Rheumatoid Arthritis

PARIS — Sacroiliitis is an often-underappreciated hallmark of psoriatic arthritis, according to Dr. Augustin Sellas of Vall d'Hebron Hospital, Barcelona.

Peripheral joint disease in psoriatic arthritis patients draws considerable physician attention.

But sacroiliitis is highly prevalent as well, he noted at the annual European Congress of Rheumatology.

Dr. Sellas retrospectively reviewed x-rays of 128 PsA patients, 51% of whom had radiographic evidence of sacroiliitis.

The prevalence was similar in men and women. Sacroiliitis was bilateral in 47 of 65 affected patients, or 72%.

Seventeen percent of psoriatic arthritis patients were HLA-B27 positive. Sacroiliitis was present in three-quarters of this subgroup, with all but one case being bilateral.

The reported prevalence of sacroiliitis in PsA patients has ranged from 30% to 78% in other studies, said Dr. Sellas.

PARIS — Sacroiliitis is an often-underappreciated hallmark of psoriatic arthritis, according to Dr. Augustin Sellas of Vall d'Hebron Hospital, Barcelona.

Peripheral joint disease in psoriatic arthritis patients draws considerable physician attention.

But sacroiliitis is highly prevalent as well, he noted at the annual European Congress of Rheumatology.

Dr. Sellas retrospectively reviewed x-rays of 128 PsA patients, 51% of whom had radiographic evidence of sacroiliitis.

The prevalence was similar in men and women. Sacroiliitis was bilateral in 47 of 65 affected patients, or 72%.

Seventeen percent of psoriatic arthritis patients were HLA-B27 positive. Sacroiliitis was present in three-quarters of this subgroup, with all but one case being bilateral.

The reported prevalence of sacroiliitis in PsA patients has ranged from 30% to 78% in other studies, said Dr. Sellas.

PARIS — Sacroiliitis is an often-underappreciated hallmark of psoriatic arthritis, according to Dr. Augustin Sellas of Vall d'Hebron Hospital, Barcelona.

Peripheral joint disease in psoriatic arthritis patients draws considerable physician attention.

But sacroiliitis is highly prevalent as well, he noted at the annual European Congress of Rheumatology.

Dr. Sellas retrospectively reviewed x-rays of 128 PsA patients, 51% of whom had radiographic evidence of sacroiliitis.

The prevalence was similar in men and women. Sacroiliitis was bilateral in 47 of 65 affected patients, or 72%.

Seventeen percent of psoriatic arthritis patients were HLA-B27 positive. Sacroiliitis was present in three-quarters of this subgroup, with all but one case being bilateral.

The reported prevalence of sacroiliitis in PsA patients has ranged from 30% to 78% in other studies, said Dr. Sellas.

PARIS — Patients with rheumatoid arthritis receiving abatacept showed an increasing magnitude of clinical response between months 6 and 12, Dr. Michael Schiff reported.

In RA, it's important to evaluate efficacy not only at the group level—mean changes that occur in a group as a whole over time—but also at the individual level, and to measure changes in a patient's response over time, Dr. Schiff said in a press conference at the annual European Congress of Rheumatology.

In a post-hoc analysis of ATTEST (Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy and Safety in Treating RA), patients who achieved an ACR 20 at 6 months were reevaluated at 12 months to determine whether they further improved, retained, or lost their response.

The larger ATTEST trial, sponsored by Bristol-Myers Squibb Co., included 431 patients who had an inadequate response to methotrexate, and randomized them to abatacept, approximately 10 mg/kg every 4 weeks; infliximab, 3 mg/kg every 8 weeks; or placebo. They also were on background methotrexate, 10-30 mg/week.

At baseline, patients' mean age was 49 years and mean disease duration was 8 years. The majority were women. Mean number of swollen joints was 20, mean number of tender joints was 30, and mean disease activity score (DAS) 28 was 6.4.

At month 6, a total of 32 patients receiving abatacept and 27 patients receiving infliximab had achieved an ACR 20 response, though not ACR 50 or ARC 70 responses. The responses in this subgroup of patients were then analyzed at 12 months.

A similar percentage of patients receiving abatacept and infliximab achieved at least an ACR 50 response at 1 year. A total of 28.1% of patients on abatacept and 29.6% of patients on infliximab continued to improve to this degree, a clinically significant response, said Dr. Schiff, a clinical professor of medicine in the rheumatology division, University of Colorado, Denver.

The proportion of patients who maintained an ACR 20 response at 1 year was 59.4% for abatacept and 44.4% for infliximab, while the proportions who lost their ACR 20 response at 1 year were 12.5% and 25.9%, respectively.

Among the 24 patients treated with abatacept who achieved a low disease activity score (DAS28 below 3.2) at 6 months, 41.7% went on to clinical remission (DAS28 below 2.6) at 1 year. Among the 25 patients treated with infliximab who achieved a low disease activity score at 6 months, 28% went on to remission at 1 year.

A total of 12.5% and 16% of the abatacept- and infliximab-treated patients retained their low disease activity score at 1 year, while 45.8% and 56% lost this response by 1 year.

“These findings highlight the importance of examining clinical benefits at the level of the individual patient,” Dr. Schiff wrote in a poster. “Abatacept has the potential to provide clinical benefits to patients that increase in magnitude over time.”

Dr. Schiff has received research grants and consulting fees from Bristol-Myers Squibb and Centocor.

PARIS — Patients with rheumatoid arthritis receiving abatacept showed an increasing magnitude of clinical response between months 6 and 12, Dr. Michael Schiff reported.

In RA, it's important to evaluate efficacy not only at the group level—mean changes that occur in a group as a whole over time—but also at the individual level, and to measure changes in a patient's response over time, Dr. Schiff said in a press conference at the annual European Congress of Rheumatology.

In a post-hoc analysis of ATTEST (Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy and Safety in Treating RA), patients who achieved an ACR 20 at 6 months were reevaluated at 12 months to determine whether they further improved, retained, or lost their response.

The larger ATTEST trial, sponsored by Bristol-Myers Squibb Co., included 431 patients who had an inadequate response to methotrexate, and randomized them to abatacept, approximately 10 mg/kg every 4 weeks; infliximab, 3 mg/kg every 8 weeks; or placebo. They also were on background methotrexate, 10-30 mg/week.

At baseline, patients' mean age was 49 years and mean disease duration was 8 years. The majority were women. Mean number of swollen joints was 20, mean number of tender joints was 30, and mean disease activity score (DAS) 28 was 6.4.

At month 6, a total of 32 patients receiving abatacept and 27 patients receiving infliximab had achieved an ACR 20 response, though not ACR 50 or ARC 70 responses. The responses in this subgroup of patients were then analyzed at 12 months.

A similar percentage of patients receiving abatacept and infliximab achieved at least an ACR 50 response at 1 year. A total of 28.1% of patients on abatacept and 29.6% of patients on infliximab continued to improve to this degree, a clinically significant response, said Dr. Schiff, a clinical professor of medicine in the rheumatology division, University of Colorado, Denver.

The proportion of patients who maintained an ACR 20 response at 1 year was 59.4% for abatacept and 44.4% for infliximab, while the proportions who lost their ACR 20 response at 1 year were 12.5% and 25.9%, respectively.

Among the 24 patients treated with abatacept who achieved a low disease activity score (DAS28 below 3.2) at 6 months, 41.7% went on to clinical remission (DAS28 below 2.6) at 1 year. Among the 25 patients treated with infliximab who achieved a low disease activity score at 6 months, 28% went on to remission at 1 year.

A total of 12.5% and 16% of the abatacept- and infliximab-treated patients retained their low disease activity score at 1 year, while 45.8% and 56% lost this response by 1 year.

“These findings highlight the importance of examining clinical benefits at the level of the individual patient,” Dr. Schiff wrote in a poster. “Abatacept has the potential to provide clinical benefits to patients that increase in magnitude over time.”

Dr. Schiff has received research grants and consulting fees from Bristol-Myers Squibb and Centocor.

PARIS — Patients with rheumatoid arthritis receiving abatacept showed an increasing magnitude of clinical response between months 6 and 12, Dr. Michael Schiff reported.

In RA, it's important to evaluate efficacy not only at the group level—mean changes that occur in a group as a whole over time—but also at the individual level, and to measure changes in a patient's response over time, Dr. Schiff said in a press conference at the annual European Congress of Rheumatology.

In a post-hoc analysis of ATTEST (Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy and Safety in Treating RA), patients who achieved an ACR 20 at 6 months were reevaluated at 12 months to determine whether they further improved, retained, or lost their response.

The larger ATTEST trial, sponsored by Bristol-Myers Squibb Co., included 431 patients who had an inadequate response to methotrexate, and randomized them to abatacept, approximately 10 mg/kg every 4 weeks; infliximab, 3 mg/kg every 8 weeks; or placebo. They also were on background methotrexate, 10-30 mg/week.

At baseline, patients' mean age was 49 years and mean disease duration was 8 years. The majority were women. Mean number of swollen joints was 20, mean number of tender joints was 30, and mean disease activity score (DAS) 28 was 6.4.

At month 6, a total of 32 patients receiving abatacept and 27 patients receiving infliximab had achieved an ACR 20 response, though not ACR 50 or ARC 70 responses. The responses in this subgroup of patients were then analyzed at 12 months.

A similar percentage of patients receiving abatacept and infliximab achieved at least an ACR 50 response at 1 year. A total of 28.1% of patients on abatacept and 29.6% of patients on infliximab continued to improve to this degree, a clinically significant response, said Dr. Schiff, a clinical professor of medicine in the rheumatology division, University of Colorado, Denver.

The proportion of patients who maintained an ACR 20 response at 1 year was 59.4% for abatacept and 44.4% for infliximab, while the proportions who lost their ACR 20 response at 1 year were 12.5% and 25.9%, respectively.

Among the 24 patients treated with abatacept who achieved a low disease activity score (DAS28 below 3.2) at 6 months, 41.7% went on to clinical remission (DAS28 below 2.6) at 1 year. Among the 25 patients treated with infliximab who achieved a low disease activity score at 6 months, 28% went on to remission at 1 year.

A total of 12.5% and 16% of the abatacept- and infliximab-treated patients retained their low disease activity score at 1 year, while 45.8% and 56% lost this response by 1 year.

“These findings highlight the importance of examining clinical benefits at the level of the individual patient,” Dr. Schiff wrote in a poster. “Abatacept has the potential to provide clinical benefits to patients that increase in magnitude over time.”

Dr. Schiff has received research grants and consulting fees from Bristol-Myers Squibb and Centocor.

PARIS — The European League Against Rheumatism Task Force on Cardiovascular Risk Management in Rheumatoid Arthritis has recommended annual cardiovascular risk screening for all patients with rheumatoid arthritis.

The task force also advised annual screening be considered for patients with ankylosing spondylitis or psoriatic arthritis as well, said task force member Dr. Mike J.L. Peters, in an interview.

These recommendations, to be published by year's end, were announced at the annual European Congress of Rheumatology. Included will be guidance on employing a multiplier or conversion factor in conjunction with the Systematic Coronary Risk Evaluation (SCORE)—the European equivalent of the Framingham Risk Score—in order to more accurately reflect the increased cardiovascular risk of patients with inflammatory arthritis.

In a separate presentation, Dr. Peters reported on his own data showing that the increased cardiovascular risk of RA patients is similar in magnitude to that associated with type 2 diabetes. This supports arguments for aggressive risk factor management in the RA population, especially given that type 2 diabetes is considered a coronary heart disease equivalent, meaning that diabetic individuals have roughly the same risk of future cardiovascular events as patients who've already had an acute MI, according to Dr. Peters of VU University Medical Center, Amsterdam.

Dr. Peters reported on 353 normoglycemic patients with RA of an average 7 years' duration and varied severity, 194 type 2 diabetic patients, and 258 healthy controls. All were aged 50-75. The prevalence of objective cardio- and/or cerebrovascular disease was 21.6% in patients with type 2 diabetes, 15.7% in those with RA, and 9.7% in controls.

After adjustment for differences in age, gender, and rates of the traditional cardiovascular risk factors, the prevalence of cardiovascular disease was found to be 85% greater in diabetic patients than controls, and 51% greater in the RA group than controls. The rates in diabetic and RA patients were not significantly different.

Audience member Dr. Daniel H. Solomon urged a cautious interpretation of the Dutch findings.

“When we think about diabetes as a risk factor for cardiovascular disease, we understand that some of the management techniques—aspirin, statins, other preventive measures—have been tested specifically in diabetic populations. But at this point, we have almost no data on the benefits of these sorts of preventive measures in a rheumatoid population,” according to Dr. Solomon of Harvard Medical School, Boston.

“I'd be very careful about concluding that similar preventive measures would be beneficial in rheumatoids. We just don't have those data. I don't disagree that they might be, but I don't think we have enough data to make an evidence-based statement about that,” he said. Dr. Peters said he agreed.

In a separate presentation, Dr. Peters reported that the rate of major cardiovascular events in 329 Dutch RA patients followed prospectively for nearly 3 years was 8.6%, compared with 4.3% in 1,852 controls drawn from the general population.

The RA patients had higher rates of smoking, hypertension, and some other traditional cardiovascular risk factors, as has been reported in other studies. But after adjusting for age, gender, and traditional risk factors, the cardiovascular event rate in the RA population remained twofold greater than in the general population, according to Dr. Peters.

PARIS — The European League Against Rheumatism Task Force on Cardiovascular Risk Management in Rheumatoid Arthritis has recommended annual cardiovascular risk screening for all patients with rheumatoid arthritis.

The task force also advised annual screening be considered for patients with ankylosing spondylitis or psoriatic arthritis as well, said task force member Dr. Mike J.L. Peters, in an interview.

These recommendations, to be published by year's end, were announced at the annual European Congress of Rheumatology. Included will be guidance on employing a multiplier or conversion factor in conjunction with the Systematic Coronary Risk Evaluation (SCORE)—the European equivalent of the Framingham Risk Score—in order to more accurately reflect the increased cardiovascular risk of patients with inflammatory arthritis.

In a separate presentation, Dr. Peters reported on his own data showing that the increased cardiovascular risk of RA patients is similar in magnitude to that associated with type 2 diabetes. This supports arguments for aggressive risk factor management in the RA population, especially given that type 2 diabetes is considered a coronary heart disease equivalent, meaning that diabetic individuals have roughly the same risk of future cardiovascular events as patients who've already had an acute MI, according to Dr. Peters of VU University Medical Center, Amsterdam.

Dr. Peters reported on 353 normoglycemic patients with RA of an average 7 years' duration and varied severity, 194 type 2 diabetic patients, and 258 healthy controls. All were aged 50-75. The prevalence of objective cardio- and/or cerebrovascular disease was 21.6% in patients with type 2 diabetes, 15.7% in those with RA, and 9.7% in controls.

After adjustment for differences in age, gender, and rates of the traditional cardiovascular risk factors, the prevalence of cardiovascular disease was found to be 85% greater in diabetic patients than controls, and 51% greater in the RA group than controls. The rates in diabetic and RA patients were not significantly different.

Audience member Dr. Daniel H. Solomon urged a cautious interpretation of the Dutch findings.

“When we think about diabetes as a risk factor for cardiovascular disease, we understand that some of the management techniques—aspirin, statins, other preventive measures—have been tested specifically in diabetic populations. But at this point, we have almost no data on the benefits of these sorts of preventive measures in a rheumatoid population,” according to Dr. Solomon of Harvard Medical School, Boston.

“I'd be very careful about concluding that similar preventive measures would be beneficial in rheumatoids. We just don't have those data. I don't disagree that they might be, but I don't think we have enough data to make an evidence-based statement about that,” he said. Dr. Peters said he agreed.

In a separate presentation, Dr. Peters reported that the rate of major cardiovascular events in 329 Dutch RA patients followed prospectively for nearly 3 years was 8.6%, compared with 4.3% in 1,852 controls drawn from the general population.

The RA patients had higher rates of smoking, hypertension, and some other traditional cardiovascular risk factors, as has been reported in other studies. But after adjusting for age, gender, and traditional risk factors, the cardiovascular event rate in the RA population remained twofold greater than in the general population, according to Dr. Peters.

PARIS — The European League Against Rheumatism Task Force on Cardiovascular Risk Management in Rheumatoid Arthritis has recommended annual cardiovascular risk screening for all patients with rheumatoid arthritis.

The task force also advised annual screening be considered for patients with ankylosing spondylitis or psoriatic arthritis as well, said task force member Dr. Mike J.L. Peters, in an interview.

These recommendations, to be published by year's end, were announced at the annual European Congress of Rheumatology. Included will be guidance on employing a multiplier or conversion factor in conjunction with the Systematic Coronary Risk Evaluation (SCORE)—the European equivalent of the Framingham Risk Score—in order to more accurately reflect the increased cardiovascular risk of patients with inflammatory arthritis.

In a separate presentation, Dr. Peters reported on his own data showing that the increased cardiovascular risk of RA patients is similar in magnitude to that associated with type 2 diabetes. This supports arguments for aggressive risk factor management in the RA population, especially given that type 2 diabetes is considered a coronary heart disease equivalent, meaning that diabetic individuals have roughly the same risk of future cardiovascular events as patients who've already had an acute MI, according to Dr. Peters of VU University Medical Center, Amsterdam.

Dr. Peters reported on 353 normoglycemic patients with RA of an average 7 years' duration and varied severity, 194 type 2 diabetic patients, and 258 healthy controls. All were aged 50-75. The prevalence of objective cardio- and/or cerebrovascular disease was 21.6% in patients with type 2 diabetes, 15.7% in those with RA, and 9.7% in controls.

After adjustment for differences in age, gender, and rates of the traditional cardiovascular risk factors, the prevalence of cardiovascular disease was found to be 85% greater in diabetic patients than controls, and 51% greater in the RA group than controls. The rates in diabetic and RA patients were not significantly different.

Audience member Dr. Daniel H. Solomon urged a cautious interpretation of the Dutch findings.

“When we think about diabetes as a risk factor for cardiovascular disease, we understand that some of the management techniques—aspirin, statins, other preventive measures—have been tested specifically in diabetic populations. But at this point, we have almost no data on the benefits of these sorts of preventive measures in a rheumatoid population,” according to Dr. Solomon of Harvard Medical School, Boston.

“I'd be very careful about concluding that similar preventive measures would be beneficial in rheumatoids. We just don't have those data. I don't disagree that they might be, but I don't think we have enough data to make an evidence-based statement about that,” he said. Dr. Peters said he agreed.

In a separate presentation, Dr. Peters reported that the rate of major cardiovascular events in 329 Dutch RA patients followed prospectively for nearly 3 years was 8.6%, compared with 4.3% in 1,852 controls drawn from the general population.

The RA patients had higher rates of smoking, hypertension, and some other traditional cardiovascular risk factors, as has been reported in other studies. But after adjusting for age, gender, and traditional risk factors, the cardiovascular event rate in the RA population remained twofold greater than in the general population, according to Dr. Peters.

PARIS — The anti-interleukin-6 monoclonal antibody tocilizumab may offer a new alternative for the most refractory patients with rheumatoid arthritis, including those who have failed antitumor necrosis factor drugs.

Both interleukin (IL)-6 and tumor necrosis factor (TNF)-? play major roles in the development and maintenance of rheumatoid arthritis (RA), explained Dr. Paul Emery, Arthritis Research Campaign Professor of Rheumatology and head of the academic section of musculoskeletal diseases at the University of Leeds (England). He gave his presentation at the annual European Congress of Rheumatology.

“While anti-TNF therapies have become established treatments for RA, significant proportions of patients do not achieve an adequate response or become refractory to them,” Dr. Emery said. Inhibiting the ubiquitous cytokine IL-6, which drives the acute phase response among other effects, may offer an additional way of achieving disease control, he said.

In the Research on Actemra Determining Efficacy after Anti-TNF Failure (RADIATE) trial, 498 patients who had previously failed anti-TNF therapy were randomized to receive placebo or tocilizumab in doses of 4 mg/kg or 8 mg/kg administered intravenously every 4 weeks for 24 weeks. A total of 160 were randomized to placebo, 163 to 4 mg/kg, and 175 to 8 mg/kg.

Patients also were receiving stable doses of methotrexate, 10-25 mg/week, and corticosteroids, 10 mg or less/day.

Mean age of patients was 53 years and mean disease duration was 11 years. Most were seropositive, and disease activity scores (DAS) were high, at a mean of 6.8.

Approximately half the patients had failed one anti-TNF agent, another third had failed two, and 12%-18% had failed three prior agents, he said. The study design allowed for escape at 16 weeks. A total of 60% of the controls had withdrawn or were on 8-mg/kg rescue therapy by week 24, as had 34% of the 4-mg group and 25% of the 8-mg group.

ACR 20 responses were seen in 50% of patients receiving the 8-mg/kg dose, according to Dr. Emery, who was lead investigator of the trial, funded by Roche.

Significantly greater improvements were also seen in the 8-mg/kg group on other end points.

“Probably the most impressive finding was that one-third of patients who had previously failed the best we had to offer were able to get into remission, which is a much higher rate than previously has been seen in patients failing TNF,” Dr. Emery said. Remission was defined as a DAS28 score below 2.6.

“This is our worst population, for whom we have no easy options, and the results were equal to or better than what we've seen before,” he added.

Serious adverse events were seen in 11%, 7%, and 6% of the placebo, 4-mg/kg, and 8-mg/kg groups, respectively. Infections occurred in 41%, 47%, and 50% of the placebo, 4-mg, and 8-mg patients, while serious infections were seen in 3%, 2%, and 5%, respectively. There were no opportunistic infections or cases of tuberculosis.

Over the past 12 months, there have been research reports that tocilizumab improves quality of life in RA (RHEUMATOLOGY NEWS, May 2008, p. 6); lessens the articular and systemic manifestations of RA when used with disease-modifying antirheumatic drugs (RHEUMATOLOGY NEWS, January 2008, p. 1); and was beneficial in moderate to severe RA (RHEUMATOLOGY NEWS, October 2007, p. 20). The drug remains investigational both in the United States and Europe.

Dr. Emery has received consulting fees from Roche.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — The anti-interleukin-6 monoclonal antibody tocilizumab may offer a new alternative for the most refractory patients with rheumatoid arthritis, including those who have failed antitumor necrosis factor drugs.

Both interleukin (IL)-6 and tumor necrosis factor (TNF)-? play major roles in the development and maintenance of rheumatoid arthritis (RA), explained Dr. Paul Emery, Arthritis Research Campaign Professor of Rheumatology and head of the academic section of musculoskeletal diseases at the University of Leeds (England). He gave his presentation at the annual European Congress of Rheumatology.

“While anti-TNF therapies have become established treatments for RA, significant proportions of patients do not achieve an adequate response or become refractory to them,” Dr. Emery said. Inhibiting the ubiquitous cytokine IL-6, which drives the acute phase response among other effects, may offer an additional way of achieving disease control, he said.

In the Research on Actemra Determining Efficacy after Anti-TNF Failure (RADIATE) trial, 498 patients who had previously failed anti-TNF therapy were randomized to receive placebo or tocilizumab in doses of 4 mg/kg or 8 mg/kg administered intravenously every 4 weeks for 24 weeks. A total of 160 were randomized to placebo, 163 to 4 mg/kg, and 175 to 8 mg/kg.

Patients also were receiving stable doses of methotrexate, 10-25 mg/week, and corticosteroids, 10 mg or less/day.

Mean age of patients was 53 years and mean disease duration was 11 years. Most were seropositive, and disease activity scores (DAS) were high, at a mean of 6.8.

Approximately half the patients had failed one anti-TNF agent, another third had failed two, and 12%-18% had failed three prior agents, he said. The study design allowed for escape at 16 weeks. A total of 60% of the controls had withdrawn or were on 8-mg/kg rescue therapy by week 24, as had 34% of the 4-mg group and 25% of the 8-mg group.

ACR 20 responses were seen in 50% of patients receiving the 8-mg/kg dose, according to Dr. Emery, who was lead investigator of the trial, funded by Roche.

Significantly greater improvements were also seen in the 8-mg/kg group on other end points.

“Probably the most impressive finding was that one-third of patients who had previously failed the best we had to offer were able to get into remission, which is a much higher rate than previously has been seen in patients failing TNF,” Dr. Emery said. Remission was defined as a DAS28 score below 2.6.

“This is our worst population, for whom we have no easy options, and the results were equal to or better than what we've seen before,” he added.

Serious adverse events were seen in 11%, 7%, and 6% of the placebo, 4-mg/kg, and 8-mg/kg groups, respectively. Infections occurred in 41%, 47%, and 50% of the placebo, 4-mg, and 8-mg patients, while serious infections were seen in 3%, 2%, and 5%, respectively. There were no opportunistic infections or cases of tuberculosis.

Over the past 12 months, there have been research reports that tocilizumab improves quality of life in RA (RHEUMATOLOGY NEWS, May 2008, p. 6); lessens the articular and systemic manifestations of RA when used with disease-modifying antirheumatic drugs (RHEUMATOLOGY NEWS, January 2008, p. 1); and was beneficial in moderate to severe RA (RHEUMATOLOGY NEWS, October 2007, p. 20). The drug remains investigational both in the United States and Europe.

Dr. Emery has received consulting fees from Roche.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — The anti-interleukin-6 monoclonal antibody tocilizumab may offer a new alternative for the most refractory patients with rheumatoid arthritis, including those who have failed antitumor necrosis factor drugs.

Both interleukin (IL)-6 and tumor necrosis factor (TNF)-? play major roles in the development and maintenance of rheumatoid arthritis (RA), explained Dr. Paul Emery, Arthritis Research Campaign Professor of Rheumatology and head of the academic section of musculoskeletal diseases at the University of Leeds (England). He gave his presentation at the annual European Congress of Rheumatology.

“While anti-TNF therapies have become established treatments for RA, significant proportions of patients do not achieve an adequate response or become refractory to them,” Dr. Emery said. Inhibiting the ubiquitous cytokine IL-6, which drives the acute phase response among other effects, may offer an additional way of achieving disease control, he said.

In the Research on Actemra Determining Efficacy after Anti-TNF Failure (RADIATE) trial, 498 patients who had previously failed anti-TNF therapy were randomized to receive placebo or tocilizumab in doses of 4 mg/kg or 8 mg/kg administered intravenously every 4 weeks for 24 weeks. A total of 160 were randomized to placebo, 163 to 4 mg/kg, and 175 to 8 mg/kg.

Patients also were receiving stable doses of methotrexate, 10-25 mg/week, and corticosteroids, 10 mg or less/day.

Mean age of patients was 53 years and mean disease duration was 11 years. Most were seropositive, and disease activity scores (DAS) were high, at a mean of 6.8.

Approximately half the patients had failed one anti-TNF agent, another third had failed two, and 12%-18% had failed three prior agents, he said. The study design allowed for escape at 16 weeks. A total of 60% of the controls had withdrawn or were on 8-mg/kg rescue therapy by week 24, as had 34% of the 4-mg group and 25% of the 8-mg group.

ACR 20 responses were seen in 50% of patients receiving the 8-mg/kg dose, according to Dr. Emery, who was lead investigator of the trial, funded by Roche.

Significantly greater improvements were also seen in the 8-mg/kg group on other end points.

“Probably the most impressive finding was that one-third of patients who had previously failed the best we had to offer were able to get into remission, which is a much higher rate than previously has been seen in patients failing TNF,” Dr. Emery said. Remission was defined as a DAS28 score below 2.6.

“This is our worst population, for whom we have no easy options, and the results were equal to or better than what we've seen before,” he added.

Serious adverse events were seen in 11%, 7%, and 6% of the placebo, 4-mg/kg, and 8-mg/kg groups, respectively. Infections occurred in 41%, 47%, and 50% of the placebo, 4-mg, and 8-mg patients, while serious infections were seen in 3%, 2%, and 5%, respectively. There were no opportunistic infections or cases of tuberculosis.

Over the past 12 months, there have been research reports that tocilizumab improves quality of life in RA (RHEUMATOLOGY NEWS, May 2008, p. 6); lessens the articular and systemic manifestations of RA when used with disease-modifying antirheumatic drugs (RHEUMATOLOGY NEWS, January 2008, p. 1); and was beneficial in moderate to severe RA (RHEUMATOLOGY NEWS, October 2007, p. 20). The drug remains investigational both in the United States and Europe.

Dr. Emery has received consulting fees from Roche.

ELSEVIER GLOBAL MEDICAL NEWS

LIVERPOOL, ENGLAND — Patients with rheumatoid arthritis who have a history of cigarette smoking are more likely to have a poor response to anti-tumor necrosis factor therapy than are those who have never smoked.

Recent studies have provided strong evidence that cigarette smoking is a risk factor in susceptibility to rheumatoid arthritis (RA) and more severe disease. Smokers with RA appear to have increased production of cytokines like tumor necrosis factor, and autoantibodies such as rheumatoid factor. A recent study from the British Society for Rheumatology's biologics register found current smokers had a low response rate to infliximab (Rheumatology [Oxford] 2006;45:1558-65).

“To see if smoking affects the response to therapy in our patients and to determine if there is a relationship between response and pack-year history, we collected demographic data and smoking histories for all patients at our hospital who were started on anti-TNF drugs since 2002,” said Dr. Derek L. Mattey of Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent (England). A total of 154 patients whose mean age was 65 years were included. Infliximab was the agent used by 83 patients, etanercept by 55, and adalimumab by 16.

Two-thirds of the patients reported ever having smoked, but only 25% were still current smokers at the time they initiated treatment.

The extent of previous smoking was quantified, with one pack-year being equivalent to 20 cigarettes per day for 1 year, and intensity of smoking stratified as never (0 pack-years), light (1–15 pack-years), moderate (16–30 pack-years), and heavy (more than 30 pack-years).

At baseline, smokers were more likely to be rheumatoid factor positive and have nodular disease, but smokers and nonsmokers did not differ in baseline Disease Activity Score (DAS) 28, Health Assessment Questionnaire (HAQ) scores, pain scores, or C-reactive protein level, Dr. Mattey said.

Response was defined according to the EULAR (European League AgainstRheumatism) improvement criteria, based on 3-month DAS28 and absolute change in DAS28 from baseline.

At 3 months, there were significant differences between the groups, with patients whose smoking history exceeded 30 pack-years having an odds ratio of 7.4 for nonresponse versus patients who never smoked. The odds ratios for those in the light and moderate groups were 1.9 and 1.8, respectively.

Multivariate logistic regression analysis showed that the association of pack-year history with nonresponse was independent of age, sex, disease duration, baseline DAS28, and HAQ scores.

Moreover, the association was independent of smoking status at initiation of anti-TNF treatment.

Analysis also determined that the association of smoking and nonresponse was significant at 3 months only for infliximab, but there also was a trend for nonresponse by 12 months for etanercept.

On the DAS28, the subjective areas of patient global assessment and tender joint count were associated with increased pack-year history, unlike the objective areas of erythrocyte sedimentation rate and swollen joint count. “There also was an inverse relationship between pack-years smoked and change in pain scores,” he said at the annual meeting of the British Society for Rheumatology.

Dr. Mattey also undertook an analysis of the cytokine and metalloproteinase profiles in a group of 80 patients with early RA, to identify the possible impact of smoking at this level. In a poster, they reported that on ELISA and multiplex analyses, elevated levels of interleukin-8, vascular endothelial growth factor, and metalloproteinases 1, 8, and 9 were associated with smoking, and vascular endothelial growth factor and metalloproteinases 8 and 9 showed significant associations with number of pack-years.

LIVERPOOL, ENGLAND — Patients with rheumatoid arthritis who have a history of cigarette smoking are more likely to have a poor response to anti-tumor necrosis factor therapy than are those who have never smoked.

Recent studies have provided strong evidence that cigarette smoking is a risk factor in susceptibility to rheumatoid arthritis (RA) and more severe disease. Smokers with RA appear to have increased production of cytokines like tumor necrosis factor, and autoantibodies such as rheumatoid factor. A recent study from the British Society for Rheumatology's biologics register found current smokers had a low response rate to infliximab (Rheumatology [Oxford] 2006;45:1558-65).

“To see if smoking affects the response to therapy in our patients and to determine if there is a relationship between response and pack-year history, we collected demographic data and smoking histories for all patients at our hospital who were started on anti-TNF drugs since 2002,” said Dr. Derek L. Mattey of Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent (England). A total of 154 patients whose mean age was 65 years were included. Infliximab was the agent used by 83 patients, etanercept by 55, and adalimumab by 16.

Two-thirds of the patients reported ever having smoked, but only 25% were still current smokers at the time they initiated treatment.

The extent of previous smoking was quantified, with one pack-year being equivalent to 20 cigarettes per day for 1 year, and intensity of smoking stratified as never (0 pack-years), light (1–15 pack-years), moderate (16–30 pack-years), and heavy (more than 30 pack-years).

At baseline, smokers were more likely to be rheumatoid factor positive and have nodular disease, but smokers and nonsmokers did not differ in baseline Disease Activity Score (DAS) 28, Health Assessment Questionnaire (HAQ) scores, pain scores, or C-reactive protein level, Dr. Mattey said.

Response was defined according to the EULAR (European League AgainstRheumatism) improvement criteria, based on 3-month DAS28 and absolute change in DAS28 from baseline.

At 3 months, there were significant differences between the groups, with patients whose smoking history exceeded 30 pack-years having an odds ratio of 7.4 for nonresponse versus patients who never smoked. The odds ratios for those in the light and moderate groups were 1.9 and 1.8, respectively.

Multivariate logistic regression analysis showed that the association of pack-year history with nonresponse was independent of age, sex, disease duration, baseline DAS28, and HAQ scores.

Moreover, the association was independent of smoking status at initiation of anti-TNF treatment.

Analysis also determined that the association of smoking and nonresponse was significant at 3 months only for infliximab, but there also was a trend for nonresponse by 12 months for etanercept.

On the DAS28, the subjective areas of patient global assessment and tender joint count were associated with increased pack-year history, unlike the objective areas of erythrocyte sedimentation rate and swollen joint count. “There also was an inverse relationship between pack-years smoked and change in pain scores,” he said at the annual meeting of the British Society for Rheumatology.

Dr. Mattey also undertook an analysis of the cytokine and metalloproteinase profiles in a group of 80 patients with early RA, to identify the possible impact of smoking at this level. In a poster, they reported that on ELISA and multiplex analyses, elevated levels of interleukin-8, vascular endothelial growth factor, and metalloproteinases 1, 8, and 9 were associated with smoking, and vascular endothelial growth factor and metalloproteinases 8 and 9 showed significant associations with number of pack-years.

LIVERPOOL, ENGLAND — Patients with rheumatoid arthritis who have a history of cigarette smoking are more likely to have a poor response to anti-tumor necrosis factor therapy than are those who have never smoked.

Recent studies have provided strong evidence that cigarette smoking is a risk factor in susceptibility to rheumatoid arthritis (RA) and more severe disease. Smokers with RA appear to have increased production of cytokines like tumor necrosis factor, and autoantibodies such as rheumatoid factor. A recent study from the British Society for Rheumatology's biologics register found current smokers had a low response rate to infliximab (Rheumatology [Oxford] 2006;45:1558-65).

“To see if smoking affects the response to therapy in our patients and to determine if there is a relationship between response and pack-year history, we collected demographic data and smoking histories for all patients at our hospital who were started on anti-TNF drugs since 2002,” said Dr. Derek L. Mattey of Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent (England). A total of 154 patients whose mean age was 65 years were included. Infliximab was the agent used by 83 patients, etanercept by 55, and adalimumab by 16.

Two-thirds of the patients reported ever having smoked, but only 25% were still current smokers at the time they initiated treatment.

The extent of previous smoking was quantified, with one pack-year being equivalent to 20 cigarettes per day for 1 year, and intensity of smoking stratified as never (0 pack-years), light (1–15 pack-years), moderate (16–30 pack-years), and heavy (more than 30 pack-years).

At baseline, smokers were more likely to be rheumatoid factor positive and have nodular disease, but smokers and nonsmokers did not differ in baseline Disease Activity Score (DAS) 28, Health Assessment Questionnaire (HAQ) scores, pain scores, or C-reactive protein level, Dr. Mattey said.

Response was defined according to the EULAR (European League AgainstRheumatism) improvement criteria, based on 3-month DAS28 and absolute change in DAS28 from baseline.

At 3 months, there were significant differences between the groups, with patients whose smoking history exceeded 30 pack-years having an odds ratio of 7.4 for nonresponse versus patients who never smoked. The odds ratios for those in the light and moderate groups were 1.9 and 1.8, respectively.

Multivariate logistic regression analysis showed that the association of pack-year history with nonresponse was independent of age, sex, disease duration, baseline DAS28, and HAQ scores.

Moreover, the association was independent of smoking status at initiation of anti-TNF treatment.

Analysis also determined that the association of smoking and nonresponse was significant at 3 months only for infliximab, but there also was a trend for nonresponse by 12 months for etanercept.

On the DAS28, the subjective areas of patient global assessment and tender joint count were associated with increased pack-year history, unlike the objective areas of erythrocyte sedimentation rate and swollen joint count. “There also was an inverse relationship between pack-years smoked and change in pain scores,” he said at the annual meeting of the British Society for Rheumatology.

Dr. Mattey also undertook an analysis of the cytokine and metalloproteinase profiles in a group of 80 patients with early RA, to identify the possible impact of smoking at this level. In a poster, they reported that on ELISA and multiplex analyses, elevated levels of interleukin-8, vascular endothelial growth factor, and metalloproteinases 1, 8, and 9 were associated with smoking, and vascular endothelial growth factor and metalloproteinases 8 and 9 showed significant associations with number of pack-years.

LIVERPOOL, ENGLAND — Rituximab has been used successfully in a real-world setting as a first-line biologic therapy for rheumatoid arthritis that does not respond to conventional disease-modifying drugs, Dr. Ai Lyn Tan reported at the annual meeting of the British Society for Rheumatology.

Rituximab is licensed in the United Kingdom for the treatment of adults with rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, conventional disease-modifying anti-rheumatic drugs (DMARDs) and to one or more tumor necrosis factor (TNF) inhibitors. In the United States it is licensed for use in combination with methotrexate for management of moderately to severely active RA that has not responded to treatment with one or more anti-TNF agents.

Licensure of the TNF inhibitors posed financial strains on the U.K. health care system, and the drugs were restricted in availability in some areas. Because of this lack of availability and the fact that rituximab had been shown to be effective in RA in trials of patients who had not previously received anti-TNF therapy, this drug has been used as a first-line biologic since 2004 by Dr. Tan and her colleagues at the University of Leeds (England) and Chapel Allerton Hospital, Leeds.

A total of 39 patients who had failed at least one DMARD have received two initial infusions of rituximab 2 weeks apart. In 17 patients the doses were 1,000 mg each, and in 22 the doses were 500 mg each.

Two-thirds of the patients were women. Their median age was 58 years and median disease duration was 7 years. Thirty of the patients were rheumatoid factor (RF) positive at baseline, and 16 were also antinuclear antibody (ANA) positive.

Clinical outcome data were available for 37 patients and safety data for all 39.

Clinical assessments using the Disease Activity Score (DAS)28 and EULAR response criteria were done at 3, 6, 9, and 12 months. The EULAR response criteria use the change in DAS and the level of DAS achieved to classify patients as good, moderate, or nonresponders.

At all time points, there was a significant improvement in DAS28. EULAR good responses were seen in 40% of patients at 3 months and in 50% of patients at 12 months, while overall EULAR responses were seen in 88% and 77%, respectively, at those time points.

By 6 months ANA became negative in 40% of patients in whom it had been positive at baseline, and in 88% of RF-positive patients the antibody level had fallen. Four of the previously RF-positive patients became seronegative by 6 months, and these reductions were sustained at 12 months, Dr. Tan wrote in a poster presented at the meeting.

Slightly better responses were seen in patients who received the higher dose, with 82% in the 500-mg group and 94% of those in the 1,000-mg group achieving EULAR responses. Nonetheless, she suggested that it might be “prudent” to start on lower doses since treatment is likely to be needed long term.

Thus far 25 patients have been retreated, at a median of 13 months after the initial infusions, and 7 have received a third treatment, at a median of 11 months after the second treatment.

Two patients were switched to anti-TNF therapy following early treatment failure and a third was switched following an allergic reaction to the second infusion of rituximab, according to Dr. Tan, who declared no conflicts of interest.

One 67-year-old patient with preexisting lung disease died 3 months after treatment from presumed bilateral bronchopneumonia and possible methotrexate pneumonitis, and a second 61-year-old man died of a myocardial infarction while awaiting coronary angiography for angina pectoris. This outcome was not considered to be related to therapy.

In an interview, Dr. Tan said that her study showed that rituximab is effective as first-line therapy in patients with severe RA. “This is important because it can be used in patients in whom the TNF blockers are contraindicated,” she said.

Almost half of the patients in this study had disease features that could have caused concerns with TNF blockade, such as risks of infection and strong ANA positivity (Rheumatology 2008:47;865-7).

“I think this will be an important role for rituximab in RA,” Dr. Tan said.

LIVERPOOL, ENGLAND — Rituximab has been used successfully in a real-world setting as a first-line biologic therapy for rheumatoid arthritis that does not respond to conventional disease-modifying drugs, Dr. Ai Lyn Tan reported at the annual meeting of the British Society for Rheumatology.

Rituximab is licensed in the United Kingdom for the treatment of adults with rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, conventional disease-modifying anti-rheumatic drugs (DMARDs) and to one or more tumor necrosis factor (TNF) inhibitors. In the United States it is licensed for use in combination with methotrexate for management of moderately to severely active RA that has not responded to treatment with one or more anti-TNF agents.

Licensure of the TNF inhibitors posed financial strains on the U.K. health care system, and the drugs were restricted in availability in some areas. Because of this lack of availability and the fact that rituximab had been shown to be effective in RA in trials of patients who had not previously received anti-TNF therapy, this drug has been used as a first-line biologic since 2004 by Dr. Tan and her colleagues at the University of Leeds (England) and Chapel Allerton Hospital, Leeds.

A total of 39 patients who had failed at least one DMARD have received two initial infusions of rituximab 2 weeks apart. In 17 patients the doses were 1,000 mg each, and in 22 the doses were 500 mg each.

Two-thirds of the patients were women. Their median age was 58 years and median disease duration was 7 years. Thirty of the patients were rheumatoid factor (RF) positive at baseline, and 16 were also antinuclear antibody (ANA) positive.

Clinical outcome data were available for 37 patients and safety data for all 39.

Clinical assessments using the Disease Activity Score (DAS)28 and EULAR response criteria were done at 3, 6, 9, and 12 months. The EULAR response criteria use the change in DAS and the level of DAS achieved to classify patients as good, moderate, or nonresponders.

At all time points, there was a significant improvement in DAS28. EULAR good responses were seen in 40% of patients at 3 months and in 50% of patients at 12 months, while overall EULAR responses were seen in 88% and 77%, respectively, at those time points.

By 6 months ANA became negative in 40% of patients in whom it had been positive at baseline, and in 88% of RF-positive patients the antibody level had fallen. Four of the previously RF-positive patients became seronegative by 6 months, and these reductions were sustained at 12 months, Dr. Tan wrote in a poster presented at the meeting.

Slightly better responses were seen in patients who received the higher dose, with 82% in the 500-mg group and 94% of those in the 1,000-mg group achieving EULAR responses. Nonetheless, she suggested that it might be “prudent” to start on lower doses since treatment is likely to be needed long term.

Thus far 25 patients have been retreated, at a median of 13 months after the initial infusions, and 7 have received a third treatment, at a median of 11 months after the second treatment.

Two patients were switched to anti-TNF therapy following early treatment failure and a third was switched following an allergic reaction to the second infusion of rituximab, according to Dr. Tan, who declared no conflicts of interest.

One 67-year-old patient with preexisting lung disease died 3 months after treatment from presumed bilateral bronchopneumonia and possible methotrexate pneumonitis, and a second 61-year-old man died of a myocardial infarction while awaiting coronary angiography for angina pectoris. This outcome was not considered to be related to therapy.

In an interview, Dr. Tan said that her study showed that rituximab is effective as first-line therapy in patients with severe RA. “This is important because it can be used in patients in whom the TNF blockers are contraindicated,” she said.

Almost half of the patients in this study had disease features that could have caused concerns with TNF blockade, such as risks of infection and strong ANA positivity (Rheumatology 2008:47;865-7).

“I think this will be an important role for rituximab in RA,” Dr. Tan said.

LIVERPOOL, ENGLAND — Rituximab has been used successfully in a real-world setting as a first-line biologic therapy for rheumatoid arthritis that does not respond to conventional disease-modifying drugs, Dr. Ai Lyn Tan reported at the annual meeting of the British Society for Rheumatology.

Rituximab is licensed in the United Kingdom for the treatment of adults with rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, conventional disease-modifying anti-rheumatic drugs (DMARDs) and to one or more tumor necrosis factor (TNF) inhibitors. In the United States it is licensed for use in combination with methotrexate for management of moderately to severely active RA that has not responded to treatment with one or more anti-TNF agents.

Licensure of the TNF inhibitors posed financial strains on the U.K. health care system, and the drugs were restricted in availability in some areas. Because of this lack of availability and the fact that rituximab had been shown to be effective in RA in trials of patients who had not previously received anti-TNF therapy, this drug has been used as a first-line biologic since 2004 by Dr. Tan and her colleagues at the University of Leeds (England) and Chapel Allerton Hospital, Leeds.

A total of 39 patients who had failed at least one DMARD have received two initial infusions of rituximab 2 weeks apart. In 17 patients the doses were 1,000 mg each, and in 22 the doses were 500 mg each.

Two-thirds of the patients were women. Their median age was 58 years and median disease duration was 7 years. Thirty of the patients were rheumatoid factor (RF) positive at baseline, and 16 were also antinuclear antibody (ANA) positive.

Clinical outcome data were available for 37 patients and safety data for all 39.

Clinical assessments using the Disease Activity Score (DAS)28 and EULAR response criteria were done at 3, 6, 9, and 12 months. The EULAR response criteria use the change in DAS and the level of DAS achieved to classify patients as good, moderate, or nonresponders.

At all time points, there was a significant improvement in DAS28. EULAR good responses were seen in 40% of patients at 3 months and in 50% of patients at 12 months, while overall EULAR responses were seen in 88% and 77%, respectively, at those time points.

By 6 months ANA became negative in 40% of patients in whom it had been positive at baseline, and in 88% of RF-positive patients the antibody level had fallen. Four of the previously RF-positive patients became seronegative by 6 months, and these reductions were sustained at 12 months, Dr. Tan wrote in a poster presented at the meeting.

Slightly better responses were seen in patients who received the higher dose, with 82% in the 500-mg group and 94% of those in the 1,000-mg group achieving EULAR responses. Nonetheless, she suggested that it might be “prudent” to start on lower doses since treatment is likely to be needed long term.

Thus far 25 patients have been retreated, at a median of 13 months after the initial infusions, and 7 have received a third treatment, at a median of 11 months after the second treatment.

Two patients were switched to anti-TNF therapy following early treatment failure and a third was switched following an allergic reaction to the second infusion of rituximab, according to Dr. Tan, who declared no conflicts of interest.

One 67-year-old patient with preexisting lung disease died 3 months after treatment from presumed bilateral bronchopneumonia and possible methotrexate pneumonitis, and a second 61-year-old man died of a myocardial infarction while awaiting coronary angiography for angina pectoris. This outcome was not considered to be related to therapy.

In an interview, Dr. Tan said that her study showed that rituximab is effective as first-line therapy in patients with severe RA. “This is important because it can be used in patients in whom the TNF blockers are contraindicated,” she said.

Almost half of the patients in this study had disease features that could have caused concerns with TNF blockade, such as risks of infection and strong ANA positivity (Rheumatology 2008:47;865-7).

“I think this will be an important role for rituximab in RA,” Dr. Tan said.

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.

LIVERPOOL, ENGLAND — The majority of patients with ankylosing spondylitis being treated with anti-tumor necrosis factor agents in a routine care setting experienced improvements in disease activity after 6 months of treatment, according to Dr. Paul A. Lord of the University of Manchester (England).

Clinical trials have demonstrated the efficacy of these biologic drugs in ankylosing spondylitis (AS), but few data exist regarding the effectiveness in a real world setting.

Accordingly, the British Society for Rheumatology's Biologics Register began recruiting AS patients in 2002, recording baseline demographics, disease duration, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, as well as current and former drug treatments.

A total of 572 patients have been recruited, and data have now been analyzed for 261, with the primary outcome being changes in BASDAI and BASFI scores at 6 months.

The patients were predominantly young, with a median age of 43 years, and 81% were male. The median baseline BASDAI score was 7.6 and the median baseline BASFI score was 7.9. “They had severe disease,” Dr. Lord said at the annual meeting of the British Society for Rheumatology.

At 6 months, mean improvements of 3.5 and 2.7 U, respectively, were seen on BASDAI and BASFI. Additionally, 71% had improvements on BASDAI of at least 2 U, and 52% achieved a BASDAI 50 response, which represents a major clinical response, he said.

The first TNF blocker given was etanercept in 57%, infliximab in 36%, and adalimumab in 7%. Conventional disease-modifying antirheumatic drugs (DMARDs) also were being used by 54% and 55% of those on infliximab and adalimumab, respectively, compared with 37% of those on etanercept.

Lesser responses were seen in those with higher baseline BASFI scores, and women had a 1-U greater improvement on BASFI at 6 months compared with men.

Concurrent use of DMARDs was associated with improved functional status, demonstrated by a 0.8-U greater improvement on BASFI compared with those on monotherapy, but was not associated with absolute change in BASDAI.

Patients whose inflammatory markers were elevated at baseline had a 0.9-U greater response than those whose ESR and CRP level were normal at baseline, suggesting that these patients may be more responsive to anti-TNF therapy, Dr. Lord said.

Although the patients with baseline inflammatory markers had a better response to anti-TNF therapy, the benefits were not confined to this group, he noted.

Dr. Lord and his colleagues from the biologics register have reported no conflicts of interest.

LIVERPOOL, ENGLAND — The majority of patients with ankylosing spondylitis being treated with anti-tumor necrosis factor agents in a routine care setting experienced improvements in disease activity after 6 months of treatment, according to Dr. Paul A. Lord of the University of Manchester (England).

Clinical trials have demonstrated the efficacy of these biologic drugs in ankylosing spondylitis (AS), but few data exist regarding the effectiveness in a real world setting.

Accordingly, the British Society for Rheumatology's Biologics Register began recruiting AS patients in 2002, recording baseline demographics, disease duration, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, as well as current and former drug treatments.

A total of 572 patients have been recruited, and data have now been analyzed for 261, with the primary outcome being changes in BASDAI and BASFI scores at 6 months.

The patients were predominantly young, with a median age of 43 years, and 81% were male. The median baseline BASDAI score was 7.6 and the median baseline BASFI score was 7.9. “They had severe disease,” Dr. Lord said at the annual meeting of the British Society for Rheumatology.

At 6 months, mean improvements of 3.5 and 2.7 U, respectively, were seen on BASDAI and BASFI. Additionally, 71% had improvements on BASDAI of at least 2 U, and 52% achieved a BASDAI 50 response, which represents a major clinical response, he said.

The first TNF blocker given was etanercept in 57%, infliximab in 36%, and adalimumab in 7%. Conventional disease-modifying antirheumatic drugs (DMARDs) also were being used by 54% and 55% of those on infliximab and adalimumab, respectively, compared with 37% of those on etanercept.

Lesser responses were seen in those with higher baseline BASFI scores, and women had a 1-U greater improvement on BASFI at 6 months compared with men.

Concurrent use of DMARDs was associated with improved functional status, demonstrated by a 0.8-U greater improvement on BASFI compared with those on monotherapy, but was not associated with absolute change in BASDAI.

Patients whose inflammatory markers were elevated at baseline had a 0.9-U greater response than those whose ESR and CRP level were normal at baseline, suggesting that these patients may be more responsive to anti-TNF therapy, Dr. Lord said.

Although the patients with baseline inflammatory markers had a better response to anti-TNF therapy, the benefits were not confined to this group, he noted.

Dr. Lord and his colleagues from the biologics register have reported no conflicts of interest.

LIVERPOOL, ENGLAND — The majority of patients with ankylosing spondylitis being treated with anti-tumor necrosis factor agents in a routine care setting experienced improvements in disease activity after 6 months of treatment, according to Dr. Paul A. Lord of the University of Manchester (England).

Clinical trials have demonstrated the efficacy of these biologic drugs in ankylosing spondylitis (AS), but few data exist regarding the effectiveness in a real world setting.

Accordingly, the British Society for Rheumatology's Biologics Register began recruiting AS patients in 2002, recording baseline demographics, disease duration, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, as well as current and former drug treatments.

A total of 572 patients have been recruited, and data have now been analyzed for 261, with the primary outcome being changes in BASDAI and BASFI scores at 6 months.

The patients were predominantly young, with a median age of 43 years, and 81% were male. The median baseline BASDAI score was 7.6 and the median baseline BASFI score was 7.9. “They had severe disease,” Dr. Lord said at the annual meeting of the British Society for Rheumatology.

At 6 months, mean improvements of 3.5 and 2.7 U, respectively, were seen on BASDAI and BASFI. Additionally, 71% had improvements on BASDAI of at least 2 U, and 52% achieved a BASDAI 50 response, which represents a major clinical response, he said.

The first TNF blocker given was etanercept in 57%, infliximab in 36%, and adalimumab in 7%. Conventional disease-modifying antirheumatic drugs (DMARDs) also were being used by 54% and 55% of those on infliximab and adalimumab, respectively, compared with 37% of those on etanercept.

Lesser responses were seen in those with higher baseline BASFI scores, and women had a 1-U greater improvement on BASFI at 6 months compared with men.

Concurrent use of DMARDs was associated with improved functional status, demonstrated by a 0.8-U greater improvement on BASFI compared with those on monotherapy, but was not associated with absolute change in BASDAI.

Patients whose inflammatory markers were elevated at baseline had a 0.9-U greater response than those whose ESR and CRP level were normal at baseline, suggesting that these patients may be more responsive to anti-TNF therapy, Dr. Lord said.

Although the patients with baseline inflammatory markers had a better response to anti-TNF therapy, the benefits were not confined to this group, he noted.

Dr. Lord and his colleagues from the biologics register have reported no conflicts of interest.

LIVERPOOL, ENGLAND — B-cell depletion with rituximab showed benefits on magnetic resonance imaging for patients with active ankylosing spondylitis in a pilot study, but clinical effects were less pronounced, said Dr. Jonathan C. Packham of Keele (England) University.

Populations of CD20-positive B cells have been identified on histologic analysis of the spine in AS, and B-cell-producing germinal centers similar to those seen in RA have been found in the sacroiliac joints in AS, suggesting anti-CD20 treatment might have beneficial therapeutic effects. “We therefore performed a 6-month open-label study of rituximab … using MRI to evaluate its effects on spinal enthesitis,” Dr. Packham said at the annual meeting of the British Society for Rheumatology.

Rituximab was administered as two infusions of 1 g each, 2 weeks apart, in seven patients. Clinical assessments, made at four points during the study, included inflammatory markers, tender and swollen joint counts, patient global assessment, nocturnal and total back pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and AS quality of life (ASQOL).

At baseline, mean BASDAI and BASFI were 7.8 and 7.9, respectively, and all patients had C-reactive protein levels higher than 10 mg/dL. The mean number of sites of MRI-determined enthesitis/osteitis per patient fell by 49% between baseline and 6 months, from 19.4 to 9.9, which was statistically significant, Dr. Packham said. Significant improvements on MRI were seen in both lumbar spine and sacroiliac joints. The number of swollen joints fell from a mean of 3.9 to 2.6.

There was a nonsignificant trend in improvement in BASDAI and BASFI, with both indices decreased by 1.6 units over 6 months. There were no detectable changes in erythrocyte sedimentation rate, C-reactive protein, or ASQOL scores, however.

In an interview, Dr. Packham said he remains uncertain about whether these results represent a true effect of rituximab or the disease process itself settling down. “Levels of inflammation decreased by half on MRI, but this didn't appear to translate into clinical improvements. The response to rituximab does not seem to be as good as with anti-TNF agents in [AS],” he said. “But it's early days yet. Two other pilot studies are ongoing in Europe.”

Dr. Packham disclosed receiving an unrestricted educational grant from F. Hoffmann-La Roche Ltd.

LIVERPOOL, ENGLAND — B-cell depletion with rituximab showed benefits on magnetic resonance imaging for patients with active ankylosing spondylitis in a pilot study, but clinical effects were less pronounced, said Dr. Jonathan C. Packham of Keele (England) University.

Populations of CD20-positive B cells have been identified on histologic analysis of the spine in AS, and B-cell-producing germinal centers similar to those seen in RA have been found in the sacroiliac joints in AS, suggesting anti-CD20 treatment might have beneficial therapeutic effects. “We therefore performed a 6-month open-label study of rituximab … using MRI to evaluate its effects on spinal enthesitis,” Dr. Packham said at the annual meeting of the British Society for Rheumatology.

Rituximab was administered as two infusions of 1 g each, 2 weeks apart, in seven patients. Clinical assessments, made at four points during the study, included inflammatory markers, tender and swollen joint counts, patient global assessment, nocturnal and total back pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and AS quality of life (ASQOL).

At baseline, mean BASDAI and BASFI were 7.8 and 7.9, respectively, and all patients had C-reactive protein levels higher than 10 mg/dL. The mean number of sites of MRI-determined enthesitis/osteitis per patient fell by 49% between baseline and 6 months, from 19.4 to 9.9, which was statistically significant, Dr. Packham said. Significant improvements on MRI were seen in both lumbar spine and sacroiliac joints. The number of swollen joints fell from a mean of 3.9 to 2.6.

There was a nonsignificant trend in improvement in BASDAI and BASFI, with both indices decreased by 1.6 units over 6 months. There were no detectable changes in erythrocyte sedimentation rate, C-reactive protein, or ASQOL scores, however.

In an interview, Dr. Packham said he remains uncertain about whether these results represent a true effect of rituximab or the disease process itself settling down. “Levels of inflammation decreased by half on MRI, but this didn't appear to translate into clinical improvements. The response to rituximab does not seem to be as good as with anti-TNF agents in [AS],” he said. “But it's early days yet. Two other pilot studies are ongoing in Europe.”

Dr. Packham disclosed receiving an unrestricted educational grant from F. Hoffmann-La Roche Ltd.

LIVERPOOL, ENGLAND — B-cell depletion with rituximab showed benefits on magnetic resonance imaging for patients with active ankylosing spondylitis in a pilot study, but clinical effects were less pronounced, said Dr. Jonathan C. Packham of Keele (England) University.

Populations of CD20-positive B cells have been identified on histologic analysis of the spine in AS, and B-cell-producing germinal centers similar to those seen in RA have been found in the sacroiliac joints in AS, suggesting anti-CD20 treatment might have beneficial therapeutic effects. “We therefore performed a 6-month open-label study of rituximab … using MRI to evaluate its effects on spinal enthesitis,” Dr. Packham said at the annual meeting of the British Society for Rheumatology.

Rituximab was administered as two infusions of 1 g each, 2 weeks apart, in seven patients. Clinical assessments, made at four points during the study, included inflammatory markers, tender and swollen joint counts, patient global assessment, nocturnal and total back pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and AS quality of life (ASQOL).

At baseline, mean BASDAI and BASFI were 7.8 and 7.9, respectively, and all patients had C-reactive protein levels higher than 10 mg/dL. The mean number of sites of MRI-determined enthesitis/osteitis per patient fell by 49% between baseline and 6 months, from 19.4 to 9.9, which was statistically significant, Dr. Packham said. Significant improvements on MRI were seen in both lumbar spine and sacroiliac joints. The number of swollen joints fell from a mean of 3.9 to 2.6.

There was a nonsignificant trend in improvement in BASDAI and BASFI, with both indices decreased by 1.6 units over 6 months. There were no detectable changes in erythrocyte sedimentation rate, C-reactive protein, or ASQOL scores, however.

In an interview, Dr. Packham said he remains uncertain about whether these results represent a true effect of rituximab or the disease process itself settling down. “Levels of inflammation decreased by half on MRI, but this didn't appear to translate into clinical improvements. The response to rituximab does not seem to be as good as with anti-TNF agents in [AS],” he said. “But it's early days yet. Two other pilot studies are ongoing in Europe.”

Dr. Packham disclosed receiving an unrestricted educational grant from F. Hoffmann-La Roche Ltd.

LIVERPOOL, ENGLAND — Increasing experience with rituximab in patients with rheumatoid arthritis is showing that infection rates remain stable with repeat courses of treatment, Dr. Shouvik Dass has reported.

All patients who participated in the pivotal trials of rituximab in RA were entitled to enter into an open-label phase in which they can receive further courses of treatment, depending on disease activity.

As of September 2006, 1,053 RA patients had received rituximab. There are now 2,438 patient-years of exposure, with 400 patients having had three courses and 142 having had four, said Dr. Dass of the academic unit of musculoskeletal disease, University of Leeds (England).

Both adverse events and serious adverse events have decreased with each course. A total of 702 patients (67%) reported any infection; most were upper respiratory tract and urinary tract infections.

“Importantly, in the context of biologic therapy, there have been no opportunistic infections or cases of viral reactivation or tuberculosis,” Dr. Dass said at the annual meeting of the British Society for Rheumatology. Serious adverse event rates also are low and not changing through four courses, he said.

In all, 36 malignancies have been seen in 32 patients, four of which had fatal outcomes. “RA carries its own risk for malignancy, particularly lymphoproliferative disease, but there have been no lymphoproliferative malignancies and no evidence has emerged of increasing malignancies with repeated courses of treatment,” he said.

The B-cell depletion that occurs with rituximab therapy also raises concerns about the levels of immunoglobulins, secreted by plasma cells. Up to one-quarter of patients have low IgM by their fourth course of treatment. About 4%–5% have low IgG.

To determine if this decrease in immunoglobulin levels is clinically significant, infection rates were analyzed according to IgM and IgG levels. For patients with normal IgM, the serious infection rate was 4.9 per 100 patient-years, and for those with low IgM it was 6.4 per 100 patient years, a difference that was not statistically significant.

For IgG, the rate of all infections was 109 per 100 patient-years in patients with the lowest levels of IgG, and 63 per 100 patient years among those who had the highest levels, a significant difference, Dr. Dass said.

The rates of serious infections, however, were similar, with 6.8 per 100 patient-years in the lowest IgG group and 5 per 100 patient-years in the highest IgG group.

These findings are consistent with earlier data. “We need to see if there is any further association between changes in immunoglobulins and risk of infection and whether in the future that will affect our clinical practice,” he said.

Dr. Dass declared no conflicts.

LIVERPOOL, ENGLAND — Increasing experience with rituximab in patients with rheumatoid arthritis is showing that infection rates remain stable with repeat courses of treatment, Dr. Shouvik Dass has reported.

All patients who participated in the pivotal trials of rituximab in RA were entitled to enter into an open-label phase in which they can receive further courses of treatment, depending on disease activity.

As of September 2006, 1,053 RA patients had received rituximab. There are now 2,438 patient-years of exposure, with 400 patients having had three courses and 142 having had four, said Dr. Dass of the academic unit of musculoskeletal disease, University of Leeds (England).

Both adverse events and serious adverse events have decreased with each course. A total of 702 patients (67%) reported any infection; most were upper respiratory tract and urinary tract infections.

“Importantly, in the context of biologic therapy, there have been no opportunistic infections or cases of viral reactivation or tuberculosis,” Dr. Dass said at the annual meeting of the British Society for Rheumatology. Serious adverse event rates also are low and not changing through four courses, he said.

In all, 36 malignancies have been seen in 32 patients, four of which had fatal outcomes. “RA carries its own risk for malignancy, particularly lymphoproliferative disease, but there have been no lymphoproliferative malignancies and no evidence has emerged of increasing malignancies with repeated courses of treatment,” he said.

The B-cell depletion that occurs with rituximab therapy also raises concerns about the levels of immunoglobulins, secreted by plasma cells. Up to one-quarter of patients have low IgM by their fourth course of treatment. About 4%–5% have low IgG.

To determine if this decrease in immunoglobulin levels is clinically significant, infection rates were analyzed according to IgM and IgG levels. For patients with normal IgM, the serious infection rate was 4.9 per 100 patient-years, and for those with low IgM it was 6.4 per 100 patient years, a difference that was not statistically significant.

For IgG, the rate of all infections was 109 per 100 patient-years in patients with the lowest levels of IgG, and 63 per 100 patient years among those who had the highest levels, a significant difference, Dr. Dass said.

The rates of serious infections, however, were similar, with 6.8 per 100 patient-years in the lowest IgG group and 5 per 100 patient-years in the highest IgG group.

These findings are consistent with earlier data. “We need to see if there is any further association between changes in immunoglobulins and risk of infection and whether in the future that will affect our clinical practice,” he said.

Dr. Dass declared no conflicts.

LIVERPOOL, ENGLAND — Increasing experience with rituximab in patients with rheumatoid arthritis is showing that infection rates remain stable with repeat courses of treatment, Dr. Shouvik Dass has reported.

All patients who participated in the pivotal trials of rituximab in RA were entitled to enter into an open-label phase in which they can receive further courses of treatment, depending on disease activity.

As of September 2006, 1,053 RA patients had received rituximab. There are now 2,438 patient-years of exposure, with 400 patients having had three courses and 142 having had four, said Dr. Dass of the academic unit of musculoskeletal disease, University of Leeds (England).

Both adverse events and serious adverse events have decreased with each course. A total of 702 patients (67%) reported any infection; most were upper respiratory tract and urinary tract infections.

“Importantly, in the context of biologic therapy, there have been no opportunistic infections or cases of viral reactivation or tuberculosis,” Dr. Dass said at the annual meeting of the British Society for Rheumatology. Serious adverse event rates also are low and not changing through four courses, he said.

In all, 36 malignancies have been seen in 32 patients, four of which had fatal outcomes. “RA carries its own risk for malignancy, particularly lymphoproliferative disease, but there have been no lymphoproliferative malignancies and no evidence has emerged of increasing malignancies with repeated courses of treatment,” he said.

The B-cell depletion that occurs with rituximab therapy also raises concerns about the levels of immunoglobulins, secreted by plasma cells. Up to one-quarter of patients have low IgM by their fourth course of treatment. About 4%–5% have low IgG.

To determine if this decrease in immunoglobulin levels is clinically significant, infection rates were analyzed according to IgM and IgG levels. For patients with normal IgM, the serious infection rate was 4.9 per 100 patient-years, and for those with low IgM it was 6.4 per 100 patient years, a difference that was not statistically significant.

For IgG, the rate of all infections was 109 per 100 patient-years in patients with the lowest levels of IgG, and 63 per 100 patient years among those who had the highest levels, a significant difference, Dr. Dass said.

The rates of serious infections, however, were similar, with 6.8 per 100 patient-years in the lowest IgG group and 5 per 100 patient-years in the highest IgG group.

These findings are consistent with earlier data. “We need to see if there is any further association between changes in immunoglobulins and risk of infection and whether in the future that will affect our clinical practice,” he said.

Dr. Dass declared no conflicts.