Rheumatoid Arthritis

AMSTERDAM — The therapeutic options for patients with rheumatoid arthritis who do not respond to methotrexate alone continue to expand, with a new tumor necrosis factor-α blocker showing efficacy in a phase II trial.

In preclinical studies, the human monoclonal antibody golimumab was shown to be more effective at neutralizing tumor necrosis factor-α (TNF-α) than the other currently available biologic agents, Dr. Jonathan Kay wrote in a poster session at the annual European Congress of Rheumatology.

And while golimumab must be given subcutaneously, the dosing interval is once every 4 weeks rather than twice weekly as is the case with etanercept, or every other week as with adalimumab. Because the drug can be given once a month, it may provide a convenient alternative for patients, Dr. Kay told RHEUMATOLOGY NEWS in an interview.

The investigators randomly assigned 172 patients with rheumatoid arthritis (RA) of at least 3 months' duration to placebo or treatment with golimumab with one of four dosages: 50 mg every 2 weeks, 50 mg every 4 weeks, 100 mg every 2 weeks, or 100 mg every 4 weeks. All patients also were on stable doses of methotrexate.

At week 16, 62% of patients who were receiving golimumab plus methotrexate achieved an American College of Rheumatology 20 response, which was the primary end point, compared with 37% of those patients who were receiving placebo plus stable doses of methotrexate, according to Dr. Kay of the rheumatology unit at Massachusetts General Hospital, Boston.

A secondary end point of the trial was the Disease Activity Score 28 response to active and placebo treatments.

This outcome measure can be calculated using either the erythrocyte sedimentation rate or C-reactive protein levels, and patients' responses to therapies are categorized as good, moderate, remission, and nonresponse.

Using the erythrocyte sedimentation rate, Disease Activity Score 28 remission plus good/moderate responses were seen in 72% and 10% of the golimumab and placebo groups, respectively, and in 74% and 27%, respectively, using C-reactive protein levels.

Serious adverse events were reported by 8% of patients receiving golimumab plus methotrexate and by 5.9% of those receiving methotrexate plus placebo.

“Clinically relevant” adverse events reported in the golimumab group included two cases of pneumonia, one case of heart failure, one case of lung cancer, and one case of cardiac tamponade, Dr. Kay reported.

There were no deaths or cases of tuberculosis or opportunistic infections, however.

The phase II study was supported by Centocor Research and Development Inc. The pharmaceutical company has initiated Phase III studies that are underway to evaluate golimumab in patients with RA, psoriatic arthritis, and ankylosing spondylitis.

The drug is being given in doses of 50 or 100 mg every 4 weeks in these trials, which will follow patients for 5 years.

AMSTERDAM — The therapeutic options for patients with rheumatoid arthritis who do not respond to methotrexate alone continue to expand, with a new tumor necrosis factor-α blocker showing efficacy in a phase II trial.

In preclinical studies, the human monoclonal antibody golimumab was shown to be more effective at neutralizing tumor necrosis factor-α (TNF-α) than the other currently available biologic agents, Dr. Jonathan Kay wrote in a poster session at the annual European Congress of Rheumatology.

And while golimumab must be given subcutaneously, the dosing interval is once every 4 weeks rather than twice weekly as is the case with etanercept, or every other week as with adalimumab. Because the drug can be given once a month, it may provide a convenient alternative for patients, Dr. Kay told RHEUMATOLOGY NEWS in an interview.

The investigators randomly assigned 172 patients with rheumatoid arthritis (RA) of at least 3 months' duration to placebo or treatment with golimumab with one of four dosages: 50 mg every 2 weeks, 50 mg every 4 weeks, 100 mg every 2 weeks, or 100 mg every 4 weeks. All patients also were on stable doses of methotrexate.

At week 16, 62% of patients who were receiving golimumab plus methotrexate achieved an American College of Rheumatology 20 response, which was the primary end point, compared with 37% of those patients who were receiving placebo plus stable doses of methotrexate, according to Dr. Kay of the rheumatology unit at Massachusetts General Hospital, Boston.

A secondary end point of the trial was the Disease Activity Score 28 response to active and placebo treatments.

This outcome measure can be calculated using either the erythrocyte sedimentation rate or C-reactive protein levels, and patients' responses to therapies are categorized as good, moderate, remission, and nonresponse.

Using the erythrocyte sedimentation rate, Disease Activity Score 28 remission plus good/moderate responses were seen in 72% and 10% of the golimumab and placebo groups, respectively, and in 74% and 27%, respectively, using C-reactive protein levels.

Serious adverse events were reported by 8% of patients receiving golimumab plus methotrexate and by 5.9% of those receiving methotrexate plus placebo.

“Clinically relevant” adverse events reported in the golimumab group included two cases of pneumonia, one case of heart failure, one case of lung cancer, and one case of cardiac tamponade, Dr. Kay reported.

There were no deaths or cases of tuberculosis or opportunistic infections, however.

The phase II study was supported by Centocor Research and Development Inc. The pharmaceutical company has initiated Phase III studies that are underway to evaluate golimumab in patients with RA, psoriatic arthritis, and ankylosing spondylitis.

The drug is being given in doses of 50 or 100 mg every 4 weeks in these trials, which will follow patients for 5 years.

AMSTERDAM — The therapeutic options for patients with rheumatoid arthritis who do not respond to methotrexate alone continue to expand, with a new tumor necrosis factor-α blocker showing efficacy in a phase II trial.

In preclinical studies, the human monoclonal antibody golimumab was shown to be more effective at neutralizing tumor necrosis factor-α (TNF-α) than the other currently available biologic agents, Dr. Jonathan Kay wrote in a poster session at the annual European Congress of Rheumatology.

And while golimumab must be given subcutaneously, the dosing interval is once every 4 weeks rather than twice weekly as is the case with etanercept, or every other week as with adalimumab. Because the drug can be given once a month, it may provide a convenient alternative for patients, Dr. Kay told RHEUMATOLOGY NEWS in an interview.

The investigators randomly assigned 172 patients with rheumatoid arthritis (RA) of at least 3 months' duration to placebo or treatment with golimumab with one of four dosages: 50 mg every 2 weeks, 50 mg every 4 weeks, 100 mg every 2 weeks, or 100 mg every 4 weeks. All patients also were on stable doses of methotrexate.

At week 16, 62% of patients who were receiving golimumab plus methotrexate achieved an American College of Rheumatology 20 response, which was the primary end point, compared with 37% of those patients who were receiving placebo plus stable doses of methotrexate, according to Dr. Kay of the rheumatology unit at Massachusetts General Hospital, Boston.

A secondary end point of the trial was the Disease Activity Score 28 response to active and placebo treatments.

This outcome measure can be calculated using either the erythrocyte sedimentation rate or C-reactive protein levels, and patients' responses to therapies are categorized as good, moderate, remission, and nonresponse.

Using the erythrocyte sedimentation rate, Disease Activity Score 28 remission plus good/moderate responses were seen in 72% and 10% of the golimumab and placebo groups, respectively, and in 74% and 27%, respectively, using C-reactive protein levels.

Serious adverse events were reported by 8% of patients receiving golimumab plus methotrexate and by 5.9% of those receiving methotrexate plus placebo.

“Clinically relevant” adverse events reported in the golimumab group included two cases of pneumonia, one case of heart failure, one case of lung cancer, and one case of cardiac tamponade, Dr. Kay reported.

There were no deaths or cases of tuberculosis or opportunistic infections, however.

The phase II study was supported by Centocor Research and Development Inc. The pharmaceutical company has initiated Phase III studies that are underway to evaluate golimumab in patients with RA, psoriatic arthritis, and ankylosing spondylitis.

The drug is being given in doses of 50 or 100 mg every 4 weeks in these trials, which will follow patients for 5 years.

AMSTERDAM — Baseline levels of the leukocyte protein calprotectin in patients with rheumatoid arthritis correlated with clinical and radiographic outcomes at 10 years in a prospective longitudinal study, suggesting that this biomarker may be a useful predictor of joint damage, Dr. Hilde Berner Hammer reported at the annual European Congress of Rheumatology.

A cohort of 145 patients with early rheumatoid arthritis (RA) were enrolled during 1991 and 1992—before the era of biologic treatment—from the rheumatology departments of Diakonhjemmet Hospital in Oslo and University Hospital Maastricht (the Netherlands).

Baseline measurements included calprotectin levels, erythrocyte sedimentation rates (ESRs), and C-reactive protein levels. Radiographs of the hands were obtained, and modified Sharp scores were calculated. Damage was assessed according to the RA articular damage (RAAD) score and all measurements were repeated at 10 years, Dr. Berner Hammer wrote in a poster session at the meeting, sponsored by the European League Against Rheumatism.

The 88 patients with elevated levels of calprotectin (0.9 mg/L or more) at baseline and at 10 years also had high modified Sharp and RAAD scores at both time points. (See box.)

Moreover, patients who were rheumatoid factor positive had elevated calprotectin levels as well as high ESRs, modified Sharp scores, and RAAD scores, according to Dr. Berner Hammer of Diakonhjemmet Hospital.

Calprotectin is one of the calcium-binding proinflammatory S100 proteins released during cell activation. High levels of the protein have been found in the synovial fluid of RA patients. It is also upregulated in other immunopathologic conditions, particularly in the setting of acute inflammation or Th1-mediated reactions (Physiol. Res. 2004;53:245–53). An immunoassay for the detection of fecal calprotectin in patients with inflammatory bowel disease—marketed as PhiCal by Genova Diagnostics Inc.—was recently approved by the Food and Drug Administration.

This marker has also been investigated as a measure of disease activity in polymyalgia rheumatica and temporal arteritis. A group of 47 patients, 33 with polymyalgia rheumatica, 10 with temporal arteritis, and 4 with both conditions, were followed prospectively for up to 3 years. Calprotectin was highly correlated with acute phase parameters and ESRs, and levels fell significantly after the initiation of prednisone therapy (Scand. J. Rheumatol. 2005;34:125–8).

ELSEVIER GLOBAL MEDICAL NEWS

AMSTERDAM — Baseline levels of the leukocyte protein calprotectin in patients with rheumatoid arthritis correlated with clinical and radiographic outcomes at 10 years in a prospective longitudinal study, suggesting that this biomarker may be a useful predictor of joint damage, Dr. Hilde Berner Hammer reported at the annual European Congress of Rheumatology.

A cohort of 145 patients with early rheumatoid arthritis (RA) were enrolled during 1991 and 1992—before the era of biologic treatment—from the rheumatology departments of Diakonhjemmet Hospital in Oslo and University Hospital Maastricht (the Netherlands).

Baseline measurements included calprotectin levels, erythrocyte sedimentation rates (ESRs), and C-reactive protein levels. Radiographs of the hands were obtained, and modified Sharp scores were calculated. Damage was assessed according to the RA articular damage (RAAD) score and all measurements were repeated at 10 years, Dr. Berner Hammer wrote in a poster session at the meeting, sponsored by the European League Against Rheumatism.

The 88 patients with elevated levels of calprotectin (0.9 mg/L or more) at baseline and at 10 years also had high modified Sharp and RAAD scores at both time points. (See box.)

Moreover, patients who were rheumatoid factor positive had elevated calprotectin levels as well as high ESRs, modified Sharp scores, and RAAD scores, according to Dr. Berner Hammer of Diakonhjemmet Hospital.

Calprotectin is one of the calcium-binding proinflammatory S100 proteins released during cell activation. High levels of the protein have been found in the synovial fluid of RA patients. It is also upregulated in other immunopathologic conditions, particularly in the setting of acute inflammation or Th1-mediated reactions (Physiol. Res. 2004;53:245–53). An immunoassay for the detection of fecal calprotectin in patients with inflammatory bowel disease—marketed as PhiCal by Genova Diagnostics Inc.—was recently approved by the Food and Drug Administration.

This marker has also been investigated as a measure of disease activity in polymyalgia rheumatica and temporal arteritis. A group of 47 patients, 33 with polymyalgia rheumatica, 10 with temporal arteritis, and 4 with both conditions, were followed prospectively for up to 3 years. Calprotectin was highly correlated with acute phase parameters and ESRs, and levels fell significantly after the initiation of prednisone therapy (Scand. J. Rheumatol. 2005;34:125–8).

ELSEVIER GLOBAL MEDICAL NEWS

AMSTERDAM — Baseline levels of the leukocyte protein calprotectin in patients with rheumatoid arthritis correlated with clinical and radiographic outcomes at 10 years in a prospective longitudinal study, suggesting that this biomarker may be a useful predictor of joint damage, Dr. Hilde Berner Hammer reported at the annual European Congress of Rheumatology.

A cohort of 145 patients with early rheumatoid arthritis (RA) were enrolled during 1991 and 1992—before the era of biologic treatment—from the rheumatology departments of Diakonhjemmet Hospital in Oslo and University Hospital Maastricht (the Netherlands).

Baseline measurements included calprotectin levels, erythrocyte sedimentation rates (ESRs), and C-reactive protein levels. Radiographs of the hands were obtained, and modified Sharp scores were calculated. Damage was assessed according to the RA articular damage (RAAD) score and all measurements were repeated at 10 years, Dr. Berner Hammer wrote in a poster session at the meeting, sponsored by the European League Against Rheumatism.

The 88 patients with elevated levels of calprotectin (0.9 mg/L or more) at baseline and at 10 years also had high modified Sharp and RAAD scores at both time points. (See box.)

Moreover, patients who were rheumatoid factor positive had elevated calprotectin levels as well as high ESRs, modified Sharp scores, and RAAD scores, according to Dr. Berner Hammer of Diakonhjemmet Hospital.

Calprotectin is one of the calcium-binding proinflammatory S100 proteins released during cell activation. High levels of the protein have been found in the synovial fluid of RA patients. It is also upregulated in other immunopathologic conditions, particularly in the setting of acute inflammation or Th1-mediated reactions (Physiol. Res. 2004;53:245–53). An immunoassay for the detection of fecal calprotectin in patients with inflammatory bowel disease—marketed as PhiCal by Genova Diagnostics Inc.—was recently approved by the Food and Drug Administration.

This marker has also been investigated as a measure of disease activity in polymyalgia rheumatica and temporal arteritis. A group of 47 patients, 33 with polymyalgia rheumatica, 10 with temporal arteritis, and 4 with both conditions, were followed prospectively for up to 3 years. Calprotectin was highly correlated with acute phase parameters and ESRs, and levels fell significantly after the initiation of prednisone therapy (Scand. J. Rheumatol. 2005;34:125–8).

ELSEVIER GLOBAL MEDICAL NEWS

Canadian researchers have taken an important step in the long-running process of identifying genetic causes of psoriatic arthritis.

The analysis, which targeted polymorphisms in the tumor necrosis factor-α (TNF-α) gene in two psoriatic arthritis populations, suggests that the −238(A) variant is a significant risk factor for this disease (Ann. Rheum. Dis. 2006;65:919–23).

The study involved 237 psoriatic arthritis patients and 103 controls from Newfoundland and 203 patients and 101 controls from Toronto. The mean age of patients in both groups was 50 years. With respect to the subtype of psoriatic arthritis in the two populations, 61% had the polyarticular pattern, 27% had the oligoarticular pattern, 5% had isolated spondyloarthropathy, and 7% had assorted other patterns, explained Dr. Proton Rahman and colleagues at St. Clare's Mercy Hospital in St. Johns, Newfoundland.

“Before our study, a significant association for TNF-α and psoriatic arthritis was noted only in German populations. We examined five common variants with the TNF-α promoter gene, including −238 and −308. We noted a significant association between −238 variant and psoriatic arthritis,” explained the investigators, who took the additional step of conducting a pooled analysis of nine cohorts from eight studies (including their own two Canadian cohorts). Again, the −238(A) gene polymorphism was a significant risk factor, though the six outside studies each used fewer than 150 probands and may have been underpowered.

“We acknowledge that population stratification was not entirely avoided as family-based controls were not used in these studies,” the authors said, adding that publication bias may exist in the metaanalysis, because small, negative association studies often are not published. “As demonstrated in our study, because metaanalysis of association studies in complex diseases [is] helpful in estimating population-wide genetic effects, further efforts must be made to track all association data for a given polymorphism,” they wrote.

The targeting of the TNF-α gene is supported by studies noting significantly higher serum, synovial fluid, and synovial membrane levels of TNF-α in patients with psoriatic arthritis, compared with either patients with osteoarthritis or healthy controls, the investigators point out. “The importance of TNF-α in psoriatic arthritis is further strengthened by the marked clinical response of TNF-α blockade.”

However, genetic studies have produced conflicting results, with inconsistencies that may reflect insufficient sample sizes, differences in populations, the presence of linkage disequilibrium, or multiple testing, the authors said.

Canadian researchers have taken an important step in the long-running process of identifying genetic causes of psoriatic arthritis.

The analysis, which targeted polymorphisms in the tumor necrosis factor-α (TNF-α) gene in two psoriatic arthritis populations, suggests that the −238(A) variant is a significant risk factor for this disease (Ann. Rheum. Dis. 2006;65:919–23).

The study involved 237 psoriatic arthritis patients and 103 controls from Newfoundland and 203 patients and 101 controls from Toronto. The mean age of patients in both groups was 50 years. With respect to the subtype of psoriatic arthritis in the two populations, 61% had the polyarticular pattern, 27% had the oligoarticular pattern, 5% had isolated spondyloarthropathy, and 7% had assorted other patterns, explained Dr. Proton Rahman and colleagues at St. Clare's Mercy Hospital in St. Johns, Newfoundland.

“Before our study, a significant association for TNF-α and psoriatic arthritis was noted only in German populations. We examined five common variants with the TNF-α promoter gene, including −238 and −308. We noted a significant association between −238 variant and psoriatic arthritis,” explained the investigators, who took the additional step of conducting a pooled analysis of nine cohorts from eight studies (including their own two Canadian cohorts). Again, the −238(A) gene polymorphism was a significant risk factor, though the six outside studies each used fewer than 150 probands and may have been underpowered.

“We acknowledge that population stratification was not entirely avoided as family-based controls were not used in these studies,” the authors said, adding that publication bias may exist in the metaanalysis, because small, negative association studies often are not published. “As demonstrated in our study, because metaanalysis of association studies in complex diseases [is] helpful in estimating population-wide genetic effects, further efforts must be made to track all association data for a given polymorphism,” they wrote.

The targeting of the TNF-α gene is supported by studies noting significantly higher serum, synovial fluid, and synovial membrane levels of TNF-α in patients with psoriatic arthritis, compared with either patients with osteoarthritis or healthy controls, the investigators point out. “The importance of TNF-α in psoriatic arthritis is further strengthened by the marked clinical response of TNF-α blockade.”

However, genetic studies have produced conflicting results, with inconsistencies that may reflect insufficient sample sizes, differences in populations, the presence of linkage disequilibrium, or multiple testing, the authors said.

Canadian researchers have taken an important step in the long-running process of identifying genetic causes of psoriatic arthritis.

The analysis, which targeted polymorphisms in the tumor necrosis factor-α (TNF-α) gene in two psoriatic arthritis populations, suggests that the −238(A) variant is a significant risk factor for this disease (Ann. Rheum. Dis. 2006;65:919–23).

The study involved 237 psoriatic arthritis patients and 103 controls from Newfoundland and 203 patients and 101 controls from Toronto. The mean age of patients in both groups was 50 years. With respect to the subtype of psoriatic arthritis in the two populations, 61% had the polyarticular pattern, 27% had the oligoarticular pattern, 5% had isolated spondyloarthropathy, and 7% had assorted other patterns, explained Dr. Proton Rahman and colleagues at St. Clare's Mercy Hospital in St. Johns, Newfoundland.

“Before our study, a significant association for TNF-α and psoriatic arthritis was noted only in German populations. We examined five common variants with the TNF-α promoter gene, including −238 and −308. We noted a significant association between −238 variant and psoriatic arthritis,” explained the investigators, who took the additional step of conducting a pooled analysis of nine cohorts from eight studies (including their own two Canadian cohorts). Again, the −238(A) gene polymorphism was a significant risk factor, though the six outside studies each used fewer than 150 probands and may have been underpowered.

“We acknowledge that population stratification was not entirely avoided as family-based controls were not used in these studies,” the authors said, adding that publication bias may exist in the metaanalysis, because small, negative association studies often are not published. “As demonstrated in our study, because metaanalysis of association studies in complex diseases [is] helpful in estimating population-wide genetic effects, further efforts must be made to track all association data for a given polymorphism,” they wrote.

The targeting of the TNF-α gene is supported by studies noting significantly higher serum, synovial fluid, and synovial membrane levels of TNF-α in patients with psoriatic arthritis, compared with either patients with osteoarthritis or healthy controls, the investigators point out. “The importance of TNF-α in psoriatic arthritis is further strengthened by the marked clinical response of TNF-α blockade.”

However, genetic studies have produced conflicting results, with inconsistencies that may reflect insufficient sample sizes, differences in populations, the presence of linkage disequilibrium, or multiple testing, the authors said.

AMSTERDAM — Efforts to broaden the spectrum of biologic agents available for use in the treatment of rheumatoid arthritis continue, with early studies suggesting possible eventual roles for antibodies targeting two interleukins.

In a phase II study, the safety and efficacy of a human monoclonal antibody to IL-15 (AMG 714) were evaluated in 180 patients who had active rheumatoid arthritis (RA) and had failed at least one disease-modifying antirheumatic drug but who had not previously received any biologic intervention, Dr. Ian McInnes said at the annual European Congress of Rheumatology.

An initial group of 110 patients were randomized to receive the anti-IL-15 antibody in doses of 40, 80, 160, or 280 mg or placebo by subcutaneous infusion. Following a protocol amendment, an additional 70 patients were randomized to receive 280 mg or placebo every 2 weeks for 12 weeks. Efficacy was evaluated in the 114 patients who received the highest dose or placebo, with the primary end point being the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at week 14.

A significantly greater number of patients receiving 280 mg of AMG 714 achieved an ACR 20 response than did those receiving placebo at week 12 (64% vs. 34%, respectively) and at week 16 (66% vs. 38%), said Dr. McInnes of the Glasgow (Scotland) Royal Infirmary.

At week 14, however, ACR 20 was achieved by 54% of the active treatment group and 38% of the placebo group, which was not a statistically significant difference.

Levels of acute phase reactants decreased significantly in the 280-mg group, compared with those on placebo, with C-reactive protein (CRP) levels remaining 50%–67% lower than in the placebo group throughout the study. “These data demonstrate pharmacologic activity of AMG 714 as indicated by the reduction of acute phase reactant levels,” Dr. McInnes said.

Serious infections were reported by one patient in the 80-mg active treatment group (sepsis) and by one patient in the placebo group (viral bronchitis).

Dr. McInnes said that although the primary efficacy end point was not met, the overall clinical results suggest that inhibiting IL-15 with this antibody may be an important treatment strategy for RA and other inflammatory conditions.

In another phase I/II proof-of-concept study conducted in 13 centers in Germany, the Netherlands, and Switzerland, the fully human anti-IL-1β monoclonal antibody ACZ885 was evaluated in 53 patients with active rheumatoid arthritis, Dr. Rieke Alten said at the meeting, sponsored by the European League Against Rheumatism.

All patients had more than six tender joints, six swollen joints, and CRP levels greater than 0.6 mg/dL or an erythrocyte sedimentation rate greater than 28 mm/h despite optimal doses of methotrexate (7.5–25 mg/week) for at least 10–12 weeks.

They were randomized to receive placebo or 0.3, 1, 3, or 10 mg/kg of the anti-IL-1β antibody, which was administered as a 2-hour intravenous infusion on days 1 and 15. Although the main objective of the study was to evaluate the pharmacokinetics and pharmacodynamics of the drug, a larger number of patients were included in the 10 mg/kg group so that some initial data on efficacy could be obtained, according to Dr. Alten of Schlosspark-Klinik, Berlin, Germany.

In the 3-mg group, 4 of 6 patients (67%) achieved ACR 20 responses, as did 6 of 19 (32%) in the 10-mg group.

In addition, in the 10-mg group, three patients (16%) and two patients (11%) reached ACR 50 and 70 responses, respectively, Dr. Alten said.

These were “important clinical improvements,” he said.

Decreases in CRP levels occurred within 1–2 weeks in all dose groups, and the duration of CRP suppression was dose dependent. No human antihuman antibodies developed on follow-up through day 112, and there were no changes in pharmacokinetics that would suggest the development of anti-ACZ885 antibodies, he said.

The infusions were well tolerated, and there were no drug-related laboratory abnormalities. Infections were limited to one case of erysipelas and one of pneumonia, both of which resolved with standard antibiotic therapy.

Studies to determine an optimal dosing regimen and characterize clinical effects in RA are warranted, Dr. Alten concluded.

AMSTERDAM — Efforts to broaden the spectrum of biologic agents available for use in the treatment of rheumatoid arthritis continue, with early studies suggesting possible eventual roles for antibodies targeting two interleukins.

In a phase II study, the safety and efficacy of a human monoclonal antibody to IL-15 (AMG 714) were evaluated in 180 patients who had active rheumatoid arthritis (RA) and had failed at least one disease-modifying antirheumatic drug but who had not previously received any biologic intervention, Dr. Ian McInnes said at the annual European Congress of Rheumatology.

An initial group of 110 patients were randomized to receive the anti-IL-15 antibody in doses of 40, 80, 160, or 280 mg or placebo by subcutaneous infusion. Following a protocol amendment, an additional 70 patients were randomized to receive 280 mg or placebo every 2 weeks for 12 weeks. Efficacy was evaluated in the 114 patients who received the highest dose or placebo, with the primary end point being the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at week 14.

A significantly greater number of patients receiving 280 mg of AMG 714 achieved an ACR 20 response than did those receiving placebo at week 12 (64% vs. 34%, respectively) and at week 16 (66% vs. 38%), said Dr. McInnes of the Glasgow (Scotland) Royal Infirmary.

At week 14, however, ACR 20 was achieved by 54% of the active treatment group and 38% of the placebo group, which was not a statistically significant difference.

Levels of acute phase reactants decreased significantly in the 280-mg group, compared with those on placebo, with C-reactive protein (CRP) levels remaining 50%–67% lower than in the placebo group throughout the study. “These data demonstrate pharmacologic activity of AMG 714 as indicated by the reduction of acute phase reactant levels,” Dr. McInnes said.

Serious infections were reported by one patient in the 80-mg active treatment group (sepsis) and by one patient in the placebo group (viral bronchitis).

Dr. McInnes said that although the primary efficacy end point was not met, the overall clinical results suggest that inhibiting IL-15 with this antibody may be an important treatment strategy for RA and other inflammatory conditions.

In another phase I/II proof-of-concept study conducted in 13 centers in Germany, the Netherlands, and Switzerland, the fully human anti-IL-1β monoclonal antibody ACZ885 was evaluated in 53 patients with active rheumatoid arthritis, Dr. Rieke Alten said at the meeting, sponsored by the European League Against Rheumatism.

All patients had more than six tender joints, six swollen joints, and CRP levels greater than 0.6 mg/dL or an erythrocyte sedimentation rate greater than 28 mm/h despite optimal doses of methotrexate (7.5–25 mg/week) for at least 10–12 weeks.

They were randomized to receive placebo or 0.3, 1, 3, or 10 mg/kg of the anti-IL-1β antibody, which was administered as a 2-hour intravenous infusion on days 1 and 15. Although the main objective of the study was to evaluate the pharmacokinetics and pharmacodynamics of the drug, a larger number of patients were included in the 10 mg/kg group so that some initial data on efficacy could be obtained, according to Dr. Alten of Schlosspark-Klinik, Berlin, Germany.

In the 3-mg group, 4 of 6 patients (67%) achieved ACR 20 responses, as did 6 of 19 (32%) in the 10-mg group.

In addition, in the 10-mg group, three patients (16%) and two patients (11%) reached ACR 50 and 70 responses, respectively, Dr. Alten said.

These were “important clinical improvements,” he said.

Decreases in CRP levels occurred within 1–2 weeks in all dose groups, and the duration of CRP suppression was dose dependent. No human antihuman antibodies developed on follow-up through day 112, and there were no changes in pharmacokinetics that would suggest the development of anti-ACZ885 antibodies, he said.

The infusions were well tolerated, and there were no drug-related laboratory abnormalities. Infections were limited to one case of erysipelas and one of pneumonia, both of which resolved with standard antibiotic therapy.

Studies to determine an optimal dosing regimen and characterize clinical effects in RA are warranted, Dr. Alten concluded.

AMSTERDAM — Efforts to broaden the spectrum of biologic agents available for use in the treatment of rheumatoid arthritis continue, with early studies suggesting possible eventual roles for antibodies targeting two interleukins.

In a phase II study, the safety and efficacy of a human monoclonal antibody to IL-15 (AMG 714) were evaluated in 180 patients who had active rheumatoid arthritis (RA) and had failed at least one disease-modifying antirheumatic drug but who had not previously received any biologic intervention, Dr. Ian McInnes said at the annual European Congress of Rheumatology.

An initial group of 110 patients were randomized to receive the anti-IL-15 antibody in doses of 40, 80, 160, or 280 mg or placebo by subcutaneous infusion. Following a protocol amendment, an additional 70 patients were randomized to receive 280 mg or placebo every 2 weeks for 12 weeks. Efficacy was evaluated in the 114 patients who received the highest dose or placebo, with the primary end point being the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at week 14.

A significantly greater number of patients receiving 280 mg of AMG 714 achieved an ACR 20 response than did those receiving placebo at week 12 (64% vs. 34%, respectively) and at week 16 (66% vs. 38%), said Dr. McInnes of the Glasgow (Scotland) Royal Infirmary.

At week 14, however, ACR 20 was achieved by 54% of the active treatment group and 38% of the placebo group, which was not a statistically significant difference.

Levels of acute phase reactants decreased significantly in the 280-mg group, compared with those on placebo, with C-reactive protein (CRP) levels remaining 50%–67% lower than in the placebo group throughout the study. “These data demonstrate pharmacologic activity of AMG 714 as indicated by the reduction of acute phase reactant levels,” Dr. McInnes said.

Serious infections were reported by one patient in the 80-mg active treatment group (sepsis) and by one patient in the placebo group (viral bronchitis).

Dr. McInnes said that although the primary efficacy end point was not met, the overall clinical results suggest that inhibiting IL-15 with this antibody may be an important treatment strategy for RA and other inflammatory conditions.

In another phase I/II proof-of-concept study conducted in 13 centers in Germany, the Netherlands, and Switzerland, the fully human anti-IL-1β monoclonal antibody ACZ885 was evaluated in 53 patients with active rheumatoid arthritis, Dr. Rieke Alten said at the meeting, sponsored by the European League Against Rheumatism.

All patients had more than six tender joints, six swollen joints, and CRP levels greater than 0.6 mg/dL or an erythrocyte sedimentation rate greater than 28 mm/h despite optimal doses of methotrexate (7.5–25 mg/week) for at least 10–12 weeks.

They were randomized to receive placebo or 0.3, 1, 3, or 10 mg/kg of the anti-IL-1β antibody, which was administered as a 2-hour intravenous infusion on days 1 and 15. Although the main objective of the study was to evaluate the pharmacokinetics and pharmacodynamics of the drug, a larger number of patients were included in the 10 mg/kg group so that some initial data on efficacy could be obtained, according to Dr. Alten of Schlosspark-Klinik, Berlin, Germany.

In the 3-mg group, 4 of 6 patients (67%) achieved ACR 20 responses, as did 6 of 19 (32%) in the 10-mg group.

In addition, in the 10-mg group, three patients (16%) and two patients (11%) reached ACR 50 and 70 responses, respectively, Dr. Alten said.

These were “important clinical improvements,” he said.

Decreases in CRP levels occurred within 1–2 weeks in all dose groups, and the duration of CRP suppression was dose dependent. No human antihuman antibodies developed on follow-up through day 112, and there were no changes in pharmacokinetics that would suggest the development of anti-ACZ885 antibodies, he said.

The infusions were well tolerated, and there were no drug-related laboratory abnormalities. Infections were limited to one case of erysipelas and one of pneumonia, both of which resolved with standard antibiotic therapy.

Studies to determine an optimal dosing regimen and characterize clinical effects in RA are warranted, Dr. Alten concluded.

AMSTERDAM — In the first direct comparison of oral versus subcutaneous methotrexate for patients with active rheumatoid arthritis, the injectable formulation was significantly more effective, Dr. Jürgen Braun said at the annual European Congress of Rheumatology.

The multicenter study involved 384 patients, none of whom had previously taken methotrexate (MTX) or biologics. They were predominantly female. Mean age was 59 and mean time since diagnosis was 2 months, said Dr. Braun of Rheumazentrum Ruhrgebiet, Ruhr-University Bochum, Herne, Germany.

They were randomized to 15 mg oral MTX plus placebo injections or injectable MTX in the same dose plus dummy pills, once weekly, for 24 weeks. At week 16, patients receiving oral MTX could be switched to subcutaneous, and those receiving the injectable drug could have a dosage increase to 20 mg, he said.

A total of 78% of patients on subcutaneous MTX met the primary efficacy outcome of ACR20 response at 24 weeks, compared with 67% of those on oral MTX, Dr. Braun reported at the meeting, sponsored by the European League Against Rheumatism. This difference was statistically significant, as was the difference in percentages achieving ACR70 responses (43% vs. 31%, respectively).

Remission, defined as a Disease Activity Score 28 less than 2.6, was reached by 34% of patients on the subcutaneous formulation, compared with only 24% of those on the oral drug, a statistically significant difference.

AMSTERDAM — In the first direct comparison of oral versus subcutaneous methotrexate for patients with active rheumatoid arthritis, the injectable formulation was significantly more effective, Dr. Jürgen Braun said at the annual European Congress of Rheumatology.

The multicenter study involved 384 patients, none of whom had previously taken methotrexate (MTX) or biologics. They were predominantly female. Mean age was 59 and mean time since diagnosis was 2 months, said Dr. Braun of Rheumazentrum Ruhrgebiet, Ruhr-University Bochum, Herne, Germany.

They were randomized to 15 mg oral MTX plus placebo injections or injectable MTX in the same dose plus dummy pills, once weekly, for 24 weeks. At week 16, patients receiving oral MTX could be switched to subcutaneous, and those receiving the injectable drug could have a dosage increase to 20 mg, he said.

A total of 78% of patients on subcutaneous MTX met the primary efficacy outcome of ACR20 response at 24 weeks, compared with 67% of those on oral MTX, Dr. Braun reported at the meeting, sponsored by the European League Against Rheumatism. This difference was statistically significant, as was the difference in percentages achieving ACR70 responses (43% vs. 31%, respectively).

Remission, defined as a Disease Activity Score 28 less than 2.6, was reached by 34% of patients on the subcutaneous formulation, compared with only 24% of those on the oral drug, a statistically significant difference.

AMSTERDAM — In the first direct comparison of oral versus subcutaneous methotrexate for patients with active rheumatoid arthritis, the injectable formulation was significantly more effective, Dr. Jürgen Braun said at the annual European Congress of Rheumatology.

The multicenter study involved 384 patients, none of whom had previously taken methotrexate (MTX) or biologics. They were predominantly female. Mean age was 59 and mean time since diagnosis was 2 months, said Dr. Braun of Rheumazentrum Ruhrgebiet, Ruhr-University Bochum, Herne, Germany.

They were randomized to 15 mg oral MTX plus placebo injections or injectable MTX in the same dose plus dummy pills, once weekly, for 24 weeks. At week 16, patients receiving oral MTX could be switched to subcutaneous, and those receiving the injectable drug could have a dosage increase to 20 mg, he said.

A total of 78% of patients on subcutaneous MTX met the primary efficacy outcome of ACR20 response at 24 weeks, compared with 67% of those on oral MTX, Dr. Braun reported at the meeting, sponsored by the European League Against Rheumatism. This difference was statistically significant, as was the difference in percentages achieving ACR70 responses (43% vs. 31%, respectively).

Remission, defined as a Disease Activity Score 28 less than 2.6, was reached by 34% of patients on the subcutaneous formulation, compared with only 24% of those on the oral drug, a statistically significant difference.

AMSTERDAM — Physicians have largely overlooked the sizable adverse impact rheumatoid arthritis often has on sexuality, Ylva Helland said at the annual European Congress of Rheumatology.

Her survey of 1,041 Oslo-area patients with a median 14-year duration of rheumatoid arthritis (RA) showed that while 31% reported their disease had no impact upon sexual function, an equal percentage indicated RA had a major negative effect in this domain.

Indeed, 21% of respondents said RA had a “considerable” adverse impact on their sexual function, another 7% reported their disease made sexual activity impossible, and 3% characterized sexual activity as nearly impossible, reported Ms. Helland, a research nurse at the University of Oslo.

The rest of the respondents, 38%, indicated that their disease had “little impact” on sexual activity.

Patients who reported that RA had a large impact upon their sex life tended to have worse health status across the full spectrum of physical and psychological dimensions.

A greater impact of RA on sexual activity was reported by men, patients with less than 12 years of education, and those who reported higher levels of fatigue, she said at the congress sponsored by the European League Against Rheumatism.

Ms. Helland and her coinvestigators received a EULAR/Abbott award honoring their study as one of the six best clinical studies presented at the meeting.

At a press conference aimed at boosting physician awareness of sexual issues in RA patients, Connie Ziegler of the Danish Rheumatism Association said that during the course of several decades as an RA patient, not a single physician had ever asked her if the disease had affected her sexual function. “In Denmark we say that rheumatoid arthritis patients are better lovers,” she added. “It's because we have to use our imagination, since there are some positions not available to us.”

AMSTERDAM — Physicians have largely overlooked the sizable adverse impact rheumatoid arthritis often has on sexuality, Ylva Helland said at the annual European Congress of Rheumatology.

Her survey of 1,041 Oslo-area patients with a median 14-year duration of rheumatoid arthritis (RA) showed that while 31% reported their disease had no impact upon sexual function, an equal percentage indicated RA had a major negative effect in this domain.

Indeed, 21% of respondents said RA had a “considerable” adverse impact on their sexual function, another 7% reported their disease made sexual activity impossible, and 3% characterized sexual activity as nearly impossible, reported Ms. Helland, a research nurse at the University of Oslo.

The rest of the respondents, 38%, indicated that their disease had “little impact” on sexual activity.

Patients who reported that RA had a large impact upon their sex life tended to have worse health status across the full spectrum of physical and psychological dimensions.

A greater impact of RA on sexual activity was reported by men, patients with less than 12 years of education, and those who reported higher levels of fatigue, she said at the congress sponsored by the European League Against Rheumatism.

Ms. Helland and her coinvestigators received a EULAR/Abbott award honoring their study as one of the six best clinical studies presented at the meeting.

At a press conference aimed at boosting physician awareness of sexual issues in RA patients, Connie Ziegler of the Danish Rheumatism Association said that during the course of several decades as an RA patient, not a single physician had ever asked her if the disease had affected her sexual function. “In Denmark we say that rheumatoid arthritis patients are better lovers,” she added. “It's because we have to use our imagination, since there are some positions not available to us.”

AMSTERDAM — Physicians have largely overlooked the sizable adverse impact rheumatoid arthritis often has on sexuality, Ylva Helland said at the annual European Congress of Rheumatology.

Her survey of 1,041 Oslo-area patients with a median 14-year duration of rheumatoid arthritis (RA) showed that while 31% reported their disease had no impact upon sexual function, an equal percentage indicated RA had a major negative effect in this domain.

Indeed, 21% of respondents said RA had a “considerable” adverse impact on their sexual function, another 7% reported their disease made sexual activity impossible, and 3% characterized sexual activity as nearly impossible, reported Ms. Helland, a research nurse at the University of Oslo.

The rest of the respondents, 38%, indicated that their disease had “little impact” on sexual activity.

Patients who reported that RA had a large impact upon their sex life tended to have worse health status across the full spectrum of physical and psychological dimensions.

A greater impact of RA on sexual activity was reported by men, patients with less than 12 years of education, and those who reported higher levels of fatigue, she said at the congress sponsored by the European League Against Rheumatism.

Ms. Helland and her coinvestigators received a EULAR/Abbott award honoring their study as one of the six best clinical studies presented at the meeting.

At a press conference aimed at boosting physician awareness of sexual issues in RA patients, Connie Ziegler of the Danish Rheumatism Association said that during the course of several decades as an RA patient, not a single physician had ever asked her if the disease had affected her sexual function. “In Denmark we say that rheumatoid arthritis patients are better lovers,” she added. “It's because we have to use our imagination, since there are some positions not available to us.”

STOCKHOLM — Researchers are beginning to shed light on the pathophysiology of psoriatic arthritis, with recent findings focusing on the role of bone formation factors such as vascular endothelial growth factor and nuclear factor-kappa B ligand.

Psoriatic arthritis appears to have a different vascular and immunologic profile than rheumatoid arthritis, Dr. Christopher T. Ritchlin said at an international conference on psoriasis and psoriatic arthritis.

Spondyloarthritic tissue (including psoriatic tissue) is more vascular and has more neutrophil infiltration than normal tissue. This tissue also has infiltration of CD163-positive macrophages. “These are infrequent findings in rheumatoid arthritis,” said Dr. Ritchlin of the clinical immunology research center at the University of Rochester (N.Y.). These findings seem to correlate with swollen joint count. In addition, no cyclic citrullinated peptide was found, which is a characteristic finding in rheumatoid arthritis.

Psoriatic arthritis tissue has been shown to contain greater levels of vascular endothelial growth factor (VEGF) than does rheumatoid arthritis tissue. VEGF is particularly interesting in PsA because it is involved in the stimulation of osteoclastogenesis, thereby enhancing bone formation.

Some patients with PsA have marked osteolysis in the distal digits of the feet and hands. To understand this process, Dr. Ritchlin and his colleagues looked at tissue samples of the bone/pannus junction from patients with PsA.

“We found very large, multinucleated osteoclasts at this junction,” said Dr. Ritchlin. These osteoclasts were eroding deep pits into the bone. In addition, osteoclasts were found in greater numbers in patients with PsA than in those with RA; multinucleated osteoclasts were absent in patients with osteoarthritis.

Osteoclasts arise from CD14 monocytes. When CD14 monocytes are exposed to receptor activator of nuclear factor-kappa B ligand (RANKL)—which is expressed on synovial lining cells—and either macrophage colony stimulating factor (MCSF) or RANKL and VEGF, they differentiate into osteoclasts within a few days.

The researchers also found that RANKL is highly expressed in the synovial lining tissue of patients with PsA. In addition, staining of tissue from patients with PsA also showed that the expression of osteoprotegerin—which is an antagonist to RANKL, shutting down osteoclastogenesis—was limited to endothelial cells beneath the synovial lining.

Dr. Ritchlin and his colleagues hypothesized that osteoclast precursors move from subsynovial blood vessels toward RANKL-positive synovial lining tissue, where they convert to osteoclasts.

The researchers also hypothesized that CD14 monocytes in patients with PsA might already be committed to becoming osteoclasts. To test this, the researchers collected peripheral blood mononuclear cells from psoriatic arthritis patients and left them in culture for 2 weeks.

The cultures were then stained for osteoclasts. Stained cells with three or more nuclei were counted as osteoclasts.

The researchers found numerous osteoclasts even in the absence of exogenous RANKL or MCSF. Very few such cells were found in cultures from healthy controls.

The researchers then treated the cultures with RANKL and MCSF. The osteoclasts from PsA patients increased in size, containing 30–40 nuclei. Fewer osteoclasts were seen in cultures from healthy controls and these were smaller (with fewer nuclei).

In another recent study, Dr. Ritchlin and his collaborators analyzed peripheral blood mononuclear cells from 19 patients with PsA, 46 healthy controls, and 48 patients with rheumatoid arthritis using gene expression profiling. They found 257 genes that were underexpressed and 56 that were overexpressed in patients with PsA compared with healthy controls (Molec. Med., www.molmed.org/content/obp/10.2119_2006-00003.Gulko.pdf

In particular, genes involved with mitogen-activated protein kinase pathways, ras protein, and B-cell function were expressed at reduced levels in patients with PsA, which supports dysregulation of the immune system.

STOCKHOLM — Researchers are beginning to shed light on the pathophysiology of psoriatic arthritis, with recent findings focusing on the role of bone formation factors such as vascular endothelial growth factor and nuclear factor-kappa B ligand.

Psoriatic arthritis appears to have a different vascular and immunologic profile than rheumatoid arthritis, Dr. Christopher T. Ritchlin said at an international conference on psoriasis and psoriatic arthritis.

Spondyloarthritic tissue (including psoriatic tissue) is more vascular and has more neutrophil infiltration than normal tissue. This tissue also has infiltration of CD163-positive macrophages. “These are infrequent findings in rheumatoid arthritis,” said Dr. Ritchlin of the clinical immunology research center at the University of Rochester (N.Y.). These findings seem to correlate with swollen joint count. In addition, no cyclic citrullinated peptide was found, which is a characteristic finding in rheumatoid arthritis.

Psoriatic arthritis tissue has been shown to contain greater levels of vascular endothelial growth factor (VEGF) than does rheumatoid arthritis tissue. VEGF is particularly interesting in PsA because it is involved in the stimulation of osteoclastogenesis, thereby enhancing bone formation.

Some patients with PsA have marked osteolysis in the distal digits of the feet and hands. To understand this process, Dr. Ritchlin and his colleagues looked at tissue samples of the bone/pannus junction from patients with PsA.

“We found very large, multinucleated osteoclasts at this junction,” said Dr. Ritchlin. These osteoclasts were eroding deep pits into the bone. In addition, osteoclasts were found in greater numbers in patients with PsA than in those with RA; multinucleated osteoclasts were absent in patients with osteoarthritis.

Osteoclasts arise from CD14 monocytes. When CD14 monocytes are exposed to receptor activator of nuclear factor-kappa B ligand (RANKL)—which is expressed on synovial lining cells—and either macrophage colony stimulating factor (MCSF) or RANKL and VEGF, they differentiate into osteoclasts within a few days.

The researchers also found that RANKL is highly expressed in the synovial lining tissue of patients with PsA. In addition, staining of tissue from patients with PsA also showed that the expression of osteoprotegerin—which is an antagonist to RANKL, shutting down osteoclastogenesis—was limited to endothelial cells beneath the synovial lining.

Dr. Ritchlin and his colleagues hypothesized that osteoclast precursors move from subsynovial blood vessels toward RANKL-positive synovial lining tissue, where they convert to osteoclasts.

The researchers also hypothesized that CD14 monocytes in patients with PsA might already be committed to becoming osteoclasts. To test this, the researchers collected peripheral blood mononuclear cells from psoriatic arthritis patients and left them in culture for 2 weeks.

The cultures were then stained for osteoclasts. Stained cells with three or more nuclei were counted as osteoclasts.

The researchers found numerous osteoclasts even in the absence of exogenous RANKL or MCSF. Very few such cells were found in cultures from healthy controls.

The researchers then treated the cultures with RANKL and MCSF. The osteoclasts from PsA patients increased in size, containing 30–40 nuclei. Fewer osteoclasts were seen in cultures from healthy controls and these were smaller (with fewer nuclei).

In another recent study, Dr. Ritchlin and his collaborators analyzed peripheral blood mononuclear cells from 19 patients with PsA, 46 healthy controls, and 48 patients with rheumatoid arthritis using gene expression profiling. They found 257 genes that were underexpressed and 56 that were overexpressed in patients with PsA compared with healthy controls (Molec. Med., www.molmed.org/content/obp/10.2119_2006-00003.Gulko.pdf

In particular, genes involved with mitogen-activated protein kinase pathways, ras protein, and B-cell function were expressed at reduced levels in patients with PsA, which supports dysregulation of the immune system.

STOCKHOLM — Researchers are beginning to shed light on the pathophysiology of psoriatic arthritis, with recent findings focusing on the role of bone formation factors such as vascular endothelial growth factor and nuclear factor-kappa B ligand.

Psoriatic arthritis appears to have a different vascular and immunologic profile than rheumatoid arthritis, Dr. Christopher T. Ritchlin said at an international conference on psoriasis and psoriatic arthritis.

Spondyloarthritic tissue (including psoriatic tissue) is more vascular and has more neutrophil infiltration than normal tissue. This tissue also has infiltration of CD163-positive macrophages. “These are infrequent findings in rheumatoid arthritis,” said Dr. Ritchlin of the clinical immunology research center at the University of Rochester (N.Y.). These findings seem to correlate with swollen joint count. In addition, no cyclic citrullinated peptide was found, which is a characteristic finding in rheumatoid arthritis.

Psoriatic arthritis tissue has been shown to contain greater levels of vascular endothelial growth factor (VEGF) than does rheumatoid arthritis tissue. VEGF is particularly interesting in PsA because it is involved in the stimulation of osteoclastogenesis, thereby enhancing bone formation.

Some patients with PsA have marked osteolysis in the distal digits of the feet and hands. To understand this process, Dr. Ritchlin and his colleagues looked at tissue samples of the bone/pannus junction from patients with PsA.

“We found very large, multinucleated osteoclasts at this junction,” said Dr. Ritchlin. These osteoclasts were eroding deep pits into the bone. In addition, osteoclasts were found in greater numbers in patients with PsA than in those with RA; multinucleated osteoclasts were absent in patients with osteoarthritis.

Osteoclasts arise from CD14 monocytes. When CD14 monocytes are exposed to receptor activator of nuclear factor-kappa B ligand (RANKL)—which is expressed on synovial lining cells—and either macrophage colony stimulating factor (MCSF) or RANKL and VEGF, they differentiate into osteoclasts within a few days.

The researchers also found that RANKL is highly expressed in the synovial lining tissue of patients with PsA. In addition, staining of tissue from patients with PsA also showed that the expression of osteoprotegerin—which is an antagonist to RANKL, shutting down osteoclastogenesis—was limited to endothelial cells beneath the synovial lining.

Dr. Ritchlin and his colleagues hypothesized that osteoclast precursors move from subsynovial blood vessels toward RANKL-positive synovial lining tissue, where they convert to osteoclasts.

The researchers also hypothesized that CD14 monocytes in patients with PsA might already be committed to becoming osteoclasts. To test this, the researchers collected peripheral blood mononuclear cells from psoriatic arthritis patients and left them in culture for 2 weeks.

The cultures were then stained for osteoclasts. Stained cells with three or more nuclei were counted as osteoclasts.

The researchers found numerous osteoclasts even in the absence of exogenous RANKL or MCSF. Very few such cells were found in cultures from healthy controls.

The researchers then treated the cultures with RANKL and MCSF. The osteoclasts from PsA patients increased in size, containing 30–40 nuclei. Fewer osteoclasts were seen in cultures from healthy controls and these were smaller (with fewer nuclei).

In another recent study, Dr. Ritchlin and his collaborators analyzed peripheral blood mononuclear cells from 19 patients with PsA, 46 healthy controls, and 48 patients with rheumatoid arthritis using gene expression profiling. They found 257 genes that were underexpressed and 56 that were overexpressed in patients with PsA compared with healthy controls (Molec. Med., www.molmed.org/content/obp/10.2119_2006-00003.Gulko.pdf

In particular, genes involved with mitogen-activated protein kinase pathways, ras protein, and B-cell function were expressed at reduced levels in patients with PsA, which supports dysregulation of the immune system.

AMSTERDAM — The diagnosis of fibromyalgia is not followed by a surge in physician office visits, according to Dr. Ernest H.S. Choy, speaking at the annual European Congress of Rheumatology.

A recent study using data from the U.K. General Practice Research Database, led by Dr. Simon Wessely, a King's College psychiatrist, compared health care utilization from 10 years before through 4 years after diagnosis of fibromyalgia in 2,260 patients and a group of age- and gender-matched controls, said Dr. Choy, of King's College London.

The investigators found that the rates of office visits, prescriptions, and medical tests were markedly higher and rising in the years prior to diagnosis in fibromyalgia patients, compared with control patients.

In the year prior to diagnosis, patients averaged 25 office visits and received 11 prescriptions, compared with 12 office visits and 4.5 prescriptions during the same year for controls. The most common reason for prediagnosis office visits by fibromyalgia patients was depression, followed by fatigue, chest pain, headache, and disrupted sleep.

Diagnosis of fibromyalgia was not followed by a surge in illness behavior and health care utilization. In fact, health care utilization declined for 2–3 years following the diagnosis before climbing back up, probably because the patients were not getting effective treatment, according to the investigators (Arthritis Rheum. 2006;54:177–83).

“Patients demand less tests and have less consultations after the diagnosis is made,” Dr. Choy commented.

Fibromyalgia is a high-cost medical condition, he noted. A classic University of Kansas 7-year prospective study determined that the mean annual per-patient cost was $2,274 in 1996 dollars. “That is a phenomenal cost. It's comparable to inflammatory arthritis. These patients are consuming a vast amount of health care resources,” he said at the congress sponsored by the European League Against Rheumatism (EULAR).

Another recent large observational study undercuts claims that fibromyalgia is simply part of a single larger, ill-defined somatization disorder that also includes conditions like chronic fatigue syndrome, irritable bowel syndrome, and regional pain disorders. This study involved 18,122 U.K. patients diagnosed by their primary care physician as having a fatigue syndrome during 1988–2001.

The key finding was that outcomes differed significantly for patients with various diagnostic labels, being best for those with postviral fatigue syndrome, worst for myalgic encephalomyelitis and chronic fatigue syndrome, and intermediate for those with fibromyalgia (Fam. Pract. 2005;22:383–8).

As for treatment options, Dr. Choy presented new EULAR evidence-based recommendations for fibromyalgia management. The recommendations, to be published later this year, identified a number of interventions with what he termed “moderate to good” effectiveness, including drugs, exercise, and cognitive-behavioral therapy.

AMSTERDAM — The diagnosis of fibromyalgia is not followed by a surge in physician office visits, according to Dr. Ernest H.S. Choy, speaking at the annual European Congress of Rheumatology.

A recent study using data from the U.K. General Practice Research Database, led by Dr. Simon Wessely, a King's College psychiatrist, compared health care utilization from 10 years before through 4 years after diagnosis of fibromyalgia in 2,260 patients and a group of age- and gender-matched controls, said Dr. Choy, of King's College London.

The investigators found that the rates of office visits, prescriptions, and medical tests were markedly higher and rising in the years prior to diagnosis in fibromyalgia patients, compared with control patients.

In the year prior to diagnosis, patients averaged 25 office visits and received 11 prescriptions, compared with 12 office visits and 4.5 prescriptions during the same year for controls. The most common reason for prediagnosis office visits by fibromyalgia patients was depression, followed by fatigue, chest pain, headache, and disrupted sleep.

Diagnosis of fibromyalgia was not followed by a surge in illness behavior and health care utilization. In fact, health care utilization declined for 2–3 years following the diagnosis before climbing back up, probably because the patients were not getting effective treatment, according to the investigators (Arthritis Rheum. 2006;54:177–83).

“Patients demand less tests and have less consultations after the diagnosis is made,” Dr. Choy commented.

Fibromyalgia is a high-cost medical condition, he noted. A classic University of Kansas 7-year prospective study determined that the mean annual per-patient cost was $2,274 in 1996 dollars. “That is a phenomenal cost. It's comparable to inflammatory arthritis. These patients are consuming a vast amount of health care resources,” he said at the congress sponsored by the European League Against Rheumatism (EULAR).

Another recent large observational study undercuts claims that fibromyalgia is simply part of a single larger, ill-defined somatization disorder that also includes conditions like chronic fatigue syndrome, irritable bowel syndrome, and regional pain disorders. This study involved 18,122 U.K. patients diagnosed by their primary care physician as having a fatigue syndrome during 1988–2001.

The key finding was that outcomes differed significantly for patients with various diagnostic labels, being best for those with postviral fatigue syndrome, worst for myalgic encephalomyelitis and chronic fatigue syndrome, and intermediate for those with fibromyalgia (Fam. Pract. 2005;22:383–8).

As for treatment options, Dr. Choy presented new EULAR evidence-based recommendations for fibromyalgia management. The recommendations, to be published later this year, identified a number of interventions with what he termed “moderate to good” effectiveness, including drugs, exercise, and cognitive-behavioral therapy.

AMSTERDAM — The diagnosis of fibromyalgia is not followed by a surge in physician office visits, according to Dr. Ernest H.S. Choy, speaking at the annual European Congress of Rheumatology.

A recent study using data from the U.K. General Practice Research Database, led by Dr. Simon Wessely, a King's College psychiatrist, compared health care utilization from 10 years before through 4 years after diagnosis of fibromyalgia in 2,260 patients and a group of age- and gender-matched controls, said Dr. Choy, of King's College London.

The investigators found that the rates of office visits, prescriptions, and medical tests were markedly higher and rising in the years prior to diagnosis in fibromyalgia patients, compared with control patients.

In the year prior to diagnosis, patients averaged 25 office visits and received 11 prescriptions, compared with 12 office visits and 4.5 prescriptions during the same year for controls. The most common reason for prediagnosis office visits by fibromyalgia patients was depression, followed by fatigue, chest pain, headache, and disrupted sleep.

Diagnosis of fibromyalgia was not followed by a surge in illness behavior and health care utilization. In fact, health care utilization declined for 2–3 years following the diagnosis before climbing back up, probably because the patients were not getting effective treatment, according to the investigators (Arthritis Rheum. 2006;54:177–83).

“Patients demand less tests and have less consultations after the diagnosis is made,” Dr. Choy commented.

Fibromyalgia is a high-cost medical condition, he noted. A classic University of Kansas 7-year prospective study determined that the mean annual per-patient cost was $2,274 in 1996 dollars. “That is a phenomenal cost. It's comparable to inflammatory arthritis. These patients are consuming a vast amount of health care resources,” he said at the congress sponsored by the European League Against Rheumatism (EULAR).

Another recent large observational study undercuts claims that fibromyalgia is simply part of a single larger, ill-defined somatization disorder that also includes conditions like chronic fatigue syndrome, irritable bowel syndrome, and regional pain disorders. This study involved 18,122 U.K. patients diagnosed by their primary care physician as having a fatigue syndrome during 1988–2001.

The key finding was that outcomes differed significantly for patients with various diagnostic labels, being best for those with postviral fatigue syndrome, worst for myalgic encephalomyelitis and chronic fatigue syndrome, and intermediate for those with fibromyalgia (Fam. Pract. 2005;22:383–8).

As for treatment options, Dr. Choy presented new EULAR evidence-based recommendations for fibromyalgia management. The recommendations, to be published later this year, identified a number of interventions with what he termed “moderate to good” effectiveness, including drugs, exercise, and cognitive-behavioral therapy.

AMSTERDAM — Concomitant aspirin use may fully reverse the increased atherothrombotic risk associated with cyclooxygenase-2 selective NSAIDs, Dr. Gurkirpal Singh reported at the annual European Congress of Rheumatology.

In addition, aspirin may also reduce—albeit only partially in some instances—the cardiovascular risk conferred by most traditional nonselective NSAIDs, said Dr. Singh of Stanford (Calif.) University.

Although these findings from a large case-control study provide insight into the mechanism by which NSAIDs increase cardiovascular risk, he stressed that adding a daily aspirin in order to mitigate that cardiovascular risk is not a practical solution for arthritis patients seeking pain relief. That's because there is some evidence that concomitant use of aspirin and NSAIDs, whether COX-2 selective or not, appears to magnify the risk of NSAID-associated GI bleeding, he said.

Dr. Singh utilized the California Medicare database to identify all adults with rheumatoid arthritis or osteoarthritis treated with a COX-2 selective or nonselective NSAID from 1999 through the first half of 2004.

During nearly 2.4 million patient-years of follow-up, 15,343 arthritis patients experienced an acute MI, 8% of which were fatal. Each MI patient was matched to four controls.

The adjusted relative risk of MI was increased by 31% in patients being treated with rofecoxib and by 12% in patients being treated with celecoxib, compared with the rate in remote users of any NSAID. Both differences were significant.

The MI risk was also increased by 65% in current users of indomethacin, by 52% with meloxicam, and by 47% with sulindac, but was not significantly elevated in current ibuprofen users.

Concurrent use of aspirin completely reversed the increased MI risk associated with rofecoxib, celecoxib, meloxicam, and sulindac. However, the increased risk in current users of indomethacin was only partially and nonsignificantly reduced, such that patients on concomitant aspirin and indomethacin still had a 20% increased risk, he explained.

In a separate presentation, Dr. Steven B. Abramson said he thought Dr. Singh's findings make a lot of sense. “My instincts are that there will be some cardioprotection because you're getting 24-hour inhibition of platelets with a single aspirin,” added Dr. Abramson, professor of medicine and associate dean for clinical research at New York University.

It has been shown that 500 mg of naproxen provides good platelet inhibition for close to 12 hours. Moreover, a recent large metaanalysis of trials comparing COX-2 inhibitors with nonselective NSAIDs, or drugs in either class with placebo, showed that while the COX-2 inhibitors were associated with a 42% relative increase in MIs and other vascular events relative to placebo, a comparable risk was present in patients on high doses of traditional NSAIDs—except for those on naproxen at 500 mg b.i.d.

The metaanalysis, led by investigators at the University of Oxford, involved roughly 145,000 patients in 138 randomized trials, including some unpublished ones on file with manufacturers (BMJ 2006;332:1302–8).

“It still remains uncertain whether naproxen is cardioprotective, but it probably is at 500 mg twice per day,” Dr. Abramson said. He was quick to add, however, that this will have to be shown in prospective clinical trials before the FDA would consider removing the warning of increased cardiovascular risk from naproxen's label, a warning currently applied to all COX-2 selective and traditional NSAIDs.

Dr. Abramson, who was a member of the FDA's special advisory panel on the COX-2 inhibitors' cardiovascular risk, criticized the European Union drug regulatory agency for limiting the label warning of increased cardiovascular risk to the COX-2 inhibitors. The available evidence, he said, strongly suggests the same risk applies to nonselective NSAIDs, with the likely exception of high-dose naproxen. He is concerned that this labeling may give many European physicians and patients a false sense of security about treatment with traditional NSAIDs.

AMSTERDAM — Concomitant aspirin use may fully reverse the increased atherothrombotic risk associated with cyclooxygenase-2 selective NSAIDs, Dr. Gurkirpal Singh reported at the annual European Congress of Rheumatology.

In addition, aspirin may also reduce—albeit only partially in some instances—the cardiovascular risk conferred by most traditional nonselective NSAIDs, said Dr. Singh of Stanford (Calif.) University.

Although these findings from a large case-control study provide insight into the mechanism by which NSAIDs increase cardiovascular risk, he stressed that adding a daily aspirin in order to mitigate that cardiovascular risk is not a practical solution for arthritis patients seeking pain relief. That's because there is some evidence that concomitant use of aspirin and NSAIDs, whether COX-2 selective or not, appears to magnify the risk of NSAID-associated GI bleeding, he said.

Dr. Singh utilized the California Medicare database to identify all adults with rheumatoid arthritis or osteoarthritis treated with a COX-2 selective or nonselective NSAID from 1999 through the first half of 2004.

During nearly 2.4 million patient-years of follow-up, 15,343 arthritis patients experienced an acute MI, 8% of which were fatal. Each MI patient was matched to four controls.

The adjusted relative risk of MI was increased by 31% in patients being treated with rofecoxib and by 12% in patients being treated with celecoxib, compared with the rate in remote users of any NSAID. Both differences were significant.

The MI risk was also increased by 65% in current users of indomethacin, by 52% with meloxicam, and by 47% with sulindac, but was not significantly elevated in current ibuprofen users.

Concurrent use of aspirin completely reversed the increased MI risk associated with rofecoxib, celecoxib, meloxicam, and sulindac. However, the increased risk in current users of indomethacin was only partially and nonsignificantly reduced, such that patients on concomitant aspirin and indomethacin still had a 20% increased risk, he explained.

In a separate presentation, Dr. Steven B. Abramson said he thought Dr. Singh's findings make a lot of sense. “My instincts are that there will be some cardioprotection because you're getting 24-hour inhibition of platelets with a single aspirin,” added Dr. Abramson, professor of medicine and associate dean for clinical research at New York University.

It has been shown that 500 mg of naproxen provides good platelet inhibition for close to 12 hours. Moreover, a recent large metaanalysis of trials comparing COX-2 inhibitors with nonselective NSAIDs, or drugs in either class with placebo, showed that while the COX-2 inhibitors were associated with a 42% relative increase in MIs and other vascular events relative to placebo, a comparable risk was present in patients on high doses of traditional NSAIDs—except for those on naproxen at 500 mg b.i.d.

The metaanalysis, led by investigators at the University of Oxford, involved roughly 145,000 patients in 138 randomized trials, including some unpublished ones on file with manufacturers (BMJ 2006;332:1302–8).

“It still remains uncertain whether naproxen is cardioprotective, but it probably is at 500 mg twice per day,” Dr. Abramson said. He was quick to add, however, that this will have to be shown in prospective clinical trials before the FDA would consider removing the warning of increased cardiovascular risk from naproxen's label, a warning currently applied to all COX-2 selective and traditional NSAIDs.

Dr. Abramson, who was a member of the FDA's special advisory panel on the COX-2 inhibitors' cardiovascular risk, criticized the European Union drug regulatory agency for limiting the label warning of increased cardiovascular risk to the COX-2 inhibitors. The available evidence, he said, strongly suggests the same risk applies to nonselective NSAIDs, with the likely exception of high-dose naproxen. He is concerned that this labeling may give many European physicians and patients a false sense of security about treatment with traditional NSAIDs.

AMSTERDAM — Concomitant aspirin use may fully reverse the increased atherothrombotic risk associated with cyclooxygenase-2 selective NSAIDs, Dr. Gurkirpal Singh reported at the annual European Congress of Rheumatology.

In addition, aspirin may also reduce—albeit only partially in some instances—the cardiovascular risk conferred by most traditional nonselective NSAIDs, said Dr. Singh of Stanford (Calif.) University.

Although these findings from a large case-control study provide insight into the mechanism by which NSAIDs increase cardiovascular risk, he stressed that adding a daily aspirin in order to mitigate that cardiovascular risk is not a practical solution for arthritis patients seeking pain relief. That's because there is some evidence that concomitant use of aspirin and NSAIDs, whether COX-2 selective or not, appears to magnify the risk of NSAID-associated GI bleeding, he said.

Dr. Singh utilized the California Medicare database to identify all adults with rheumatoid arthritis or osteoarthritis treated with a COX-2 selective or nonselective NSAID from 1999 through the first half of 2004.

During nearly 2.4 million patient-years of follow-up, 15,343 arthritis patients experienced an acute MI, 8% of which were fatal. Each MI patient was matched to four controls.

The adjusted relative risk of MI was increased by 31% in patients being treated with rofecoxib and by 12% in patients being treated with celecoxib, compared with the rate in remote users of any NSAID. Both differences were significant.

The MI risk was also increased by 65% in current users of indomethacin, by 52% with meloxicam, and by 47% with sulindac, but was not significantly elevated in current ibuprofen users.

Concurrent use of aspirin completely reversed the increased MI risk associated with rofecoxib, celecoxib, meloxicam, and sulindac. However, the increased risk in current users of indomethacin was only partially and nonsignificantly reduced, such that patients on concomitant aspirin and indomethacin still had a 20% increased risk, he explained.

In a separate presentation, Dr. Steven B. Abramson said he thought Dr. Singh's findings make a lot of sense. “My instincts are that there will be some cardioprotection because you're getting 24-hour inhibition of platelets with a single aspirin,” added Dr. Abramson, professor of medicine and associate dean for clinical research at New York University.

It has been shown that 500 mg of naproxen provides good platelet inhibition for close to 12 hours. Moreover, a recent large metaanalysis of trials comparing COX-2 inhibitors with nonselective NSAIDs, or drugs in either class with placebo, showed that while the COX-2 inhibitors were associated with a 42% relative increase in MIs and other vascular events relative to placebo, a comparable risk was present in patients on high doses of traditional NSAIDs—except for those on naproxen at 500 mg b.i.d.

The metaanalysis, led by investigators at the University of Oxford, involved roughly 145,000 patients in 138 randomized trials, including some unpublished ones on file with manufacturers (BMJ 2006;332:1302–8).

“It still remains uncertain whether naproxen is cardioprotective, but it probably is at 500 mg twice per day,” Dr. Abramson said. He was quick to add, however, that this will have to be shown in prospective clinical trials before the FDA would consider removing the warning of increased cardiovascular risk from naproxen's label, a warning currently applied to all COX-2 selective and traditional NSAIDs.

Dr. Abramson, who was a member of the FDA's special advisory panel on the COX-2 inhibitors' cardiovascular risk, criticized the European Union drug regulatory agency for limiting the label warning of increased cardiovascular risk to the COX-2 inhibitors. The available evidence, he said, strongly suggests the same risk applies to nonselective NSAIDs, with the likely exception of high-dose naproxen. He is concerned that this labeling may give many European physicians and patients a false sense of security about treatment with traditional NSAIDs.

AMSTERDAM — For the first time, rituximab has been shown to prevent the progression of joint damage—a critical therapeutic outcome—in patients with long-standing, intractable rheumatoid arthritis, Dr. Edward Keystone said at the annual European Congress of Rheumatology.

“This is the first time we've seen an agent that can inhibit radiographic progression after the failure of tumor necrosis factor blockade,” said Dr. Keystone. Some 25%–40% of patients do not respond to tumor necrosis factor-αinhibitors.

In a double-blind trial that included 517 patients whose mean disease duration was 12 years, the mean change in total Sharp score from baseline was 2.31 among patients randomized to placebo plus methotrexate (10–25 mg/week) after 1 year of follow-up.

In contrast, among those receiving two infusions of rituximab, 1 g 2 weeks apart, plus background methotrexate, the mean change in Sharp score was 1, said Dr. Keystone, a professor of medicine at the University of Toronto. Mean changes in erosion scores were 1.32 and 0.59 in the placebo and rituximab groups, respectively, while mean changes in joint space narrowing were 0.99 and 0.41.

These differences were statistically significant and represented a 50% reduction in radiographic progression, he said at the meeting, sponsored by the European League Against Rheumatism.

Of the patients receiving rituximab, 61% had no change in erosion score from baseline, as did 52% of those receiving only methotrexate.

Clinical efficacy also was maintained among patients receiving rituximab, with 51%, 27%, and 12% of patients achieving ACR 20, 50, and 70 responses, respectively, according to Dr. Keystone.

The average time to flare was 30 weeks.

Rituximab is a selective inhibitor of CD20+ B cells. Its administration results in depletion of this subset of B cells, possibly through cell-mediated and complement-dependent mechanisms.

AMSTERDAM — For the first time, rituximab has been shown to prevent the progression of joint damage—a critical therapeutic outcome—in patients with long-standing, intractable rheumatoid arthritis, Dr. Edward Keystone said at the annual European Congress of Rheumatology.

“This is the first time we've seen an agent that can inhibit radiographic progression after the failure of tumor necrosis factor blockade,” said Dr. Keystone. Some 25%–40% of patients do not respond to tumor necrosis factor-αinhibitors.

In a double-blind trial that included 517 patients whose mean disease duration was 12 years, the mean change in total Sharp score from baseline was 2.31 among patients randomized to placebo plus methotrexate (10–25 mg/week) after 1 year of follow-up.

In contrast, among those receiving two infusions of rituximab, 1 g 2 weeks apart, plus background methotrexate, the mean change in Sharp score was 1, said Dr. Keystone, a professor of medicine at the University of Toronto. Mean changes in erosion scores were 1.32 and 0.59 in the placebo and rituximab groups, respectively, while mean changes in joint space narrowing were 0.99 and 0.41.

These differences were statistically significant and represented a 50% reduction in radiographic progression, he said at the meeting, sponsored by the European League Against Rheumatism.

Of the patients receiving rituximab, 61% had no change in erosion score from baseline, as did 52% of those receiving only methotrexate.

Clinical efficacy also was maintained among patients receiving rituximab, with 51%, 27%, and 12% of patients achieving ACR 20, 50, and 70 responses, respectively, according to Dr. Keystone.

The average time to flare was 30 weeks.

Rituximab is a selective inhibitor of CD20+ B cells. Its administration results in depletion of this subset of B cells, possibly through cell-mediated and complement-dependent mechanisms.

AMSTERDAM — For the first time, rituximab has been shown to prevent the progression of joint damage—a critical therapeutic outcome—in patients with long-standing, intractable rheumatoid arthritis, Dr. Edward Keystone said at the annual European Congress of Rheumatology.

“This is the first time we've seen an agent that can inhibit radiographic progression after the failure of tumor necrosis factor blockade,” said Dr. Keystone. Some 25%–40% of patients do not respond to tumor necrosis factor-αinhibitors.

In a double-blind trial that included 517 patients whose mean disease duration was 12 years, the mean change in total Sharp score from baseline was 2.31 among patients randomized to placebo plus methotrexate (10–25 mg/week) after 1 year of follow-up.

In contrast, among those receiving two infusions of rituximab, 1 g 2 weeks apart, plus background methotrexate, the mean change in Sharp score was 1, said Dr. Keystone, a professor of medicine at the University of Toronto. Mean changes in erosion scores were 1.32 and 0.59 in the placebo and rituximab groups, respectively, while mean changes in joint space narrowing were 0.99 and 0.41.

These differences were statistically significant and represented a 50% reduction in radiographic progression, he said at the meeting, sponsored by the European League Against Rheumatism.

Of the patients receiving rituximab, 61% had no change in erosion score from baseline, as did 52% of those receiving only methotrexate.

Clinical efficacy also was maintained among patients receiving rituximab, with 51%, 27%, and 12% of patients achieving ACR 20, 50, and 70 responses, respectively, according to Dr. Keystone.

The average time to flare was 30 weeks.

Rituximab is a selective inhibitor of CD20+ B cells. Its administration results in depletion of this subset of B cells, possibly through cell-mediated and complement-dependent mechanisms.