Nancy Walsh

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission with conventional disease-modifying drugs than patients with a normal body mass index.

Overweight and obese patients fared better if they were treated with a regimen that also included infliximab, Dr. Marjatta Leirisalo-Repo said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with RA of less than 1 year's duration from 15 centers, and randomized them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months.

Patients' mean age was 46 years, median duration of symptoms was 4 months, mean number of swollen joints was 15, and mean number of tender joints was 20. All participants had morning stiffness lasting 45 minutes or more.

At baseline, the mean erythrocyte sedimentation rate (ESR) was 33 mm/h and the mean Health Assessment Questionnaire (HAQ) score was 1.

In all, 67% of patients were female and 68% were rheumatoid factor positive. None of the patients had previously been treated with a disease-modifying antirheumatic drug (DMARD).

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/week and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg per week and prednisone in 7.5 mg/day. Patients randomized to also receive infliximab received it in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26.

Remission was defined as early-morning stiffness lasting less than 15 minutes; no fatigue, joint pain, or swollen or tender joints; and an ESR less than 30 mm/hour.

At 6 months, 53% of patients had achieved remission, said Dr. Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki.

The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively. At 12 months, the corresponding percentages were 58% and 52%.

At 6 months, 63% of placebo patients whose body mass index (BMI) was less than 25 kg/m

“No such association was seen in the infliximab-treated patients,” Dr. Leirisalo-Repo said. Remission rates in the normal, overweight, and obese groups receiving the biologic agent at 6 months were 55%, 68%, and 46%, respectively.

At 12 months, the remission rates for normal, overweight, and obese patients in the placebo group were 58%, 35%, and 25%, whereas those in the infliximab group were 45%, 74%, and 55%.

It appears obesity is associated with a lack of response to conventional DMARDs, even when these drugs are given in combination, but infliximab was able to overcome this DMARD resistance, Dr. Leirisalo-Repo said. “Fat is proinflammatory, and obesity is characterized by systemic inflammation,” she said in a press conference.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Oy in Finland.

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission with conventional disease-modifying drugs than patients with a normal body mass index.

Overweight and obese patients fared better if they were treated with a regimen that also included infliximab, Dr. Marjatta Leirisalo-Repo said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with RA of less than 1 year's duration from 15 centers, and randomized them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months.

Patients' mean age was 46 years, median duration of symptoms was 4 months, mean number of swollen joints was 15, and mean number of tender joints was 20. All participants had morning stiffness lasting 45 minutes or more.

At baseline, the mean erythrocyte sedimentation rate (ESR) was 33 mm/h and the mean Health Assessment Questionnaire (HAQ) score was 1.

In all, 67% of patients were female and 68% were rheumatoid factor positive. None of the patients had previously been treated with a disease-modifying antirheumatic drug (DMARD).

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/week and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg per week and prednisone in 7.5 mg/day. Patients randomized to also receive infliximab received it in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26.

Remission was defined as early-morning stiffness lasting less than 15 minutes; no fatigue, joint pain, or swollen or tender joints; and an ESR less than 30 mm/hour.

At 6 months, 53% of patients had achieved remission, said Dr. Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki.

The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively. At 12 months, the corresponding percentages were 58% and 52%.

At 6 months, 63% of placebo patients whose body mass index (BMI) was less than 25 kg/m

“No such association was seen in the infliximab-treated patients,” Dr. Leirisalo-Repo said. Remission rates in the normal, overweight, and obese groups receiving the biologic agent at 6 months were 55%, 68%, and 46%, respectively.

At 12 months, the remission rates for normal, overweight, and obese patients in the placebo group were 58%, 35%, and 25%, whereas those in the infliximab group were 45%, 74%, and 55%.

It appears obesity is associated with a lack of response to conventional DMARDs, even when these drugs are given in combination, but infliximab was able to overcome this DMARD resistance, Dr. Leirisalo-Repo said. “Fat is proinflammatory, and obesity is characterized by systemic inflammation,” she said in a press conference.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Oy in Finland.

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission with conventional disease-modifying drugs than patients with a normal body mass index.

Overweight and obese patients fared better if they were treated with a regimen that also included infliximab, Dr. Marjatta Leirisalo-Repo said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with RA of less than 1 year's duration from 15 centers, and randomized them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months.

Patients' mean age was 46 years, median duration of symptoms was 4 months, mean number of swollen joints was 15, and mean number of tender joints was 20. All participants had morning stiffness lasting 45 minutes or more.

At baseline, the mean erythrocyte sedimentation rate (ESR) was 33 mm/h and the mean Health Assessment Questionnaire (HAQ) score was 1.

In all, 67% of patients were female and 68% were rheumatoid factor positive. None of the patients had previously been treated with a disease-modifying antirheumatic drug (DMARD).

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/week and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg per week and prednisone in 7.5 mg/day. Patients randomized to also receive infliximab received it in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26.

Remission was defined as early-morning stiffness lasting less than 15 minutes; no fatigue, joint pain, or swollen or tender joints; and an ESR less than 30 mm/hour.

At 6 months, 53% of patients had achieved remission, said Dr. Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki.

The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively. At 12 months, the corresponding percentages were 58% and 52%.

At 6 months, 63% of placebo patients whose body mass index (BMI) was less than 25 kg/m

“No such association was seen in the infliximab-treated patients,” Dr. Leirisalo-Repo said. Remission rates in the normal, overweight, and obese groups receiving the biologic agent at 6 months were 55%, 68%, and 46%, respectively.

At 12 months, the remission rates for normal, overweight, and obese patients in the placebo group were 58%, 35%, and 25%, whereas those in the infliximab group were 45%, 74%, and 55%.

It appears obesity is associated with a lack of response to conventional DMARDs, even when these drugs are given in combination, but infliximab was able to overcome this DMARD resistance, Dr. Leirisalo-Repo said. “Fat is proinflammatory, and obesity is characterized by systemic inflammation,” she said in a press conference.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Oy in Finland.

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).

BOSTON — Although 3 decades have passed since the introduction of a regimen combining daily oral cyclophosphamide with prednisone transformed antineutrophil cytoplasmic antibody-associated vasculitis from a uniformly fatal disease to one with an 80% survival rate, the management of relapse in this and other small-vessel vasculitides remains a vexatious challenge with no approved treatments, Dr. Carol A. Langford said at the annual meeting of the American College of Rheumatology.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and microscopic polyangiitis are by nature relapsing diseases, and currently no treatment can reliably prevent recurrence.

“Until such time as we can prevent relapse, our approach must be based first on correctly identifying relapse—which sounds straightforward but frequently is not—and then selecting the treatment option that best addresses the patient's treatment history, disease severity, and that takes into account the risks and benefits of the regimen,” said Dr. Langford of the center for vasculitis care and research, department of rheumatic and immunologic diseases, Cleveland Clinic Foundation.

Assessing relapse in these antineutrophil cytoplasmic antibody-associated vasculitides generally relies on obtaining information about disease-related inflammation from the history, physical examination, laboratory studies, and diagnostic imaging. “Unfortunately, there is no blood test that can detect a relapse, and in determining if a relapse is truly a relapse, it's important also to think about infection, medication reactions, and chronic damage,” she said. A new elevation of the erythrocyte sedimentation rate, for example, can be suggestive of relapse but is nonspecific. Remember that one of the most common causes of an elevated sedimentation rate is infection, but an elevation without infection should prompt a careful evaluation to look for sites of disease activity, she said.

Other features that could be considered indicative of relapse also might not necessarily be so. New-onset hematuria or a new pulmonary infiltrate in an immunosuppressed host could represent cyclophosphamide-induced bladder injury or methotrexate pneumonitis, she cautioned.

This evaluation should include not only sites and organ systems that have previously been affected, but also sites of new activity. Some patients predictably relapse in the same way each time, but the suggestion of disease activity in one site should alert the clinician to the possibility of new activity in another site.

“In particular, you always need to watch for emerging glomerulonephritis,” Dr. Langford said.

It's also important to differentiate new disease activity from chronic disease damage, such as changes in the orbital space, sinus mucosal thickening, and even persistent lung nodules, she said.

“Once you have gone through this careful thought process and have determined that your patient is relapsing, the question becomes what approach to use, and whether the treatment of relapse is any different from initial treatment. The answer is yes and no,” she said. Overall, the treatment options remain the same; there are no regimens used solely for initial treatment or maintenance therapy. Aside from cyclophosphamide and prednisone, the most commonly used agents today are azathioprine and methotrexate.

In a recent review of patients treated at Dr. Langford's center, 57 patients with severe disease were initially treated with cyclophosphamide, and 25 with mild to moderate disease were treated with methotrexate. Following initial improvements, all patients continued on methotrexate, with sustained remission being seen in 78%. Although 45% relapsed within 1 year and 66% relapsed within 2 years, 82% of relapsed patients went on to achieve subsequent remission with additional treatment (Medicine [Baltimore] 2007;86:269-77).

Treatment after relapse must consider drug toxicities that might have occurred with past treatment, organ damage, and any new medical conditions. Other considerations include whether the dosages of medications and duration of therapy have been adequate in the past, whether the method and timing of administration have been optimal, and if the patient has been compliant.

A patient who has been doing well for several years on methotrexate and has a mild relapse does not necessarily need to receive the very effective—but very toxic—cyclophosphamide.

“I would look for ways to optimize the methotrexate, keeping in mind that, whenever possible, cyclophosphamide should be reserved for instances when its lifesaving capacity may be needed,” said Dr. Langford.

The site and severity of relapse also are important. “We rarely would consider cyclophosphamide for isolated sinonasal relapse,” Dr. Langford said.

An additional difficult question relates to the optimal duration of maintenance therapy to prevent future relapses, and “the answer unfortunately is, we don't know,” she said. Some patients are able to stop treatment and remain in remission, but studies have shown that relapse rates are higher when patients are no longer on treatment. If a patient has done well for a minimum of 2 years, consideration can be given to tapering treatment depending on risks and benefits, but this must be done on an individual basis. “However, if someone has a residual creatinine of 4 mg/dL and is fighting for every last glomerulus, I would be reluctant to stop their maintenance therapy if toxicity is not an issue,” Dr. Langford said.

Finally, new agents are becoming available, but for patients who are able to tolerate the standard treatments, unproven therapies should not be used except in the context of clinical trials. ANCA-associated vasculitis and microscopic polyangiitis are potentially life-threatening diseases. “If the agent is not effective, the disease could worsen or unexpected toxicities could be seen,” Dr. Langford said.

For example, in a trial that evaluated adding etanercept or placebo to standard therapy with cyclophosphamide or methotrexate, there were no differences between the groups in the rates of sustained remission or severe adverse events, but six patients in the etanercept group developed solid tumors, compared with no patients in the placebo group (N. Engl. J. Med. 2005;352:351-61).

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.

BOSTON — Treatment options for children with juvenile idiopathic arthritis might soon expand, with safety and efficacy now having been demonstrated for two additional biologic agents—even in patients who have failed to respond to methotrexate or another biologic, Dr. Daniel J. Lovell reported at the annual meeting of the American College of Rheumatology.

The sole biologic approved for use in juvenile idiopathic arthritis (JIA) is the tumor necrosis factor (TNF) blocker etanercept, but not all patients respond to this drug. Randomized studies now have shown benefits for the T-cell costimulation modulator abatacept and for another anti-TNF agent, adalimumab.

Both of these drugs have been studied and used extensively in adults with rheumatoid arthritis, with approval for use in JIA pending from the Food and Drug Administration, Dr. Lovell said.

The phase III abatacept study included 190 patients who had previously failed other therapies, including methotrexate, etanercept, and anakinra.

“This was the first study in which we enrolled kids who had already received a biologic. They had exhausted our current therapies but still had active disease,” said Dr. Lovell, who is associate director, division of rheumatology, Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

All patients initially received the drug as intravenous infusions of 10 mg/kg on days 1 and 15, and every 28 days thereafter in an open-label fashion for 4 months. They also were permitted (though not required) to receive methotrexate in doses of 10–30 mg/m

By the end of the open-label phase, the overall ACR pediatric 30 response rate was 65%, while the response rate among those who had previously failed on a biologic agent was 40%.

“Clearly this was a treatment that can work when other drugs have failed,” Dr. Lovell said.

A total of 123 patients who achieved an ACR pediatric 30 response during the open-label phase were then invited to enter the double-blind portion of the trial; 122 did so.

In this phase of the study, patients were randomized to continue on the active drug or placebo for up to 6 months or until their JIA flared.

As in other blinded trials for JIA, as soon as patients flared they were placed back on the active drug, Dr. Lovell said.

JIA flared in 53% of patients in the placebo group and 20% of those in the active treatment group.

During the open-label phase of the study, six patients reported serious adverse events, three relating to the underlying disease. During the double-blind phase, no serious adverse events were reported in the abatacept group, and three were seen in the placebo group. Overall, the most common adverse events were influenza, bacteriuria, nasopharyngitis, upper respiratory tract infection, and pyrexia. The safety was similar to that seen with other biologics, he said.

The adalimumab study was a phase III double-blind trial that included 171 patients ranging in age from 4 to 17 years.

“A unique aspect of this trial was that we enrolled patients who were already on methotrexate as well as patients who were earlier in the course of disease and had not yet received methotrexate. This was the first study in which a biologic agent was introduced independent of, or prior to, methotrexate,” Dr. Lovell said.

This was done at the request of the Food and Drug Administration, and the results showed efficacy in both combination and methotrexate-naive groups, he said.

As in the abatacept trial, patients first entered an open-label phase during which they received 24 mg/m

At week 16, 84% of patients had achieved an ACR pediatric 30 response, 77% achieved an ACR pediatric 50 response, 58% achieved an ACR pediatric 70 response, and 27% achieved an ACR pediatric 90 response.

Those who achieved at least an ACR pediatric 30 response were then randomized to continue adalimumab or placebo for 32 weeks or until disease flared. At week 48, ACR pediatric 30, 50, and 70 responses were achieved by 60%, 59%, and 56% of patients in the adalimumab group, respectively, compared with 35%, 35%, and 28% of patients in the placebo group.

The ACR pediatric responses represent a comprehensive picture of disease activity and impact, Dr. Lovell said in a press conference at the meeting.

For an ACR pediatric 30 response, a 30% improvement must be seen in three of six core disease parameters such as physician and parent global assessment and number of joints with active arthritis, and there can be a worsening of no more than 30% in one component.

“This system was developed back when we were just using methotrexate, when we found that if patients demonstrated a 30% response and remained at that level, their outcome was dramatically improved, compared with children who didn't reach that level of response. “It represented a clinically important difference, and it was what we could achieve most of the time with methotrexate,” Dr. Lovell said.

But when etanercept was first evaluated in JIA, the bar was raised dramatically, with 80% of patients achieving an ACR pediatric 30 response.

“Now we're talking about ACR 70s and 90s, and in the adalimumab study we even had 30% reaching ACR 100,” he said.

“With an ACR 70 response, patients report that the disease impacts their life only intermittently, maybe a few days each month, and with an ACR 90 the disease is almost nonexistent—they can do everything kids want to do.

“I don't know what an ACR 100 feels like to patients—it's so new I've never asked anyone to describe it,” he said.

Decisions on approval for the two drugs are expected in the first quarter of 2008, he said.

Dr. Lovell disclosed that he has received consulting fees from Bristol-Myers Squibb Co. and Abbott Laboratories.

BOSTON — Treatment options for children with juvenile idiopathic arthritis might soon expand, with safety and efficacy now having been demonstrated for two additional biologic agents—even in patients who have failed to respond to methotrexate or another biologic, Dr. Daniel J. Lovell reported at the annual meeting of the American College of Rheumatology.

The sole biologic approved for use in juvenile idiopathic arthritis (JIA) is the tumor necrosis factor (TNF) blocker etanercept, but not all patients respond to this drug. Randomized studies now have shown benefits for the T-cell costimulation modulator abatacept and for another anti-TNF agent, adalimumab.

Both of these drugs have been studied and used extensively in adults with rheumatoid arthritis, with approval for use in JIA pending from the Food and Drug Administration, Dr. Lovell said.

The phase III abatacept study included 190 patients who had previously failed other therapies, including methotrexate, etanercept, and anakinra.

“This was the first study in which we enrolled kids who had already received a biologic. They had exhausted our current therapies but still had active disease,” said Dr. Lovell, who is associate director, division of rheumatology, Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

All patients initially received the drug as intravenous infusions of 10 mg/kg on days 1 and 15, and every 28 days thereafter in an open-label fashion for 4 months. They also were permitted (though not required) to receive methotrexate in doses of 10–30 mg/m

By the end of the open-label phase, the overall ACR pediatric 30 response rate was 65%, while the response rate among those who had previously failed on a biologic agent was 40%.

“Clearly this was a treatment that can work when other drugs have failed,” Dr. Lovell said.

A total of 123 patients who achieved an ACR pediatric 30 response during the open-label phase were then invited to enter the double-blind portion of the trial; 122 did so.

In this phase of the study, patients were randomized to continue on the active drug or placebo for up to 6 months or until their JIA flared.

As in other blinded trials for JIA, as soon as patients flared they were placed back on the active drug, Dr. Lovell said.

JIA flared in 53% of patients in the placebo group and 20% of those in the active treatment group.

During the open-label phase of the study, six patients reported serious adverse events, three relating to the underlying disease. During the double-blind phase, no serious adverse events were reported in the abatacept group, and three were seen in the placebo group. Overall, the most common adverse events were influenza, bacteriuria, nasopharyngitis, upper respiratory tract infection, and pyrexia. The safety was similar to that seen with other biologics, he said.

The adalimumab study was a phase III double-blind trial that included 171 patients ranging in age from 4 to 17 years.

“A unique aspect of this trial was that we enrolled patients who were already on methotrexate as well as patients who were earlier in the course of disease and had not yet received methotrexate. This was the first study in which a biologic agent was introduced independent of, or prior to, methotrexate,” Dr. Lovell said.

This was done at the request of the Food and Drug Administration, and the results showed efficacy in both combination and methotrexate-naive groups, he said.

As in the abatacept trial, patients first entered an open-label phase during which they received 24 mg/m

At week 16, 84% of patients had achieved an ACR pediatric 30 response, 77% achieved an ACR pediatric 50 response, 58% achieved an ACR pediatric 70 response, and 27% achieved an ACR pediatric 90 response.

Those who achieved at least an ACR pediatric 30 response were then randomized to continue adalimumab or placebo for 32 weeks or until disease flared. At week 48, ACR pediatric 30, 50, and 70 responses were achieved by 60%, 59%, and 56% of patients in the adalimumab group, respectively, compared with 35%, 35%, and 28% of patients in the placebo group.

The ACR pediatric responses represent a comprehensive picture of disease activity and impact, Dr. Lovell said in a press conference at the meeting.

For an ACR pediatric 30 response, a 30% improvement must be seen in three of six core disease parameters such as physician and parent global assessment and number of joints with active arthritis, and there can be a worsening of no more than 30% in one component.

“This system was developed back when we were just using methotrexate, when we found that if patients demonstrated a 30% response and remained at that level, their outcome was dramatically improved, compared with children who didn't reach that level of response. “It represented a clinically important difference, and it was what we could achieve most of the time with methotrexate,” Dr. Lovell said.

But when etanercept was first evaluated in JIA, the bar was raised dramatically, with 80% of patients achieving an ACR pediatric 30 response.

“Now we're talking about ACR 70s and 90s, and in the adalimumab study we even had 30% reaching ACR 100,” he said.

“With an ACR 70 response, patients report that the disease impacts their life only intermittently, maybe a few days each month, and with an ACR 90 the disease is almost nonexistent—they can do everything kids want to do.

“I don't know what an ACR 100 feels like to patients—it's so new I've never asked anyone to describe it,” he said.

Decisions on approval for the two drugs are expected in the first quarter of 2008, he said.

Dr. Lovell disclosed that he has received consulting fees from Bristol-Myers Squibb Co. and Abbott Laboratories.

BOSTON — Treatment options for children with juvenile idiopathic arthritis might soon expand, with safety and efficacy now having been demonstrated for two additional biologic agents—even in patients who have failed to respond to methotrexate or another biologic, Dr. Daniel J. Lovell reported at the annual meeting of the American College of Rheumatology.

The sole biologic approved for use in juvenile idiopathic arthritis (JIA) is the tumor necrosis factor (TNF) blocker etanercept, but not all patients respond to this drug. Randomized studies now have shown benefits for the T-cell costimulation modulator abatacept and for another anti-TNF agent, adalimumab.

Both of these drugs have been studied and used extensively in adults with rheumatoid arthritis, with approval for use in JIA pending from the Food and Drug Administration, Dr. Lovell said.

The phase III abatacept study included 190 patients who had previously failed other therapies, including methotrexate, etanercept, and anakinra.

“This was the first study in which we enrolled kids who had already received a biologic. They had exhausted our current therapies but still had active disease,” said Dr. Lovell, who is associate director, division of rheumatology, Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

All patients initially received the drug as intravenous infusions of 10 mg/kg on days 1 and 15, and every 28 days thereafter in an open-label fashion for 4 months. They also were permitted (though not required) to receive methotrexate in doses of 10–30 mg/m

By the end of the open-label phase, the overall ACR pediatric 30 response rate was 65%, while the response rate among those who had previously failed on a biologic agent was 40%.

“Clearly this was a treatment that can work when other drugs have failed,” Dr. Lovell said.

A total of 123 patients who achieved an ACR pediatric 30 response during the open-label phase were then invited to enter the double-blind portion of the trial; 122 did so.

In this phase of the study, patients were randomized to continue on the active drug or placebo for up to 6 months or until their JIA flared.

As in other blinded trials for JIA, as soon as patients flared they were placed back on the active drug, Dr. Lovell said.

JIA flared in 53% of patients in the placebo group and 20% of those in the active treatment group.

During the open-label phase of the study, six patients reported serious adverse events, three relating to the underlying disease. During the double-blind phase, no serious adverse events were reported in the abatacept group, and three were seen in the placebo group. Overall, the most common adverse events were influenza, bacteriuria, nasopharyngitis, upper respiratory tract infection, and pyrexia. The safety was similar to that seen with other biologics, he said.

The adalimumab study was a phase III double-blind trial that included 171 patients ranging in age from 4 to 17 years.

“A unique aspect of this trial was that we enrolled patients who were already on methotrexate as well as patients who were earlier in the course of disease and had not yet received methotrexate. This was the first study in which a biologic agent was introduced independent of, or prior to, methotrexate,” Dr. Lovell said.

This was done at the request of the Food and Drug Administration, and the results showed efficacy in both combination and methotrexate-naive groups, he said.

As in the abatacept trial, patients first entered an open-label phase during which they received 24 mg/m

At week 16, 84% of patients had achieved an ACR pediatric 30 response, 77% achieved an ACR pediatric 50 response, 58% achieved an ACR pediatric 70 response, and 27% achieved an ACR pediatric 90 response.

Those who achieved at least an ACR pediatric 30 response were then randomized to continue adalimumab or placebo for 32 weeks or until disease flared. At week 48, ACR pediatric 30, 50, and 70 responses were achieved by 60%, 59%, and 56% of patients in the adalimumab group, respectively, compared with 35%, 35%, and 28% of patients in the placebo group.

The ACR pediatric responses represent a comprehensive picture of disease activity and impact, Dr. Lovell said in a press conference at the meeting.

For an ACR pediatric 30 response, a 30% improvement must be seen in three of six core disease parameters such as physician and parent global assessment and number of joints with active arthritis, and there can be a worsening of no more than 30% in one component.

“This system was developed back when we were just using methotrexate, when we found that if patients demonstrated a 30% response and remained at that level, their outcome was dramatically improved, compared with children who didn't reach that level of response. “It represented a clinically important difference, and it was what we could achieve most of the time with methotrexate,” Dr. Lovell said.

But when etanercept was first evaluated in JIA, the bar was raised dramatically, with 80% of patients achieving an ACR pediatric 30 response.

“Now we're talking about ACR 70s and 90s, and in the adalimumab study we even had 30% reaching ACR 100,” he said.

“With an ACR 70 response, patients report that the disease impacts their life only intermittently, maybe a few days each month, and with an ACR 90 the disease is almost nonexistent—they can do everything kids want to do.

“I don't know what an ACR 100 feels like to patients—it's so new I've never asked anyone to describe it,” he said.

Decisions on approval for the two drugs are expected in the first quarter of 2008, he said.

Dr. Lovell disclosed that he has received consulting fees from Bristol-Myers Squibb Co. and Abbott Laboratories.

BOSTON — Inhibition of two key immunoregulatory cytokines known to be involved in the pathogenesis of psoriasis and other autoimmune diseases led to significant improvements in psoriatic arthritis, judging from data from a new study, Dr. Alice B. Gottlieb reported at the annual meeting of the American College of Rheumatology.

Interleukin (IL)-12 and IL-23 play important roles in coordinating innate and adaptive immune responses, binding via the p40 subunit to the IL-12 receptor β1 on the surface of T cells and natural killer cells. Among the functions of IL-12 in psoriasis are T-cell differentiation and the facilitation of T-cell homing to the skin (Cell Immunol. 2007;247:1-11).

The drug ustekinumab now has also been evaluated in active psoriatic arthritis (PsA) in a multicenter, double-blind study that included 146 patients randomized to receive the active treatment at weeks 0, 1, 2, and 3, followed by placebo at weeks 12 and 16, or placebo at weeks 0, 1, 2, and 3 followed by the active treatment at weeks 12 and 16. They were then followed through week 36.

The primary end point was the percentage of patients achieving a response on the American College of Rheumatology (ACR) 20 scale at week 12. Patients in the active treatment group received four subcutaneous doses of either 63 mg (n = 59) or 90 mg (n = 17) of ustekinumab. This inconsistency in dose resulted from a change in preparation of the drug during the study, said Dr. Gottlieb, of the Tufts-New England Medical Center, Boston.

At baseline, the swollen joint count was 12, and the tender joint count was 22. Approximately 20% of patients were on concurrent methotrexate, and half were on concurrent NSAIDs, but none was taking oral corticosteroids. At week 12, 42% of patients in the ustekinumab group had achieved the primary end point, compared with 14% of patients in the placebo group.

By week 36, patients initially randomized to ustekinumab had not received any active treatment for 32 week—yet three-quarters maintained an ACR 20 response. “You do not see this with any of the anti-[tumor necrosis factor] agents,” Dr. Gottlieb said.

Moreover, patients who initially received placebo but then were crossed over to the active treatment group at week 12 also went on to have rapid and sustained responses, she said.

A higher proportion of patients in the active treatment group also reached ACR 50 and ACR 70 responses. A total of 25% and 11% of patients in the ustekinumab achieved these levels of response, compared with 7% and 0% of those in the placebo group.

The decrease from baseline on the Health Assessment Questionnaire disability index at week 12 was greater in the ustekinumab group (mean change −0.31), compared with the placebo group (−0.04).

A total of 52% of patients receiving the active treatment achieved a PASI 75 result at week 12, as did 6% of those receiving placebo. The 85% of patients with at least 3% body surface area psoriasis involvement who received ustekinumab had a greater decrease in the Dermatology Life Quality Index (mean change −8.6), compared with those who received placebo (−0.8). All of these differences were statistically significant.

There were no serious adverse events through week 12 in the active treatment group, whereas in the placebo group there was one report of myocardial infarction, one of gastric ulcer hemorrhage, and one of chest pain. There were no problems with abnormal laboratory values through week 12, nor were there any cases of tuberculosis or serious opportunistic infections, she said.

Dr. Gottlieb disclosed that she has received research grants and consulting fees from Centocor Research and Development Inc., which funded the trial and makes ustekinumab.

BOSTON — Inhibition of two key immunoregulatory cytokines known to be involved in the pathogenesis of psoriasis and other autoimmune diseases led to significant improvements in psoriatic arthritis, judging from data from a new study, Dr. Alice B. Gottlieb reported at the annual meeting of the American College of Rheumatology.

Interleukin (IL)-12 and IL-23 play important roles in coordinating innate and adaptive immune responses, binding via the p40 subunit to the IL-12 receptor β1 on the surface of T cells and natural killer cells. Among the functions of IL-12 in psoriasis are T-cell differentiation and the facilitation of T-cell homing to the skin (Cell Immunol. 2007;247:1-11).

The drug ustekinumab now has also been evaluated in active psoriatic arthritis (PsA) in a multicenter, double-blind study that included 146 patients randomized to receive the active treatment at weeks 0, 1, 2, and 3, followed by placebo at weeks 12 and 16, or placebo at weeks 0, 1, 2, and 3 followed by the active treatment at weeks 12 and 16. They were then followed through week 36.

The primary end point was the percentage of patients achieving a response on the American College of Rheumatology (ACR) 20 scale at week 12. Patients in the active treatment group received four subcutaneous doses of either 63 mg (n = 59) or 90 mg (n = 17) of ustekinumab. This inconsistency in dose resulted from a change in preparation of the drug during the study, said Dr. Gottlieb, of the Tufts-New England Medical Center, Boston.

At baseline, the swollen joint count was 12, and the tender joint count was 22. Approximately 20% of patients were on concurrent methotrexate, and half were on concurrent NSAIDs, but none was taking oral corticosteroids. At week 12, 42% of patients in the ustekinumab group had achieved the primary end point, compared with 14% of patients in the placebo group.

By week 36, patients initially randomized to ustekinumab had not received any active treatment for 32 week—yet three-quarters maintained an ACR 20 response. “You do not see this with any of the anti-[tumor necrosis factor] agents,” Dr. Gottlieb said.

Moreover, patients who initially received placebo but then were crossed over to the active treatment group at week 12 also went on to have rapid and sustained responses, she said.

A higher proportion of patients in the active treatment group also reached ACR 50 and ACR 70 responses. A total of 25% and 11% of patients in the ustekinumab achieved these levels of response, compared with 7% and 0% of those in the placebo group.

The decrease from baseline on the Health Assessment Questionnaire disability index at week 12 was greater in the ustekinumab group (mean change −0.31), compared with the placebo group (−0.04).

A total of 52% of patients receiving the active treatment achieved a PASI 75 result at week 12, as did 6% of those receiving placebo. The 85% of patients with at least 3% body surface area psoriasis involvement who received ustekinumab had a greater decrease in the Dermatology Life Quality Index (mean change −8.6), compared with those who received placebo (−0.8). All of these differences were statistically significant.

There were no serious adverse events through week 12 in the active treatment group, whereas in the placebo group there was one report of myocardial infarction, one of gastric ulcer hemorrhage, and one of chest pain. There were no problems with abnormal laboratory values through week 12, nor were there any cases of tuberculosis or serious opportunistic infections, she said.

Dr. Gottlieb disclosed that she has received research grants and consulting fees from Centocor Research and Development Inc., which funded the trial and makes ustekinumab.

BOSTON — Inhibition of two key immunoregulatory cytokines known to be involved in the pathogenesis of psoriasis and other autoimmune diseases led to significant improvements in psoriatic arthritis, judging from data from a new study, Dr. Alice B. Gottlieb reported at the annual meeting of the American College of Rheumatology.

Interleukin (IL)-12 and IL-23 play important roles in coordinating innate and adaptive immune responses, binding via the p40 subunit to the IL-12 receptor β1 on the surface of T cells and natural killer cells. Among the functions of IL-12 in psoriasis are T-cell differentiation and the facilitation of T-cell homing to the skin (Cell Immunol. 2007;247:1-11).

The drug ustekinumab now has also been evaluated in active psoriatic arthritis (PsA) in a multicenter, double-blind study that included 146 patients randomized to receive the active treatment at weeks 0, 1, 2, and 3, followed by placebo at weeks 12 and 16, or placebo at weeks 0, 1, 2, and 3 followed by the active treatment at weeks 12 and 16. They were then followed through week 36.

The primary end point was the percentage of patients achieving a response on the American College of Rheumatology (ACR) 20 scale at week 12. Patients in the active treatment group received four subcutaneous doses of either 63 mg (n = 59) or 90 mg (n = 17) of ustekinumab. This inconsistency in dose resulted from a change in preparation of the drug during the study, said Dr. Gottlieb, of the Tufts-New England Medical Center, Boston.

At baseline, the swollen joint count was 12, and the tender joint count was 22. Approximately 20% of patients were on concurrent methotrexate, and half were on concurrent NSAIDs, but none was taking oral corticosteroids. At week 12, 42% of patients in the ustekinumab group had achieved the primary end point, compared with 14% of patients in the placebo group.

By week 36, patients initially randomized to ustekinumab had not received any active treatment for 32 week—yet three-quarters maintained an ACR 20 response. “You do not see this with any of the anti-[tumor necrosis factor] agents,” Dr. Gottlieb said.

Moreover, patients who initially received placebo but then were crossed over to the active treatment group at week 12 also went on to have rapid and sustained responses, she said.

A higher proportion of patients in the active treatment group also reached ACR 50 and ACR 70 responses. A total of 25% and 11% of patients in the ustekinumab achieved these levels of response, compared with 7% and 0% of those in the placebo group.

The decrease from baseline on the Health Assessment Questionnaire disability index at week 12 was greater in the ustekinumab group (mean change −0.31), compared with the placebo group (−0.04).

A total of 52% of patients receiving the active treatment achieved a PASI 75 result at week 12, as did 6% of those receiving placebo. The 85% of patients with at least 3% body surface area psoriasis involvement who received ustekinumab had a greater decrease in the Dermatology Life Quality Index (mean change −8.6), compared with those who received placebo (−0.8). All of these differences were statistically significant.

There were no serious adverse events through week 12 in the active treatment group, whereas in the placebo group there was one report of myocardial infarction, one of gastric ulcer hemorrhage, and one of chest pain. There were no problems with abnormal laboratory values through week 12, nor were there any cases of tuberculosis or serious opportunistic infections, she said.

Dr. Gottlieb disclosed that she has received research grants and consulting fees from Centocor Research and Development Inc., which funded the trial and makes ustekinumab.

MINNEAPOLIS — Early recognition of interstitial cystitis/painful bladder syndrome by the primary care physician can prevent this common and debilitating condition from becoming refractory, Dr. Robert Moldwin said at the annual meeting of the Association of Reproductive Health Professionals.

This is an invisible condition, and there often is a lag time of 5–7 years between symptom onset and diagnosis, with patients being given multiple diagnoses, improper treatments such as antibiotics, and referrals to psychiatrists, he said.

The hallmarks of interstitial cystitis/painful bladder syndrome (IC/PBS) are pelvic pain, pressure, or discomfort, typically associated with a persistent urge to void or urinary frequency. Frequent nocturnal voiding is typical, and symptoms do not relate to infection or other pathology.

Although the precise etiology of IC/PBS remains unknown, it is now considered to be a hypersensitivity condition of the bladder wall, and increased understanding of the changes seen in the bladder urothelium are beginning to permit targeted therapies, explained Dr. Moldwin of the urology department at Albert Einstein College of Medicine, New York, and director of the Pelvic Pain Center at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The normal bladder surface is coated with impermeable mucin; in patients with IC/PBS this layer is disrupted, permitting noxious substances such as potassium in urine access to nerves and muscles in the bladder. This sets off an inflammatory response with mast cell activation and the release of histamine, substance P, and other mediators, which results in neurogenic upregulation and a pain response.

In early stages of IC/PBS the symptoms tend to be intermittent, but with increasing duration the pain can become centralized and once that happens, even if the bladder is removed, the pain may remain. This is similar to phantom limb pain, Dr. Moldwin said. “The key is identifying these patients when they still have intermittent symptoms.”

The differential diagnosis includes overactive bladder, endometriosis, and bladder cancer. IC/PBS can be differentiated from overactive bladder by the pattern of urinary urge, with overactive bladder characterized by sudden sporadic urges, whereas IC/PBS is characterized by a steadily and sometimes exponentially increasing sense of discomfort that eases with voiding, he said.

“Of course you don't want to miss bladder cancer, but a 30-year-old nonsmoker is unlikely to have bladder cancer. If there's any hematuria or you are especially concerned you can send off a urine specimen for cytology,” he said.

Otherwise, the diagnosis is empiric, and diagnostic tests such as hydrodistention under anesthesia are not routinely done. In a patient for whom infection has been ruled out, and particularly with pronounced nocturia, it's reasonable to begin empiric therapy, Dr. Moldwin said.

Management encompasses both nonpharmacologic and pharmacologic strategies. Dietary changes often help, and many patients benefit from avoidance of carbonated and caffeinated beverages, alcohol, and citrus fruits. Behavior modification, with gentle exercise, stress reduction, and muscle relaxation, also can help, he added. “I'm a big believer in having patients become empowered, taking control of their own care.”

Oral medications used for IC/PBS include pentosan polysulfate sodium, amitriptyline, and hydroxyzine. Pentosan polysulfate, the only Food and Drug Administration-approved oral medication for this condition in doses of 100 mg three times per day, coats the bladder wall and decreases sensitivity. The drug can take several months to work, and is effective in up to 60% of patients.

The tricyclic antidepressant amitriptyline is useful in helping patients troubled with nocturia sleep at night, and it also has pain reduction properties, probably through inhibition of norepinephrine reuptake in the central and peripheral nervous systems, he said. Amitriptyline can be given in low doses of 10–50 mg per day, preferably at 7 p.m. to avoid a morning hangover effect, he said.

The H₁ histamine antagonist hydroxyzine inhibits the mast cell degranulation and histamine release characteristic of the hypersensitive inflammatory response in the bladder wall. The drug is usually given at night, beginning in doses of 25 mg, but response can take a couple of months.

Intravesical agents that are used include dimethylsulfoxide, which is FDA-approved, and unapproved agents such as lidocaine and heparin.

Increased recognition of the importance of IC/PBS, which afflicts 1.2 million women and 82,000 men in the United States, along with an improved understanding of the associated pathologic events, is allowing the development of many new treatments, including antiproliferative factor, liposomes, and intravesical botulinum toxin type A.

Patients often experience comorbid conditions such as allergies, sensitive skin, irritable bowel syndrome, fibromyalgia, and pelvic floor dysfunction. “There are a lot of comorbidities with IC/PBS, but there probably is a common thread running through these patients. When we find that, we should have some better therapies,” he said.

MINNEAPOLIS — Early recognition of interstitial cystitis/painful bladder syndrome by the primary care physician can prevent this common and debilitating condition from becoming refractory, Dr. Robert Moldwin said at the annual meeting of the Association of Reproductive Health Professionals.

This is an invisible condition, and there often is a lag time of 5–7 years between symptom onset and diagnosis, with patients being given multiple diagnoses, improper treatments such as antibiotics, and referrals to psychiatrists, he said.

The hallmarks of interstitial cystitis/painful bladder syndrome (IC/PBS) are pelvic pain, pressure, or discomfort, typically associated with a persistent urge to void or urinary frequency. Frequent nocturnal voiding is typical, and symptoms do not relate to infection or other pathology.

Although the precise etiology of IC/PBS remains unknown, it is now considered to be a hypersensitivity condition of the bladder wall, and increased understanding of the changes seen in the bladder urothelium are beginning to permit targeted therapies, explained Dr. Moldwin of the urology department at Albert Einstein College of Medicine, New York, and director of the Pelvic Pain Center at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The normal bladder surface is coated with impermeable mucin; in patients with IC/PBS this layer is disrupted, permitting noxious substances such as potassium in urine access to nerves and muscles in the bladder. This sets off an inflammatory response with mast cell activation and the release of histamine, substance P, and other mediators, which results in neurogenic upregulation and a pain response.

In early stages of IC/PBS the symptoms tend to be intermittent, but with increasing duration the pain can become centralized and once that happens, even if the bladder is removed, the pain may remain. This is similar to phantom limb pain, Dr. Moldwin said. “The key is identifying these patients when they still have intermittent symptoms.”

The differential diagnosis includes overactive bladder, endometriosis, and bladder cancer. IC/PBS can be differentiated from overactive bladder by the pattern of urinary urge, with overactive bladder characterized by sudden sporadic urges, whereas IC/PBS is characterized by a steadily and sometimes exponentially increasing sense of discomfort that eases with voiding, he said.

“Of course you don't want to miss bladder cancer, but a 30-year-old nonsmoker is unlikely to have bladder cancer. If there's any hematuria or you are especially concerned you can send off a urine specimen for cytology,” he said.

Otherwise, the diagnosis is empiric, and diagnostic tests such as hydrodistention under anesthesia are not routinely done. In a patient for whom infection has been ruled out, and particularly with pronounced nocturia, it's reasonable to begin empiric therapy, Dr. Moldwin said.

Management encompasses both nonpharmacologic and pharmacologic strategies. Dietary changes often help, and many patients benefit from avoidance of carbonated and caffeinated beverages, alcohol, and citrus fruits. Behavior modification, with gentle exercise, stress reduction, and muscle relaxation, also can help, he added. “I'm a big believer in having patients become empowered, taking control of their own care.”

Oral medications used for IC/PBS include pentosan polysulfate sodium, amitriptyline, and hydroxyzine. Pentosan polysulfate, the only Food and Drug Administration-approved oral medication for this condition in doses of 100 mg three times per day, coats the bladder wall and decreases sensitivity. The drug can take several months to work, and is effective in up to 60% of patients.

The tricyclic antidepressant amitriptyline is useful in helping patients troubled with nocturia sleep at night, and it also has pain reduction properties, probably through inhibition of norepinephrine reuptake in the central and peripheral nervous systems, he said. Amitriptyline can be given in low doses of 10–50 mg per day, preferably at 7 p.m. to avoid a morning hangover effect, he said.

The H₁ histamine antagonist hydroxyzine inhibits the mast cell degranulation and histamine release characteristic of the hypersensitive inflammatory response in the bladder wall. The drug is usually given at night, beginning in doses of 25 mg, but response can take a couple of months.

Intravesical agents that are used include dimethylsulfoxide, which is FDA-approved, and unapproved agents such as lidocaine and heparin.

Increased recognition of the importance of IC/PBS, which afflicts 1.2 million women and 82,000 men in the United States, along with an improved understanding of the associated pathologic events, is allowing the development of many new treatments, including antiproliferative factor, liposomes, and intravesical botulinum toxin type A.

Patients often experience comorbid conditions such as allergies, sensitive skin, irritable bowel syndrome, fibromyalgia, and pelvic floor dysfunction. “There are a lot of comorbidities with IC/PBS, but there probably is a common thread running through these patients. When we find that, we should have some better therapies,” he said.

MINNEAPOLIS — Early recognition of interstitial cystitis/painful bladder syndrome by the primary care physician can prevent this common and debilitating condition from becoming refractory, Dr. Robert Moldwin said at the annual meeting of the Association of Reproductive Health Professionals.

This is an invisible condition, and there often is a lag time of 5–7 years between symptom onset and diagnosis, with patients being given multiple diagnoses, improper treatments such as antibiotics, and referrals to psychiatrists, he said.

The hallmarks of interstitial cystitis/painful bladder syndrome (IC/PBS) are pelvic pain, pressure, or discomfort, typically associated with a persistent urge to void or urinary frequency. Frequent nocturnal voiding is typical, and symptoms do not relate to infection or other pathology.

Although the precise etiology of IC/PBS remains unknown, it is now considered to be a hypersensitivity condition of the bladder wall, and increased understanding of the changes seen in the bladder urothelium are beginning to permit targeted therapies, explained Dr. Moldwin of the urology department at Albert Einstein College of Medicine, New York, and director of the Pelvic Pain Center at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The normal bladder surface is coated with impermeable mucin; in patients with IC/PBS this layer is disrupted, permitting noxious substances such as potassium in urine access to nerves and muscles in the bladder. This sets off an inflammatory response with mast cell activation and the release of histamine, substance P, and other mediators, which results in neurogenic upregulation and a pain response.

In early stages of IC/PBS the symptoms tend to be intermittent, but with increasing duration the pain can become centralized and once that happens, even if the bladder is removed, the pain may remain. This is similar to phantom limb pain, Dr. Moldwin said. “The key is identifying these patients when they still have intermittent symptoms.”

The differential diagnosis includes overactive bladder, endometriosis, and bladder cancer. IC/PBS can be differentiated from overactive bladder by the pattern of urinary urge, with overactive bladder characterized by sudden sporadic urges, whereas IC/PBS is characterized by a steadily and sometimes exponentially increasing sense of discomfort that eases with voiding, he said.

“Of course you don't want to miss bladder cancer, but a 30-year-old nonsmoker is unlikely to have bladder cancer. If there's any hematuria or you are especially concerned you can send off a urine specimen for cytology,” he said.

Otherwise, the diagnosis is empiric, and diagnostic tests such as hydrodistention under anesthesia are not routinely done. In a patient for whom infection has been ruled out, and particularly with pronounced nocturia, it's reasonable to begin empiric therapy, Dr. Moldwin said.

Management encompasses both nonpharmacologic and pharmacologic strategies. Dietary changes often help, and many patients benefit from avoidance of carbonated and caffeinated beverages, alcohol, and citrus fruits. Behavior modification, with gentle exercise, stress reduction, and muscle relaxation, also can help, he added. “I'm a big believer in having patients become empowered, taking control of their own care.”

Oral medications used for IC/PBS include pentosan polysulfate sodium, amitriptyline, and hydroxyzine. Pentosan polysulfate, the only Food and Drug Administration-approved oral medication for this condition in doses of 100 mg three times per day, coats the bladder wall and decreases sensitivity. The drug can take several months to work, and is effective in up to 60% of patients.

The tricyclic antidepressant amitriptyline is useful in helping patients troubled with nocturia sleep at night, and it also has pain reduction properties, probably through inhibition of norepinephrine reuptake in the central and peripheral nervous systems, he said. Amitriptyline can be given in low doses of 10–50 mg per day, preferably at 7 p.m. to avoid a morning hangover effect, he said.

The H₁ histamine antagonist hydroxyzine inhibits the mast cell degranulation and histamine release characteristic of the hypersensitive inflammatory response in the bladder wall. The drug is usually given at night, beginning in doses of 25 mg, but response can take a couple of months.

Intravesical agents that are used include dimethylsulfoxide, which is FDA-approved, and unapproved agents such as lidocaine and heparin.

Increased recognition of the importance of IC/PBS, which afflicts 1.2 million women and 82,000 men in the United States, along with an improved understanding of the associated pathologic events, is allowing the development of many new treatments, including antiproliferative factor, liposomes, and intravesical botulinum toxin type A.

Patients often experience comorbid conditions such as allergies, sensitive skin, irritable bowel syndrome, fibromyalgia, and pelvic floor dysfunction. “There are a lot of comorbidities with IC/PBS, but there probably is a common thread running through these patients. When we find that, we should have some better therapies,” he said.

More than half of hospitalized patients worldwide are at risk for venous thromboembolism, and despite the availability of evidence-based guidelines, the rate of appropriate prophylaxis remains low, a new study has found.

With pulmonary embolism accounting for 5%-10% of deaths among hospitalized patients, venous thromboembolism (VTE) remains the most common preventable cause of in-hospital death, investigators reported.

Dr. Alexander T. Cohen of King's College Hospital, London, and his colleagues enrolled 68,183 patients from 358 hospitals in 32 countries into the cross-sectional Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study.

Patients 40 years and older being treated in medical wards and those 18 years and older being treated on general surgical wards were assessed by chart review for risk for VTE according to the 2004 American College of Chest Physicians (ACCP) guidelines.

Among the 37,356 medical patients, 49% were women; the median age was 67 years. Among the 30,827 surgical patients, 48% were women; the median age was 59 years.

The researchers found that 15,487 medical patients (42%) were at risk for VTE, with the most common risk factors present before hospitalization being chronic pulmonary disease and heart failure. They identified 19,842 surgical patients (64%) who were at risk, with obesity being the most common prehospitalization risk factor.

The most common postadmission risk factors among both medical and surgical patients were complete immobilization, immobilization with bathroom privileges, and admission to intensive or critical care units. Overall, 35,329 (52%) were at risk.

Further analysis determined that only half of these at-risk patients (17,732) received ACCP-recommended types of prophylaxis, which include low-dose unfractionated heparin, low-molecular-weight heparin, graduated compression stockings, and/or intermittent pneumatic compression devices. When prophylaxis was given, low-molecular-weight heparin was the agent most often used.

Not only was prophylaxis underused in at-risk patients, but the investigators also found that 34% of surgical patients and 29% of medical patients considered at low risk for VTE were given prophylaxis (Lancet 2008;371:387–94).

Overall, the proportion of hospital patients at risk for VTE ranged from 36% to 73% and the proportion of patients receiving ACCP-recommended prophylaxis ranged from 2% to 84%, the investigators reported.

These differences could reflect factors such as physician awareness, availability of guidelines, and local resources. In the United States, 48% of at-risk medical patients and 71% of at-risk surgical patients received recommended prophylaxis, while in Thailand the corresponding figures were 4% and 0.2%.

They also noted that the use of prophylaxis was particularly low among medical patients, with only 37% of those hospitalized with active malignancy or ischemic stroke—among the highest-risk groups—receiving recommended prophylaxis.

In an editorial, Dr. Walter Ageno and Dr. Francesco Dentali of the University of Insubria, Varese, Italy, noted that local programs such as electronic alerts for clinicians are effective and should be promoted. But before such tools can be effectively implemented, the prevalence of the problem must be more broadly appreciated and disagreements about benefits and risks resolved.

“Different perceptions of the benefit-to-risk ratio of pharmacological prophylaxis exist between ischaemic stroke specialists, and some stroke guidelines do not recommend routine use of pharmacologic prevention strategies.” Guidelines should be more comprehensively endorsed among medical and surgical societies, they wrote (Lancet 2008;371:361–2).

More than half of hospitalized patients worldwide are at risk for venous thromboembolism, and despite the availability of evidence-based guidelines, the rate of appropriate prophylaxis remains low, a new study has found.

With pulmonary embolism accounting for 5%-10% of deaths among hospitalized patients, venous thromboembolism (VTE) remains the most common preventable cause of in-hospital death, investigators reported.

Dr. Alexander T. Cohen of King's College Hospital, London, and his colleagues enrolled 68,183 patients from 358 hospitals in 32 countries into the cross-sectional Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study.

Patients 40 years and older being treated in medical wards and those 18 years and older being treated on general surgical wards were assessed by chart review for risk for VTE according to the 2004 American College of Chest Physicians (ACCP) guidelines.

Among the 37,356 medical patients, 49% were women; the median age was 67 years. Among the 30,827 surgical patients, 48% were women; the median age was 59 years.

The researchers found that 15,487 medical patients (42%) were at risk for VTE, with the most common risk factors present before hospitalization being chronic pulmonary disease and heart failure. They identified 19,842 surgical patients (64%) who were at risk, with obesity being the most common prehospitalization risk factor.

The most common postadmission risk factors among both medical and surgical patients were complete immobilization, immobilization with bathroom privileges, and admission to intensive or critical care units. Overall, 35,329 (52%) were at risk.

Further analysis determined that only half of these at-risk patients (17,732) received ACCP-recommended types of prophylaxis, which include low-dose unfractionated heparin, low-molecular-weight heparin, graduated compression stockings, and/or intermittent pneumatic compression devices. When prophylaxis was given, low-molecular-weight heparin was the agent most often used.

Not only was prophylaxis underused in at-risk patients, but the investigators also found that 34% of surgical patients and 29% of medical patients considered at low risk for VTE were given prophylaxis (Lancet 2008;371:387–94).

Overall, the proportion of hospital patients at risk for VTE ranged from 36% to 73% and the proportion of patients receiving ACCP-recommended prophylaxis ranged from 2% to 84%, the investigators reported.

These differences could reflect factors such as physician awareness, availability of guidelines, and local resources. In the United States, 48% of at-risk medical patients and 71% of at-risk surgical patients received recommended prophylaxis, while in Thailand the corresponding figures were 4% and 0.2%.

They also noted that the use of prophylaxis was particularly low among medical patients, with only 37% of those hospitalized with active malignancy or ischemic stroke—among the highest-risk groups—receiving recommended prophylaxis.

In an editorial, Dr. Walter Ageno and Dr. Francesco Dentali of the University of Insubria, Varese, Italy, noted that local programs such as electronic alerts for clinicians are effective and should be promoted. But before such tools can be effectively implemented, the prevalence of the problem must be more broadly appreciated and disagreements about benefits and risks resolved.

“Different perceptions of the benefit-to-risk ratio of pharmacological prophylaxis exist between ischaemic stroke specialists, and some stroke guidelines do not recommend routine use of pharmacologic prevention strategies.” Guidelines should be more comprehensively endorsed among medical and surgical societies, they wrote (Lancet 2008;371:361–2).

More than half of hospitalized patients worldwide are at risk for venous thromboembolism, and despite the availability of evidence-based guidelines, the rate of appropriate prophylaxis remains low, a new study has found.

With pulmonary embolism accounting for 5%-10% of deaths among hospitalized patients, venous thromboembolism (VTE) remains the most common preventable cause of in-hospital death, investigators reported.

Dr. Alexander T. Cohen of King's College Hospital, London, and his colleagues enrolled 68,183 patients from 358 hospitals in 32 countries into the cross-sectional Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study.

Patients 40 years and older being treated in medical wards and those 18 years and older being treated on general surgical wards were assessed by chart review for risk for VTE according to the 2004 American College of Chest Physicians (ACCP) guidelines.

Among the 37,356 medical patients, 49% were women; the median age was 67 years. Among the 30,827 surgical patients, 48% were women; the median age was 59 years.

The researchers found that 15,487 medical patients (42%) were at risk for VTE, with the most common risk factors present before hospitalization being chronic pulmonary disease and heart failure. They identified 19,842 surgical patients (64%) who were at risk, with obesity being the most common prehospitalization risk factor.

The most common postadmission risk factors among both medical and surgical patients were complete immobilization, immobilization with bathroom privileges, and admission to intensive or critical care units. Overall, 35,329 (52%) were at risk.

Further analysis determined that only half of these at-risk patients (17,732) received ACCP-recommended types of prophylaxis, which include low-dose unfractionated heparin, low-molecular-weight heparin, graduated compression stockings, and/or intermittent pneumatic compression devices. When prophylaxis was given, low-molecular-weight heparin was the agent most often used.

Not only was prophylaxis underused in at-risk patients, but the investigators also found that 34% of surgical patients and 29% of medical patients considered at low risk for VTE were given prophylaxis (Lancet 2008;371:387–94).

Overall, the proportion of hospital patients at risk for VTE ranged from 36% to 73% and the proportion of patients receiving ACCP-recommended prophylaxis ranged from 2% to 84%, the investigators reported.

These differences could reflect factors such as physician awareness, availability of guidelines, and local resources. In the United States, 48% of at-risk medical patients and 71% of at-risk surgical patients received recommended prophylaxis, while in Thailand the corresponding figures were 4% and 0.2%.

They also noted that the use of prophylaxis was particularly low among medical patients, with only 37% of those hospitalized with active malignancy or ischemic stroke—among the highest-risk groups—receiving recommended prophylaxis.

In an editorial, Dr. Walter Ageno and Dr. Francesco Dentali of the University of Insubria, Varese, Italy, noted that local programs such as electronic alerts for clinicians are effective and should be promoted. But before such tools can be effectively implemented, the prevalence of the problem must be more broadly appreciated and disagreements about benefits and risks resolved.

“Different perceptions of the benefit-to-risk ratio of pharmacological prophylaxis exist between ischaemic stroke specialists, and some stroke guidelines do not recommend routine use of pharmacologic prevention strategies.” Guidelines should be more comprehensively endorsed among medical and surgical societies, they wrote (Lancet 2008;371:361–2).

BOSTON — Half of patients with early rheumatoid arthritis treated with a combination of etanercept and methotrexate achieved disease remission within 1 year in the first major trial to use remission as the primary end point, Dr. Paul Emery reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

“We have been talking about remission for a long time,” said Dr. Emery, who wrote a viewpoint piece more than a decade ago entitled “Early rheumatoid arthritis: Time to aim for remission?” (Ann. Rheum. Dis. 1995;54:944–7). “We now can say this is a realistic goal.”

The trial, known as COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis), compared the clinical efficacy and safety of etanercept plus methotrexate with methotrexate alone in a randomized, double-blind study that included 542 adult patients from 22 countries.

Trial participants had active disease as determined by a Disease Activity Score-28 (DAS28) of 3.2 or greater, and elevations either of erythrocyte sedimentation rate (ESR) to 28 mm/hr or higher or of C-reactive protein to 20 mg/L or more. All of the patients were methotrexate naive and had a disease duration of 2 years or less.

Baseline demographics and disease characteristics were similar in the etanercept plus methotrexate and methotrexate-alone groups. Mean age was 51 years, and median disease duration was 7 months in both groups. Mean baseline DAS28 was 6.5, so the DAS28 was high despite the short disease duration, said Dr. Emery.

About half had received corticosteroids, and 22% had previously been treated with a disease-modifying antirheumatic drug other than methotrexate.

The primary end point of remission (defined as a DAS28 less than 2.6) was achieved by 50% of patients on combination therapy by week 52, compared with 28% of patients receiving methotrexate alone. This represented a statistically significant difference, and “a considerable achievement,” said Dr. Emery, professor of rheumatology at the University of Leeds (England).

Low disease activity (defined as a DAS28 of 3.2 or less) was achieved by week 52 by 64% and 41% of patients in the combination and methotrexate groups, respectively, which also was a statistically significant difference. Moreover, it was “quite remarkable” how quickly remission was achieved, with significant differences being seen at 2 weeks, he said.

By weeks 16–20, 40% of patients in the combination group were in remission, he said. “This is a new standard of speed for achieving remission,” he noted.

Responses on the American College of Rheumatology (ACR) scales were evaluated as secondary end points. “It's traditional with most biologics to expect ACR 20, 50, and 70 responses of 60%, 40%, and 20%, but with the combination we saw response rates of 86%, 71%, and 48%, which are very high rates indeed,” Dr. Emery commented.

These levels of ACR response were seen in 67%, 49%, and 28% of the methotrexate group. Levels of C-reactive protein improved dramatically by week 2 and stabilized by week 16. By week 52, 55% of patients had normal Health Assessment Questionnaire (HAQ) scores, meaning that they had normal functional status. There also was a two-thirds reduction in workdays lost, which is important from a cost point of view, he said.

“Finally, there were no new safety signals associated with combination therapy, which is terribly important for patients who are naive to methotrexate,” he said.

Serious adverse events were reported by 12% of patients in the combination group and by 13% of patients in the methotrexate group. There were no differences in rates of serious infections or malignancies, and there were no cases of tuberculosis or demyelinating disease, he said.

Dr. Emery disclosed that he has received consulting fees from Amgen Inc. and Wyeth.

'We have been talking about remission for a long time. … I think we now can say this is a realistic goal.' DR. EMERY

BOSTON — Half of patients with early rheumatoid arthritis treated with a combination of etanercept and methotrexate achieved disease remission within 1 year in the first major trial to use remission as the primary end point, Dr. Paul Emery reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

“We have been talking about remission for a long time,” said Dr. Emery, who wrote a viewpoint piece more than a decade ago entitled “Early rheumatoid arthritis: Time to aim for remission?” (Ann. Rheum. Dis. 1995;54:944–7). “We now can say this is a realistic goal.”

The trial, known as COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis), compared the clinical efficacy and safety of etanercept plus methotrexate with methotrexate alone in a randomized, double-blind study that included 542 adult patients from 22 countries.

Trial participants had active disease as determined by a Disease Activity Score-28 (DAS28) of 3.2 or greater, and elevations either of erythrocyte sedimentation rate (ESR) to 28 mm/hr or higher or of C-reactive protein to 20 mg/L or more. All of the patients were methotrexate naive and had a disease duration of 2 years or less.

Baseline demographics and disease characteristics were similar in the etanercept plus methotrexate and methotrexate-alone groups. Mean age was 51 years, and median disease duration was 7 months in both groups. Mean baseline DAS28 was 6.5, so the DAS28 was high despite the short disease duration, said Dr. Emery.

About half had received corticosteroids, and 22% had previously been treated with a disease-modifying antirheumatic drug other than methotrexate.

The primary end point of remission (defined as a DAS28 less than 2.6) was achieved by 50% of patients on combination therapy by week 52, compared with 28% of patients receiving methotrexate alone. This represented a statistically significant difference, and “a considerable achievement,” said Dr. Emery, professor of rheumatology at the University of Leeds (England).

Low disease activity (defined as a DAS28 of 3.2 or less) was achieved by week 52 by 64% and 41% of patients in the combination and methotrexate groups, respectively, which also was a statistically significant difference. Moreover, it was “quite remarkable” how quickly remission was achieved, with significant differences being seen at 2 weeks, he said.

By weeks 16–20, 40% of patients in the combination group were in remission, he said. “This is a new standard of speed for achieving remission,” he noted.

Responses on the American College of Rheumatology (ACR) scales were evaluated as secondary end points. “It's traditional with most biologics to expect ACR 20, 50, and 70 responses of 60%, 40%, and 20%, but with the combination we saw response rates of 86%, 71%, and 48%, which are very high rates indeed,” Dr. Emery commented.

These levels of ACR response were seen in 67%, 49%, and 28% of the methotrexate group. Levels of C-reactive protein improved dramatically by week 2 and stabilized by week 16. By week 52, 55% of patients had normal Health Assessment Questionnaire (HAQ) scores, meaning that they had normal functional status. There also was a two-thirds reduction in workdays lost, which is important from a cost point of view, he said.

“Finally, there were no new safety signals associated with combination therapy, which is terribly important for patients who are naive to methotrexate,” he said.

Serious adverse events were reported by 12% of patients in the combination group and by 13% of patients in the methotrexate group. There were no differences in rates of serious infections or malignancies, and there were no cases of tuberculosis or demyelinating disease, he said.

Dr. Emery disclosed that he has received consulting fees from Amgen Inc. and Wyeth.

'We have been talking about remission for a long time. … I think we now can say this is a realistic goal.' DR. EMERY

BOSTON — Half of patients with early rheumatoid arthritis treated with a combination of etanercept and methotrexate achieved disease remission within 1 year in the first major trial to use remission as the primary end point, Dr. Paul Emery reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

“We have been talking about remission for a long time,” said Dr. Emery, who wrote a viewpoint piece more than a decade ago entitled “Early rheumatoid arthritis: Time to aim for remission?” (Ann. Rheum. Dis. 1995;54:944–7). “We now can say this is a realistic goal.”

The trial, known as COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis), compared the clinical efficacy and safety of etanercept plus methotrexate with methotrexate alone in a randomized, double-blind study that included 542 adult patients from 22 countries.

Trial participants had active disease as determined by a Disease Activity Score-28 (DAS28) of 3.2 or greater, and elevations either of erythrocyte sedimentation rate (ESR) to 28 mm/hr or higher or of C-reactive protein to 20 mg/L or more. All of the patients were methotrexate naive and had a disease duration of 2 years or less.

Baseline demographics and disease characteristics were similar in the etanercept plus methotrexate and methotrexate-alone groups. Mean age was 51 years, and median disease duration was 7 months in both groups. Mean baseline DAS28 was 6.5, so the DAS28 was high despite the short disease duration, said Dr. Emery.

About half had received corticosteroids, and 22% had previously been treated with a disease-modifying antirheumatic drug other than methotrexate.

The primary end point of remission (defined as a DAS28 less than 2.6) was achieved by 50% of patients on combination therapy by week 52, compared with 28% of patients receiving methotrexate alone. This represented a statistically significant difference, and “a considerable achievement,” said Dr. Emery, professor of rheumatology at the University of Leeds (England).

Low disease activity (defined as a DAS28 of 3.2 or less) was achieved by week 52 by 64% and 41% of patients in the combination and methotrexate groups, respectively, which also was a statistically significant difference. Moreover, it was “quite remarkable” how quickly remission was achieved, with significant differences being seen at 2 weeks, he said.

By weeks 16–20, 40% of patients in the combination group were in remission, he said. “This is a new standard of speed for achieving remission,” he noted.

Responses on the American College of Rheumatology (ACR) scales were evaluated as secondary end points. “It's traditional with most biologics to expect ACR 20, 50, and 70 responses of 60%, 40%, and 20%, but with the combination we saw response rates of 86%, 71%, and 48%, which are very high rates indeed,” Dr. Emery commented.

These levels of ACR response were seen in 67%, 49%, and 28% of the methotrexate group. Levels of C-reactive protein improved dramatically by week 2 and stabilized by week 16. By week 52, 55% of patients had normal Health Assessment Questionnaire (HAQ) scores, meaning that they had normal functional status. There also was a two-thirds reduction in workdays lost, which is important from a cost point of view, he said.

“Finally, there were no new safety signals associated with combination therapy, which is terribly important for patients who are naive to methotrexate,” he said.

Serious adverse events were reported by 12% of patients in the combination group and by 13% of patients in the methotrexate group. There were no differences in rates of serious infections or malignancies, and there were no cases of tuberculosis or demyelinating disease, he said.

Dr. Emery disclosed that he has received consulting fees from Amgen Inc. and Wyeth.

'We have been talking about remission for a long time. … I think we now can say this is a realistic goal.' DR. EMERY