EULAR (European League Against Rheumatism): 2012 Congress

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Nearly 5% of patients with systemic lupus erythematosus have a seizure, most often soon after diagnosis, based on a review of more than 1,600 patients collected by an international consortium.

Among 1,631 patients with SLE who were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) cohort, 75 (4.6%) had one or more seizures during an average follow-up of 3.5 years, Dr. John G. Hanly reported at the annual European Congress of Rheumatology. The average time from first diagnosis of SLE to the patient’s first seizure was 0.14 years (51 days), and ranged from half a year prior to the SLE diagnosis to 7.5 years after diagnosis, said Dr. Hanly, a professor of medicine at Dalhousie University in Halifax, N.S.

The 75 affected patients had a total of 91 seizures, with 59 (79%) having a single seizure and the other 16 patients each having two seizures. "In the majority of cases the seizures resolve, do not require long-term antiseizure medication, and are not associated with a negative impact on mental or physical health–related quality of life," he said. Some 78% of the seizures appeared to be linked to SLE, whereas the other 13 seemed to result from other causes; 60 of the seizures were primary generalized, and the other 31 were focal.

In a multivariate analysis of demographic and clinical features, variables with a statistically significant link with an increased incidence of seizures were African ethnicity and lower educational status, each of which linked with a roughly doubled seizure rate, and organ damage outside of the nervous system, which was associated with a 50% increased rate. Educational status likely served as a marker for lower socioeconomic status and possibly reduced access to medical care, Dr. Hanly said.

The apparent associations between seizures and treatment with various lupus-related therapies were "complex," but treatment with an antimalarial drug appeared to confer protection against a seizure.

The patients who were included in the study appeared to be typical SLE patients, and each patient fulfilled at least four of the SLE classification criteria set by the American College of Rheumatology. The SLICC designed the cohort for an inception study, and hence required enrollment within 15 months from when patients first met the American College of Rheumatology’s SLE classification criteria. The cohort patients averaged 35 years old, 89% were women, and their average disease duration was almost 6 years. Their average SLE disease activity index was 5.3 (indicating moderate disease), and on average the patients showed a low level of organ damage.

Dr. Hanly said that he had no disclosures.

BERLIN – Nearly 5% of patients with systemic lupus erythematosus have a seizure, most often soon after diagnosis, based on a review of more than 1,600 patients collected by an international consortium.

Among 1,631 patients with SLE who were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) cohort, 75 (4.6%) had one or more seizures during an average follow-up of 3.5 years, Dr. John G. Hanly reported at the annual European Congress of Rheumatology. The average time from first diagnosis of SLE to the patient’s first seizure was 0.14 years (51 days), and ranged from half a year prior to the SLE diagnosis to 7.5 years after diagnosis, said Dr. Hanly, a professor of medicine at Dalhousie University in Halifax, N.S.

The 75 affected patients had a total of 91 seizures, with 59 (79%) having a single seizure and the other 16 patients each having two seizures. "In the majority of cases the seizures resolve, do not require long-term antiseizure medication, and are not associated with a negative impact on mental or physical health–related quality of life," he said. Some 78% of the seizures appeared to be linked to SLE, whereas the other 13 seemed to result from other causes; 60 of the seizures were primary generalized, and the other 31 were focal.

In a multivariate analysis of demographic and clinical features, variables with a statistically significant link with an increased incidence of seizures were African ethnicity and lower educational status, each of which linked with a roughly doubled seizure rate, and organ damage outside of the nervous system, which was associated with a 50% increased rate. Educational status likely served as a marker for lower socioeconomic status and possibly reduced access to medical care, Dr. Hanly said.

The apparent associations between seizures and treatment with various lupus-related therapies were "complex," but treatment with an antimalarial drug appeared to confer protection against a seizure.

The patients who were included in the study appeared to be typical SLE patients, and each patient fulfilled at least four of the SLE classification criteria set by the American College of Rheumatology. The SLICC designed the cohort for an inception study, and hence required enrollment within 15 months from when patients first met the American College of Rheumatology’s SLE classification criteria. The cohort patients averaged 35 years old, 89% were women, and their average disease duration was almost 6 years. Their average SLE disease activity index was 5.3 (indicating moderate disease), and on average the patients showed a low level of organ damage.

Dr. Hanly said that he had no disclosures.

BERLIN – Nearly 5% of patients with systemic lupus erythematosus have a seizure, most often soon after diagnosis, based on a review of more than 1,600 patients collected by an international consortium.

Among 1,631 patients with SLE who were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) cohort, 75 (4.6%) had one or more seizures during an average follow-up of 3.5 years, Dr. John G. Hanly reported at the annual European Congress of Rheumatology. The average time from first diagnosis of SLE to the patient’s first seizure was 0.14 years (51 days), and ranged from half a year prior to the SLE diagnosis to 7.5 years after diagnosis, said Dr. Hanly, a professor of medicine at Dalhousie University in Halifax, N.S.

The 75 affected patients had a total of 91 seizures, with 59 (79%) having a single seizure and the other 16 patients each having two seizures. "In the majority of cases the seizures resolve, do not require long-term antiseizure medication, and are not associated with a negative impact on mental or physical health–related quality of life," he said. Some 78% of the seizures appeared to be linked to SLE, whereas the other 13 seemed to result from other causes; 60 of the seizures were primary generalized, and the other 31 were focal.

In a multivariate analysis of demographic and clinical features, variables with a statistically significant link with an increased incidence of seizures were African ethnicity and lower educational status, each of which linked with a roughly doubled seizure rate, and organ damage outside of the nervous system, which was associated with a 50% increased rate. Educational status likely served as a marker for lower socioeconomic status and possibly reduced access to medical care, Dr. Hanly said.

The apparent associations between seizures and treatment with various lupus-related therapies were "complex," but treatment with an antimalarial drug appeared to confer protection against a seizure.

The patients who were included in the study appeared to be typical SLE patients, and each patient fulfilled at least four of the SLE classification criteria set by the American College of Rheumatology. The SLICC designed the cohort for an inception study, and hence required enrollment within 15 months from when patients first met the American College of Rheumatology’s SLE classification criteria. The cohort patients averaged 35 years old, 89% were women, and their average disease duration was almost 6 years. Their average SLE disease activity index was 5.3 (indicating moderate disease), and on average the patients showed a low level of organ damage.

Dr. Hanly said that he had no disclosures.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.

A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.

Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.

In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.

"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."

The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.

Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.

Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.

BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.

A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.

Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.

In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.

"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."

The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.

Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.

Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.

BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.

A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.

Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.

In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.

"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."

The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.

Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.

Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.

BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.

"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."

These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.

"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.

Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.

After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.

"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."

The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.

Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.

Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.

"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.

"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."

"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."

Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.

Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).

Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."

He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.

"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."

Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.

"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."

These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.

"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.

Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.

After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.

"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."

The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.

Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.

Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.

"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.

"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."

"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."

Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.

Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).

Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."

He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.

"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."

Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.

"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."

These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.

"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.

Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.

After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.

"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."

The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.

Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.

Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.

"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.

"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."

"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."

Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.

Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).

Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."

He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.

"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."

Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.