. Kane of the Mayo Clinic, Rochester, Minn.

“We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In certain circumstances, such as exposure to bacterial products, the gut can become more acutely inflamed; if the inflammation is not downregulated, it can result in chronic inflammatory bowel disease (IBD).

Genetic studies have begun to reveal genes that predispose a person to an inability to downregulate gut inflammation, such as the NOD2/card15 gene, located at chromosome 16q12. This gene's product is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Environmental influences also act as disease modifiers. Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other 'illins'—and NSAIDs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions … make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Meanwhile, surgery rates for Crohn's disease have not declined. In a retrospective study of 2,573 patients treated over 25 years in a French center, the cumulative probability of receiving immunosuppressants rose from 0 in 1978 to 0.56 in 2002. But the cumulative risk of intestinal resection within 5 years remained steady, from 0.35 to 0.34 (Gut 2005;54:237-41).

Sometimes luminal inflammation is the least of the patient's problems. “With potential complications including primary sclerosing cholangitis, pyoderma gangrenosum, and anterior uveitis, a little diarrhea isn't always such a big deal,” she said.

Dr. Kane disclosed that she is a consultant for and receives research support from several companies, including Elan Pharmaceuticals Inc., Procter and Gamble, Shire Pharmaceuticals Inc., and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN

FORT LAUDERDALE, FLA. — A group of rheumatologists and dermatologists has published new recommendations for treatment of the heterogeneous manifestations of psoriatic arthritis, despite a paucity of randomized trial data.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) performed a formal literature review for the symptoms of peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis.

Significant challenges exist in the management of PsA, said lead author Dr. Christopher T. Ritchlin. There have been few double-blind, randomized trials that have examined the efficacy of traditional agents such as sulfasalazine and cyclosporine. There is also no evidence that these agents slow radiographic progression or are effective for axial disease, dactylitis, or enthesopathy, said Dr. Ritchlin, professor of medicine and director of clinical immunology, University of Rochester (New York) Medical Center.

“But it's not that we know these drugs don't work—the studies simply haven't been done,” he said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Particularly problematic is the lack of data for methotrexate, with only one older double-blind randomized clinical trial which failed to show efficacy (Arthritis Rheum. 1984;27:376–81).

Improvements in trial design in the intervening years favor newer biologics over older disease-modifying antirheumatic drugs (DMARDs). But while there have been three double-blind trials of tumor necrosis factor (TNF) inhibitors, there have been no head-to-head trials of methotrexate versus a TNF inhibitor.

The recommendations include:

▸ For mild peripheral arthritis, initial treatment can include nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections, and for moderate or severe arthritis, DMARDs or TNF inhibitors (Ann. Rheum. Dis. Oct. 24; [Epub doi:10.1136/ard.2008.094946

While TNF inhibitors are recommended for patients who have failed at least one DMARD, patients with poor prognoses can be considered for a TNF agent without DMARD failure. Prognosis is worse in patients with polyarticular disease, an elevated erythrocyte sedimentation rate, previous medication failure, or the presence of joint damage, loss of joint function, or diminished quality of life. Systemic corticosteroids are typically not used in PsA because of the possibility of psoriasis flare upon withdrawal.

▸ For skin disease, first-line therapies include phototherapy, methotrexate, fumaric acid esters, TNF inhibitors, efalizumab, and cyclosporine; second-line therapies include acitretin and alefacept; and third-line therapies include sulfasalazine and hydroxyurea. Nail disease can be managed with retinoids, oral psoralen plus ultraviolet A, cyclosporine, or TNF inhibitors.

▸ For mild to moderate axial disease, treatment includes NSAIDs, physiotherapy, analgesia, and injection of the sacroiliac joint. Moderate to severe involvement of the spine can be treated with TNF inhibitors.

▸ Mild dactylitis typically can be managed with NSAIDs and injected corticosteroids, but if symptoms are resistant DMARDs or infliximab can be tried.

▸ For mild enthesitis, typically of the Achilles' tendon area, NSAIDs, physical therapy, and corticosteroids can be used. Moderate disease can be treated with DMARDs. Severe enthesitis may respond to a TNF inhibitor.

Dr. Ritchlin disclosed grant research support from Centocor Inc. He is a consultant to Abbott Laboratories, Amgen Inc., and Wyeth. SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

Particularly problematic is a lack of data for methotrexate, with only one older double-blind RCT. DR. RITCHLIN