Rheumatoid Arthritis

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – Most patients with early active rheumatoid arthritis who discontinued adalimumab after achieving stable low disease activity on 26 weeks of combination therapy with methotrexate and adalimumab maintained that response through week 78 of treatment in a randomized, double-blind, placebo-controlled trial.

However, more patients who remained on the combination therapy achieved high levels of disease control, based on measures such as American College of Rheumatology 70% response (ACR70) and disease activity score 28 (DAS28) less than 2.6, which suggests that certain patients will benefit from remaining on combination therapy, according to Dr. Arthur F. Kavanaugh, professor of medicine and director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.

"The billion dollar question: Can we predict which patients we could [withdraw from a tumor necrosis factor inhibitor] and have absolutely no penalty ... is there a predictor?" said Dr. Kavanaugh, in discussing the implications of the findings of OPTIMA (study of the Optimal Protocol for Methotrexate and Adalimumab combination therapy in early RA) at the annual meeting of the American College of Rheumatology.

After "intense analysis of all manner of baseline characteristics," the answer is that only a low baseline score on the Health Assessment Questionnaire (HAQ) was found to predict which patients would do better with adalimumab withdrawal vs. continuation on combined therapy based on a composite outcome of DAS28 less than 2.6 or Simplified Disease Activity Index (SDAI) score of 3.3 or less and Health Assessment Questionnaire score of less than 0.5 (odds ratio, 1.9), he said.

Study participants were 207 adults aged 18 years or older from the first phase of the study. All had early active severe disease and achieved stable low disease activity defined as a DAS28 less than 3.2 on combination therapy within 26 weeks. For the current phase of the study, the patients were rerandomized to continue combination therapy or to have adalimumab withdrawn for an additional 52 weeks.

The percentage of patients achieving ACR20 and ACR50 responses, indicating 20% and 50% improvements in the signs and symptoms of disease, was 94% and 80% in the patients in whom adalimumab was withdrawn, compared with 95% and 89% in those who continued on combination therapy. The differences between the groups on these outcomes measures were not statistically significant.

Baseline characteristics in the withdrawal and continued combination therapy groups were similar; mean RA duration in both groups was 3.9 months. DAS28 was 5.9 and 5.7 in the withdrawal and continued combination therapy groups, respectively. C-reactive protein levels were 28.4 and 23.5 mg/L, mean 68-joint tender joint counts were 25.5 and 23.3, mean 66-joint swollen joint counts were 16.4 and 15.4, and mean modified total van der Heijde/Sharp scores were 12.2 and 10.8.

No significant difference was seen between the groups in regard to changes in SDAI scores of 11 or less, or in SDAI scores of 3.3 or less. No differences were seen between the groups in regard to radiographic progression as measured by mean modified total van der Heijde/Sharp scores, or in regard to changes in functional status as measured by mean HAQ scores.

The percentage who achieved ACR70, however, was 65% in the adalimumab withdrawal group, compared with 77% in the continued combination therapy group. This difference was statistically significant.

Furthermore, 81% of patients in the withdrawal group achieved DAS28 of less than 3.2, compared with 91% of those in the continued combination therapy group (P = .04), and 66% vs. 86% of patients in the groups, respectively, achieved DAS28 of 2.6 or less (P = .001).

Other than HAQ scores, nothing predicted with any strength who would do well after adalimumab withdrawal – even in univariate analysis, Dr. Kavanaugh stressed.

Dr. Kavanaugh disclosed that he received consulting fees or other remuneration from Abbott Laboratories. Other study authors also disclosed financial relationships with Abbott Laboratories and other companies, including, Bristol-Myers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MSD, Pfizer, Roche Pharmaceuticals, and/or UCB Pharma.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – The shingles vaccine does not increase the risk of shingles in patients taking biologics for autoimmune or inflammatory conditions, based on data from more than 7,000 adults. The findings were presented at the annual meeting of the American College of Rheumatology.

The findings suggest that the current recommendations that biologics users avoid live virus vaccines may be overly cautious, said Dr. Jeffrey R. Curtis of the University of Alabama, Birmingham.

The shingles vaccine (Zostavax) is recommended to protect older adults against herpes zoster, Dr. Curtis said, but concerns have been raised that reactivation of the live virus after vaccination for patients taking immunosuppressive medications might increase their risk of a shingles eruption.

To determine the risk of shingles in a population taking immunosuppressive medication, Dr. Curtis and his colleagues reviewed Medicare data from 2006 to 2009. They identified 7,781 adults aged 60 years and older who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease, and who had received a shingles vaccine while taking medication including biologics, disease modifying antirheumatic drugs (DMARDs), and oral glucocorticoids. The mean age of the study population was 74 years, most were white women, and none had any evidence of shingles infection at baseline.

Overall, the incidence rate for shingles at least 42 days after vaccination was 8 cases/1,000 person-years among vaccinated adults, compared with 12 cases/1,000 person-years in a cohort of unvaccinated adults.

In a subset of 636 vaccinated adults who were taking biologics (regardless of concomitant DMARDs or oral glucocorticoids), no cases of shingles were reported within the first 42 days after vaccination, Dr. Curtis emphasized. In fact, vaccination was associated with a decrease in herpes zoster incidence of approximately 30%, he added. By contrast, the incidence rate of shingles in unvaccinated patients taking biologics was 16 per 1,000 person-years. The incidence of infection was not significantly different in vaccinated patients taking biologics than in vaccinated patients taking non-biologic DMARDs, Dr. Curtis added.

The study was limited by the lack of information about the disease severity, Dr. Curtis noted. But the findings support the safety and effectiveness of the shingles vaccine for biologics users.

There are persistent unmet vaccination needs for patients with diseases that require immunosuppressive therapy, said Dr. Curtis. "A controlled safety trial of the zoster vaccine in biologic users may be indicated to further demonstrate its safety and effectiveness in preventing zoster infection," he said.

The study was supported by the Agency for Healthcare Research and Quality and the National Institutes of Health. Dr. Curtis has received research grants and consulting fees from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Roche, and UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Methotrexate monotherapy is recommended and widely prescribed as the initial treatment approach for patients presenting with early rheumatoid arthritis, and now results of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) Trial appear to validate the approach.

Findings from the randomized, double-blind 2-year trial involving 755 patients with early rheumatoid arthritis (RA) and a poor prognosis demonstrate that about 30% of those randomized to receive initial methotrexate monotherapy respond adequately and don’t need to step up to combination therapy. In addition, data from the study demonstrated that those who require step-up therapy because of inadequate response to methotrexate monotherapy do just as well radiographically as do those who receive combination therapy at the outset, according to Dr. James R. O’Dell, the Larson Professor of Medicine of the University of Nebraska and chief of rheumatology at the Veterans Affairs Medical Center, both in Omaha, and his colleagues reported at the annual meeting of the American College of Rheumatology.

"So there is no radiographic penalty for waiting to make that decision [to use combination therapy] clinically," said Dr. O’Dell, the new president of the American College of Rheumatology.

Patients in the TEAR Trial had active disease with a mean disease duration of 3.6 months and a mean disease activity 28 (DAS28) score of 5.8, had not received prior disease-modifying antirheumatic drug (DMARD) therapy, and had a poor prognosis based on the findings of rheumatoid factor positivity, a positive cyclic citrullinated peptide antibody test, or the presence of at least two erosions. They were randomized 2:1 to receive methotrexate monotherapy or combination therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine).

Methotrexate monotherapy patients who failed to achieve DAS28 of less than 3.2 within 24 weeks switched to one of the combinations.

Of 379 patients who received methotrexate monotherapy, 28% achieved a DAS28 below 3.2. Those who remained on monotherapy at week 102 had a mean DAS28 of 2.7, which both indicated durability of response and was nominally lower than the mean DAS28 of 3.0 in the initial combination therapy patients, Dr. O’Dell said.

Radiographic progression in the methotrexate monotherapy patients, compared with the immediate combination therapy patients was also nominally – and reassuringly – better (total sharp scores of 0.1 and 1.1, respectively), he noted. In addition, DAS28 scores as well as measures of radiographic progression were comparable in the step-up patients and the immediate combination patients beginning at 12 weeks after step-up through 102 weeks.

As for baseline differences between the patients on methotrexate monotherapy who did and did not require step-up therapy, those on step-up were more likely to be female and to have a higher DAS28 and an elevated body mass index.

"None of these differences were statistically significant, but one wonders about the overall accumulative effect of those factors on predicting response," Dr. O’Dell said.

Although methotrexate monotherapy is widely accepted as the appropriate approach to treatment in early RA patients and is recommended by both the ACR and the European League Against Rheumatism, this is the first blinded randomized trial to validate this approach, he noted.

Dr. O’Dell disclosed that he received grant money for the National Institutes of Health and the Department of Veterans Affairs. Other authors disclosed relationships with Abbott, American Shoulder and Elbow, Amgen, which provided grant money for the study, as well as BMS, Centacor, Corona, Crescendo, Genentech, Ortho Biotech Services, Pfizer, Roche, Teva Pharmaceuticals, and/or UCB.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Patients who undergo total knee replacement surgery recover just as well with postoperative, group-based, outpatient physiotherapy or a monitored, home-based physiotherapy program as with a one-on-one, outpatient center–based program, according to findings from a randomized study involving 249 patients.

With the exception of patient satisfaction with physiotherapy – which was significantly greater for the 85 patients who were randomized to one-on-one therapy and the 84 who were randomized to group-based therapy than it was for the 80 patients who received home-based therapy (mean satisfaction rates, 90%, 84%, and 73%, respectively) – no significant differences were seen in any other outcome measures during the first postsurgical year, Victoria W.M. Ko of the University of New South Wales, Sydney, and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.

For example, WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index function scores at postoperative week 10 (the primary outcome measure) were similar at a mean of 44.0, 39.32, and 35.0 in the one-on-one patients, the group-based therapy patients, and the home-based therapy patients, respectively. There also were no differences among groups in recovery of mobility as measured by a 6-minute walk distance and a timed stair test, or in HRQOL (Health-Related Quality of Life) score, knee range of motion, or patient-related overall recovery at 52 weeks, the investigators found.

Furthermore, the home-based program patients were no more likely than those in the other groups to be readmitted to the hospital or to experience any other complications.

Patient in the single-blind study were consecutive adults (mean age, 67 years) who were awaiting total knee replacement, were enrolled 2 weeks prior to surgery, and were randomized 2 weeks after surgery. During the 6-week therapy period, those who were randomized to receive one-on-one therapy or group-based therapy received 12 physiotherapy sessions, and those in the home-based program were prescribed home exercises supplemented with two sessions of one-on-one therapy and a telephone follow-up. All patients were assessed preoperatively and at postoperative weeks 2, 10, 26, and 52.

The findings are important because of the increasing volume of total knee replacement surgeries performed annually, and because home-based therapy provides a safe and more resource-efficient alternative to center-based physiotherapy, the investigators concluded. They added that this approach "will also circumvent access issues frequently associated with center-based care."

The authors reported that they had no disclosures relevant to this study.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – Mavrilimumab has shown promise for the treatment of rheumatoid arthritis in a randomized, placebo-controlled, phase II study.

The agent is a novel human monoclonal antibody that targets granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha, which has been implicated in the rheumatoid arthritis (RA) disease process by findings from prior preclinical and animal studies.

During the 12-week, dose-ranging study, 55.7% of 149 patients who were randomized to receive 10, 30, 50, or 100 mg of active treatment achieved the primary end point of at least a 1.2-point reduction in the Disease Activity Score 28 as measured using C-reactive protein (DAS28-CRP), compared with only 34.7% of 67 patients randomized to receive placebo. The difference was statistically significant, Dr. Gerd R. Burmester reported at the annual meeting of the American College of Rheumatology.

Response generally occurred within 2 weeks of treatment initiation, and the most significant improvement was seen in patients who were randomized to receive 100 mg of mavrilimumab, with 66.7%, of patients in the 100-mg group achieving the primary end point, compared with 41.0%, 61.0%, and 53.8% of those in the 10-, 30-, and 50-mg groups, respectively, said Dr. Burmester, professor of medicine in the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin.

Patients receiving active treatment also were more likely than those receiving placebo to achieve DAS28-CRP remission, with significantly higher remission rates seen both overall (18.4%) and in the 100-mg group (23.1%), compared with placebo (6.7%). ACR 20, 50, and 70 responses (American College of Rheumatology assessment scales based on 20%, 50%, and 70% improvement in specified parameters) were also better in the mavrilimumab patients, compared with the placebo patients, with significantly better improvement seen between the 100-mg group and the placebo group for all three ACR response categories, as well as overall and in the 30-mg group, compared with placebo, for the ACR 50 response category.

Mavrilimumab patients also were more likely to achieve a 0.25-point improvement in HAQ-DI (Health Assessment Questionnaire–Disability Index) scores, compared with placebo patients, with significant differences in the response rates occurring both overall (63.3%) and in the 100-mg group (74.4%), compared with placebo (48.0%), Dr. Burmester said.

Treatment in this study was well tolerated.

"Basically, there were very, very few safety signals at all," he said, noting that serious adverse events were reported in 1.3% and 1.9% of mavrilimumab and placebo patients, respectively, and that none of those events was treatment related.

Other adverse events included a decrease in carbon monoxide diffusing capacity and nasopharyngitis, which each occurred more often in the mavrilimumab patients vs. the placebo patients (11.9% vs. 5.1%, and 6.3% vs. 2.5%, respectively), and upper respiratory infections, which occurred more often in the placebo patients (3.8% vs. 5.1%). These events were generally mild or moderate in intensity.

No significant hypersensitivity reactions, anaphylaxis, opportunistic infections, or pulmonary parameters were reported, Dr. Burmester said.

Study participants were adults from Eastern Europe who had active adult-onset RA of at least 3 months’ duration, and who were positive for anti–cyclic citrullinated protein antibody and/or rheumatoid factor. They had a DAS28-CRP of at least 3.2 at baseline.

"We believe the results from this study suggest that suppressing macrophage activity and targeting the GM-CSF receptor may be a novel approach to the treatment of rheumatoid arthritis," Dr. Burmester said, concluding that the rapid and significant clinical effects seen in the study, as well as the acceptable short-term safety profile, support further clinical development of mavrilimumab.

Dr. Burmester disclosed that he has received consulting fees or other remuneration from Medimmune Ltd., the maker of mavrilimumab. Several other authors on this study also disclosed financial relationships with Medimmune and/or AstraZeneca.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – Rheumatoid arthritis more than doubles the risk of fracture in women younger than age 50, according to the results of a large population-based study.

While it’s well known that the disease drives up fracture risk in older men and women, independent of glucocorticoid use, these findings suggest that "we need to make our [younger female] patients aware" that they, too, are at increased risk so they can take precautions by not smoking, and by maintaining adequate calcium, vitamin D, and activity levels, Dr. Shreyasee Amin said at the annual meeting of the American College of Rheumatology. 

Dr. Amin and colleagues at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiologic Project, which includes inpatient and outpatient medical records for residents of Olmstead County, Minn.

The population-based cohort included 1,171 women (70%) and men (30%) diagnosed with RA during 1955-2007. Those individuals were compared with age- and sex-matched controls without RA. The researchers followed subjects until death or their last available follow-up.*

Among women with RA, 308 were younger than 50 years; among men with RA, 110 were younger than 50 years.

Causes of fractures were categorized by whether they were incidental or not and by trauma severity: severe (for example, motor vehicle accident), moderate (fall from standing height or less), spontaneous, and pathologic (malignancy). Severe or pathologic fractures were not included in the analysis.

Overall, women with RA had a 63% greater risk of fracture than women without RA. Women with RA aged 50 years or older had a 43% greater risk of fracture, and women younger than 50 years had more than twice the risk of a fracture (Hazard Ratio, 2.34).

Overall, men with RA had a 40% greater risk of a fracture, compared with those without the disease. Among men aged 50 years and older, those with RA tended to have a greater risk of fracture. In men with RA who were younger than age 50, "we didn’t see enough fractures to determine whether they were at high risk for fracture before the age of 50," said the rheumatologist.

Steroids, which are commonly used to treat the disease, can put individuals at greater risk of fracture. But RA patients also tend to have a greater risk of fracture, independent of their steroid use. "The disease itself may play a role in the loss of bone because the inflammation that drives the joint disease also affects the cells of the bone that increase bone loss," she said.

The study primarily involved a white population, so the results can’t be extrapolated to other races or ethic groups with RA.

Dr. Amin reported that she is on the scientific advisory board for Merck.

* Correction, 11/10/2011: The original version of this story misstated how patients in this study were followed. Patients were followed until death or their last available follow-up, not their first fracture.

CHICAGO – Rheumatoid arthritis more than doubles the risk of fracture in women younger than age 50, according to the results of a large population-based study.

While it’s well known that the disease drives up fracture risk in older men and women, independent of glucocorticoid use, these findings suggest that "we need to make our [younger female] patients aware" that they, too, are at increased risk so they can take precautions by not smoking, and by maintaining adequate calcium, vitamin D, and activity levels, Dr. Shreyasee Amin said at the annual meeting of the American College of Rheumatology. 

Dr. Amin and colleagues at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiologic Project, which includes inpatient and outpatient medical records for residents of Olmstead County, Minn.

The population-based cohort included 1,171 women (70%) and men (30%) diagnosed with RA during 1955-2007. Those individuals were compared with age- and sex-matched controls without RA. The researchers followed subjects until death or their last available follow-up.*

Among women with RA, 308 were younger than 50 years; among men with RA, 110 were younger than 50 years.

Causes of fractures were categorized by whether they were incidental or not and by trauma severity: severe (for example, motor vehicle accident), moderate (fall from standing height or less), spontaneous, and pathologic (malignancy). Severe or pathologic fractures were not included in the analysis.

Overall, women with RA had a 63% greater risk of fracture than women without RA. Women with RA aged 50 years or older had a 43% greater risk of fracture, and women younger than 50 years had more than twice the risk of a fracture (Hazard Ratio, 2.34).

Overall, men with RA had a 40% greater risk of a fracture, compared with those without the disease. Among men aged 50 years and older, those with RA tended to have a greater risk of fracture. In men with RA who were younger than age 50, "we didn’t see enough fractures to determine whether they were at high risk for fracture before the age of 50," said the rheumatologist.

Steroids, which are commonly used to treat the disease, can put individuals at greater risk of fracture. But RA patients also tend to have a greater risk of fracture, independent of their steroid use. "The disease itself may play a role in the loss of bone because the inflammation that drives the joint disease also affects the cells of the bone that increase bone loss," she said.

The study primarily involved a white population, so the results can’t be extrapolated to other races or ethic groups with RA.

Dr. Amin reported that she is on the scientific advisory board for Merck.

* Correction, 11/10/2011: The original version of this story misstated how patients in this study were followed. Patients were followed until death or their last available follow-up, not their first fracture.

CHICAGO – Rheumatoid arthritis more than doubles the risk of fracture in women younger than age 50, according to the results of a large population-based study.

While it’s well known that the disease drives up fracture risk in older men and women, independent of glucocorticoid use, these findings suggest that "we need to make our [younger female] patients aware" that they, too, are at increased risk so they can take precautions by not smoking, and by maintaining adequate calcium, vitamin D, and activity levels, Dr. Shreyasee Amin said at the annual meeting of the American College of Rheumatology. 

Dr. Amin and colleagues at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiologic Project, which includes inpatient and outpatient medical records for residents of Olmstead County, Minn.

The population-based cohort included 1,171 women (70%) and men (30%) diagnosed with RA during 1955-2007. Those individuals were compared with age- and sex-matched controls without RA. The researchers followed subjects until death or their last available follow-up.*

Among women with RA, 308 were younger than 50 years; among men with RA, 110 were younger than 50 years.

Causes of fractures were categorized by whether they were incidental or not and by trauma severity: severe (for example, motor vehicle accident), moderate (fall from standing height or less), spontaneous, and pathologic (malignancy). Severe or pathologic fractures were not included in the analysis.

Overall, women with RA had a 63% greater risk of fracture than women without RA. Women with RA aged 50 years or older had a 43% greater risk of fracture, and women younger than 50 years had more than twice the risk of a fracture (Hazard Ratio, 2.34).

Overall, men with RA had a 40% greater risk of a fracture, compared with those without the disease. Among men aged 50 years and older, those with RA tended to have a greater risk of fracture. In men with RA who were younger than age 50, "we didn’t see enough fractures to determine whether they were at high risk for fracture before the age of 50," said the rheumatologist.

Steroids, which are commonly used to treat the disease, can put individuals at greater risk of fracture. But RA patients also tend to have a greater risk of fracture, independent of their steroid use. "The disease itself may play a role in the loss of bone because the inflammation that drives the joint disease also affects the cells of the bone that increase bone loss," she said.

The study primarily involved a white population, so the results can’t be extrapolated to other races or ethic groups with RA.

Dr. Amin reported that she is on the scientific advisory board for Merck.

* Correction, 11/10/2011: The original version of this story misstated how patients in this study were followed. Patients were followed until death or their last available follow-up, not their first fracture.

CHICAGO – Patients with rheumatoid arthritis on antitumor necrosis factor drugs have no greater risk of developing solid cancers than RA patients on disease-modifying antirheumatic drugs, according to an analysis of registry data on more than 15,000 patients tracked for up to 5 years.

Among the 15,262 patients in the RA registry, 91 of the 3,543 participants taking DMARDs (2.6%) and 295 among 11,719 participants taking anti-TNF drugs (2.5%) developed solid cancers.

"I think these results are very reassuring and follow on nicely from results of early clinical trials. Overall, the risk of solid cancer with anti-TNF therapy does not appear to be increased," lead author Dr. Kimme Hyrich said at the annual meeting of the American College of Rheumatology.

"Of course this represents therapy only up to 5 years, and we know that cancer in general can take many, many years to develop or become clinically apparent. Therefore we need to continue to follow these patients," Dr. Hyrich noted.

The study corroborates previous studies showing a minimal cancer risk associated with the use of anti-TNF agents, many of which have been used in the treatment of RA for more than 10 years. "When they were first available for widespread use, I think there was a continuing anxiety about whether or not an agent, which blocks occult tumor necrosis factor, would actually increase the risk of cancer in patients with rheumatoid arthritis," said Dr. Hyrich, who is senior lecturer and consultant in rheumatology at the University of Manchester (England).

Studies since have been limited primarily to meta-analyses of randomized controlled trials of anti-TNF drugs. These trials tend to be of limited duration, and the participating patients tend to be highly screened. The participants may not represent patients in typical practice, Dr. Hyrich said.

In 2001, the British Society for Rheumatology Biologics Register was established to track the progress of patients with severe rheumatoid arthritis and other rheumatic diseases who are taking anti-TNF therapy. The registry also tracks patients with moderate to severe RA who are being treated with nonbiologic DMARDs; these patients served as a control group in this analysis.

Cancer cases were also identified by reviewing patient records. The study data were linked with the U.K. National Health Service Information Center’s national cancer register. "This is a mandatory reporting cancer register where every confirmed cancer in the United Kingdom is recorded," she explained.

The analysis was limited to solid cancers, specifically excluding lymphoma, leukemia, and skin cancers. The researchers compared the risk out to 5 years’ follow-up for those receiving anti-TNF therapies with the risk for those receiving nonbiologic DMARD therapies.

Dr. Hyrich noted that there were differences between the two patient groups. In particular, more men were on DMARDs, and those on DMARDs were slightly older. "Both of these are recognized risk factors for cancer in general," he said. The results, however, were statistically adjusted to balance the risk between the two groups. The investigators found no significant differences between the groups after adjustment.

Dr. Hyrich reported having no relevant financial disclosures.

CHICAGO – Patients with rheumatoid arthritis on antitumor necrosis factor drugs have no greater risk of developing solid cancers than RA patients on disease-modifying antirheumatic drugs, according to an analysis of registry data on more than 15,000 patients tracked for up to 5 years.

Among the 15,262 patients in the RA registry, 91 of the 3,543 participants taking DMARDs (2.6%) and 295 among 11,719 participants taking anti-TNF drugs (2.5%) developed solid cancers.

"I think these results are very reassuring and follow on nicely from results of early clinical trials. Overall, the risk of solid cancer with anti-TNF therapy does not appear to be increased," lead author Dr. Kimme Hyrich said at the annual meeting of the American College of Rheumatology.

"Of course this represents therapy only up to 5 years, and we know that cancer in general can take many, many years to develop or become clinically apparent. Therefore we need to continue to follow these patients," Dr. Hyrich noted.

The study corroborates previous studies showing a minimal cancer risk associated with the use of anti-TNF agents, many of which have been used in the treatment of RA for more than 10 years. "When they were first available for widespread use, I think there was a continuing anxiety about whether or not an agent, which blocks occult tumor necrosis factor, would actually increase the risk of cancer in patients with rheumatoid arthritis," said Dr. Hyrich, who is senior lecturer and consultant in rheumatology at the University of Manchester (England).

Studies since have been limited primarily to meta-analyses of randomized controlled trials of anti-TNF drugs. These trials tend to be of limited duration, and the participating patients tend to be highly screened. The participants may not represent patients in typical practice, Dr. Hyrich said.

In 2001, the British Society for Rheumatology Biologics Register was established to track the progress of patients with severe rheumatoid arthritis and other rheumatic diseases who are taking anti-TNF therapy. The registry also tracks patients with moderate to severe RA who are being treated with nonbiologic DMARDs; these patients served as a control group in this analysis.

Cancer cases were also identified by reviewing patient records. The study data were linked with the U.K. National Health Service Information Center’s national cancer register. "This is a mandatory reporting cancer register where every confirmed cancer in the United Kingdom is recorded," she explained.

The analysis was limited to solid cancers, specifically excluding lymphoma, leukemia, and skin cancers. The researchers compared the risk out to 5 years’ follow-up for those receiving anti-TNF therapies with the risk for those receiving nonbiologic DMARD therapies.

Dr. Hyrich noted that there were differences between the two patient groups. In particular, more men were on DMARDs, and those on DMARDs were slightly older. "Both of these are recognized risk factors for cancer in general," he said. The results, however, were statistically adjusted to balance the risk between the two groups. The investigators found no significant differences between the groups after adjustment.

Dr. Hyrich reported having no relevant financial disclosures.

CHICAGO – Patients with rheumatoid arthritis on antitumor necrosis factor drugs have no greater risk of developing solid cancers than RA patients on disease-modifying antirheumatic drugs, according to an analysis of registry data on more than 15,000 patients tracked for up to 5 years.

Among the 15,262 patients in the RA registry, 91 of the 3,543 participants taking DMARDs (2.6%) and 295 among 11,719 participants taking anti-TNF drugs (2.5%) developed solid cancers.

"I think these results are very reassuring and follow on nicely from results of early clinical trials. Overall, the risk of solid cancer with anti-TNF therapy does not appear to be increased," lead author Dr. Kimme Hyrich said at the annual meeting of the American College of Rheumatology.

"Of course this represents therapy only up to 5 years, and we know that cancer in general can take many, many years to develop or become clinically apparent. Therefore we need to continue to follow these patients," Dr. Hyrich noted.

The study corroborates previous studies showing a minimal cancer risk associated with the use of anti-TNF agents, many of which have been used in the treatment of RA for more than 10 years. "When they were first available for widespread use, I think there was a continuing anxiety about whether or not an agent, which blocks occult tumor necrosis factor, would actually increase the risk of cancer in patients with rheumatoid arthritis," said Dr. Hyrich, who is senior lecturer and consultant in rheumatology at the University of Manchester (England).

Studies since have been limited primarily to meta-analyses of randomized controlled trials of anti-TNF drugs. These trials tend to be of limited duration, and the participating patients tend to be highly screened. The participants may not represent patients in typical practice, Dr. Hyrich said.

In 2001, the British Society for Rheumatology Biologics Register was established to track the progress of patients with severe rheumatoid arthritis and other rheumatic diseases who are taking anti-TNF therapy. The registry also tracks patients with moderate to severe RA who are being treated with nonbiologic DMARDs; these patients served as a control group in this analysis.

Cancer cases were also identified by reviewing patient records. The study data were linked with the U.K. National Health Service Information Center’s national cancer register. "This is a mandatory reporting cancer register where every confirmed cancer in the United Kingdom is recorded," she explained.

The analysis was limited to solid cancers, specifically excluding lymphoma, leukemia, and skin cancers. The researchers compared the risk out to 5 years’ follow-up for those receiving anti-TNF therapies with the risk for those receiving nonbiologic DMARD therapies.

Dr. Hyrich noted that there were differences between the two patient groups. In particular, more men were on DMARDs, and those on DMARDs were slightly older. "Both of these are recognized risk factors for cancer in general," he said. The results, however, were statistically adjusted to balance the risk between the two groups. The investigators found no significant differences between the groups after adjustment.

Dr. Hyrich reported having no relevant financial disclosures.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

During the first year after starting a new therapy, patients with autoimmune diseases appear to experience a similar rate of serious infections irrespective of whether the new drug is a biologic or a nonbiologic agent.

Infections requiring hospitalizations were nearly identical, regardless of the initial therapy, in a large retrospective cohort study of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis and spondyloarthropathies.

But within the group of rheumatoid arthritis patients taking biologics, infliximab was associated with significantly more infections than was etanercept or adalimumab (adjusted hazard ratio 1.25). "This observation may have important implications for the interpretation of studies that report on tumor necrosis factor [TNF]–alpha [antagonists as a group, perhaps because the prevalence of infliximab use could have influenced observed associations," wrote Dr. Carlos G. Grijalva of Vanderbilt University, Nashville.

The drug regimens studied included the use of infliximab-based regimens, many of which used methotrexate to inhibit anti-infliximab antibodies. "Disentangling the effect of individual drugs when used concurrently is difficult. Nevertheless, we noted that concurrent methotrexate use was similar for the other TNF-alpha antagonists."

Also, in a strong dose-dependent fashion, glucocorticoid use at baseline significantly increased the infection risk for patients with rheumatoid arthritis or psoriasis and spondyloarthropathy, Dr. Grijalva and his colleagues wrote in a study posted online in JAMA on Nov. 6 (2011 Nov. 6 [doi:10.1001/jama.2011.1692]).

Dr. Grijalva and his coinvestigators based their findings on data extracted from four large U.S. databases – three included Medicaid and Medicare participants and one included pharmaceutical assistance programs for the elderly and disabled – as part of the Safety Assessment of Biologic Therapy (SABER) project.

Outcomes were assessed within the first 365 days of initial therapy with the TNF-alpha antagonists infliximab, adalimumab, or etanercept and with nonbiologic therapies specific to each disorder.

For rheumatoid arthritis, the comparator therapies were leflunomide, sulfasalazine, and hydroxychloroquine after any use of methotrexate in the previous year. For inflammatory bowel disease, the comparators were azathioprine and mercaptopurine. For psoriasis and the spondyloarthropathies, the comparators were methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.

The cohort consisted of 10,484 matched pairs of rheumatoid arthritis patients, 2,323 with inflammatory bowel disease, and 3,215 with psoriasis or a spondyloarthropathy. Overall, 20% of patients were aged 65 years or older. Over the 1-year follow-up period, 225 patients died; of these, 148 had rheumatoid arthritis, 38 had inflammatory bowel disease, and 39 had psoriasis.

There were 1,172 serious infections requiring hospitalization, and 53% were for pneumonia or skin and soft tissue infections. The death rate was 3.6% for RA patients, 2% for IBD patients, and 7% for those with psoriasis and the spondyloarthropathies.

Among those with RA, the infection rate was 8.16 per 100 person-years for those taking a biologic agent and 7.78 per 100 person-years for those on a nonbiologic agent, a nonsignificant difference.

However, the authors said, there was a significant difference in infections when considering glucocorticoid use. Those who used up to 5 mg/day were 32% more likely to be hospitalized; 5-10 mg/day, 78% more likely; and more than 10 mg/day, three times more likely to have a hospitalization, compared with patients not taking a glucocorticoid.

When the investigators broke the biologics down into individual infection associations, infliximab was associated with a significant increase, compared with the nonbiologics (adjusted HR 1.26). Infliximab was also associated with significantly more hospitalizations than either etanercept or adalimumab (adjusted HR 1.26 and 1.23, respectively).

Among those with IBD, the rate of infection did not differ significantly between those taking nonbiologic and biologic drugs (9.6 per 100 person-years and 10.9 per 100 person-years, respectively). Nor was there a significant association of infection with baseline glucocorticoid use.

Among those with psoriasis or a spondylarthropy, the infection rates were 5.37 per 100 person-years for nonbiologics and 5.4 per 100 person-years for biologics – not significantly different. But again, baseline glucocorticoid use significantly affected these rates. Those taking 5-10 mg/day of glucocorticoids were twice as likely to be hospitalized as those not taking the drug. Those taking more than 10 mg/day were 2.7 times more likely to have a hospitalization.

Compared with prior studies, this analysis found higher rates of infection overall, a finding that might be due to the large numbers of low-income, elderly, and disabled patients – particularly vulnerable groups.

The researchers said the findings are limited by reliance on coded information from claims and limited information on actual use of medications. The study was primarily sponsored by the Food and Drug Administration and the Department of Health and Human Services. Dr. Grijalva did not have any financial disclosures, but eight of the study investigators reported multiple associations with pharmaceutical companies.

During the first year after starting a new therapy, patients with autoimmune diseases appear to experience a similar rate of serious infections irrespective of whether the new drug is a biologic or a nonbiologic agent.

Infections requiring hospitalizations were nearly identical, regardless of the initial therapy, in a large retrospective cohort study of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis and spondyloarthropathies.

But within the group of rheumatoid arthritis patients taking biologics, infliximab was associated with significantly more infections than was etanercept or adalimumab (adjusted hazard ratio 1.25). "This observation may have important implications for the interpretation of studies that report on tumor necrosis factor [TNF]–alpha [antagonists as a group, perhaps because the prevalence of infliximab use could have influenced observed associations," wrote Dr. Carlos G. Grijalva of Vanderbilt University, Nashville.

The drug regimens studied included the use of infliximab-based regimens, many of which used methotrexate to inhibit anti-infliximab antibodies. "Disentangling the effect of individual drugs when used concurrently is difficult. Nevertheless, we noted that concurrent methotrexate use was similar for the other TNF-alpha antagonists."

Also, in a strong dose-dependent fashion, glucocorticoid use at baseline significantly increased the infection risk for patients with rheumatoid arthritis or psoriasis and spondyloarthropathy, Dr. Grijalva and his colleagues wrote in a study posted online in JAMA on Nov. 6 (2011 Nov. 6 [doi:10.1001/jama.2011.1692]).

Dr. Grijalva and his coinvestigators based their findings on data extracted from four large U.S. databases – three included Medicaid and Medicare participants and one included pharmaceutical assistance programs for the elderly and disabled – as part of the Safety Assessment of Biologic Therapy (SABER) project.

Outcomes were assessed within the first 365 days of initial therapy with the TNF-alpha antagonists infliximab, adalimumab, or etanercept and with nonbiologic therapies specific to each disorder.

For rheumatoid arthritis, the comparator therapies were leflunomide, sulfasalazine, and hydroxychloroquine after any use of methotrexate in the previous year. For inflammatory bowel disease, the comparators were azathioprine and mercaptopurine. For psoriasis and the spondyloarthropathies, the comparators were methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.

The cohort consisted of 10,484 matched pairs of rheumatoid arthritis patients, 2,323 with inflammatory bowel disease, and 3,215 with psoriasis or a spondyloarthropathy. Overall, 20% of patients were aged 65 years or older. Over the 1-year follow-up period, 225 patients died; of these, 148 had rheumatoid arthritis, 38 had inflammatory bowel disease, and 39 had psoriasis.

There were 1,172 serious infections requiring hospitalization, and 53% were for pneumonia or skin and soft tissue infections. The death rate was 3.6% for RA patients, 2% for IBD patients, and 7% for those with psoriasis and the spondyloarthropathies.

Among those with RA, the infection rate was 8.16 per 100 person-years for those taking a biologic agent and 7.78 per 100 person-years for those on a nonbiologic agent, a nonsignificant difference.

However, the authors said, there was a significant difference in infections when considering glucocorticoid use. Those who used up to 5 mg/day were 32% more likely to be hospitalized; 5-10 mg/day, 78% more likely; and more than 10 mg/day, three times more likely to have a hospitalization, compared with patients not taking a glucocorticoid.

When the investigators broke the biologics down into individual infection associations, infliximab was associated with a significant increase, compared with the nonbiologics (adjusted HR 1.26). Infliximab was also associated with significantly more hospitalizations than either etanercept or adalimumab (adjusted HR 1.26 and 1.23, respectively).

Among those with IBD, the rate of infection did not differ significantly between those taking nonbiologic and biologic drugs (9.6 per 100 person-years and 10.9 per 100 person-years, respectively). Nor was there a significant association of infection with baseline glucocorticoid use.

Among those with psoriasis or a spondylarthropy, the infection rates were 5.37 per 100 person-years for nonbiologics and 5.4 per 100 person-years for biologics – not significantly different. But again, baseline glucocorticoid use significantly affected these rates. Those taking 5-10 mg/day of glucocorticoids were twice as likely to be hospitalized as those not taking the drug. Those taking more than 10 mg/day were 2.7 times more likely to have a hospitalization.

Compared with prior studies, this analysis found higher rates of infection overall, a finding that might be due to the large numbers of low-income, elderly, and disabled patients – particularly vulnerable groups.

The researchers said the findings are limited by reliance on coded information from claims and limited information on actual use of medications. The study was primarily sponsored by the Food and Drug Administration and the Department of Health and Human Services. Dr. Grijalva did not have any financial disclosures, but eight of the study investigators reported multiple associations with pharmaceutical companies.

During the first year after starting a new therapy, patients with autoimmune diseases appear to experience a similar rate of serious infections irrespective of whether the new drug is a biologic or a nonbiologic agent.

Infections requiring hospitalizations were nearly identical, regardless of the initial therapy, in a large retrospective cohort study of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis and spondyloarthropathies.

But within the group of rheumatoid arthritis patients taking biologics, infliximab was associated with significantly more infections than was etanercept or adalimumab (adjusted hazard ratio 1.25). "This observation may have important implications for the interpretation of studies that report on tumor necrosis factor [TNF]–alpha [antagonists as a group, perhaps because the prevalence of infliximab use could have influenced observed associations," wrote Dr. Carlos G. Grijalva of Vanderbilt University, Nashville.

The drug regimens studied included the use of infliximab-based regimens, many of which used methotrexate to inhibit anti-infliximab antibodies. "Disentangling the effect of individual drugs when used concurrently is difficult. Nevertheless, we noted that concurrent methotrexate use was similar for the other TNF-alpha antagonists."

Also, in a strong dose-dependent fashion, glucocorticoid use at baseline significantly increased the infection risk for patients with rheumatoid arthritis or psoriasis and spondyloarthropathy, Dr. Grijalva and his colleagues wrote in a study posted online in JAMA on Nov. 6 (2011 Nov. 6 [doi:10.1001/jama.2011.1692]).

Dr. Grijalva and his coinvestigators based their findings on data extracted from four large U.S. databases – three included Medicaid and Medicare participants and one included pharmaceutical assistance programs for the elderly and disabled – as part of the Safety Assessment of Biologic Therapy (SABER) project.

Outcomes were assessed within the first 365 days of initial therapy with the TNF-alpha antagonists infliximab, adalimumab, or etanercept and with nonbiologic therapies specific to each disorder.

For rheumatoid arthritis, the comparator therapies were leflunomide, sulfasalazine, and hydroxychloroquine after any use of methotrexate in the previous year. For inflammatory bowel disease, the comparators were azathioprine and mercaptopurine. For psoriasis and the spondyloarthropathies, the comparators were methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.

The cohort consisted of 10,484 matched pairs of rheumatoid arthritis patients, 2,323 with inflammatory bowel disease, and 3,215 with psoriasis or a spondyloarthropathy. Overall, 20% of patients were aged 65 years or older. Over the 1-year follow-up period, 225 patients died; of these, 148 had rheumatoid arthritis, 38 had inflammatory bowel disease, and 39 had psoriasis.

There were 1,172 serious infections requiring hospitalization, and 53% were for pneumonia or skin and soft tissue infections. The death rate was 3.6% for RA patients, 2% for IBD patients, and 7% for those with psoriasis and the spondyloarthropathies.

Among those with RA, the infection rate was 8.16 per 100 person-years for those taking a biologic agent and 7.78 per 100 person-years for those on a nonbiologic agent, a nonsignificant difference.

However, the authors said, there was a significant difference in infections when considering glucocorticoid use. Those who used up to 5 mg/day were 32% more likely to be hospitalized; 5-10 mg/day, 78% more likely; and more than 10 mg/day, three times more likely to have a hospitalization, compared with patients not taking a glucocorticoid.

When the investigators broke the biologics down into individual infection associations, infliximab was associated with a significant increase, compared with the nonbiologics (adjusted HR 1.26). Infliximab was also associated with significantly more hospitalizations than either etanercept or adalimumab (adjusted HR 1.26 and 1.23, respectively).

Among those with IBD, the rate of infection did not differ significantly between those taking nonbiologic and biologic drugs (9.6 per 100 person-years and 10.9 per 100 person-years, respectively). Nor was there a significant association of infection with baseline glucocorticoid use.

Among those with psoriasis or a spondylarthropy, the infection rates were 5.37 per 100 person-years for nonbiologics and 5.4 per 100 person-years for biologics – not significantly different. But again, baseline glucocorticoid use significantly affected these rates. Those taking 5-10 mg/day of glucocorticoids were twice as likely to be hospitalized as those not taking the drug. Those taking more than 10 mg/day were 2.7 times more likely to have a hospitalization.

Compared with prior studies, this analysis found higher rates of infection overall, a finding that might be due to the large numbers of low-income, elderly, and disabled patients – particularly vulnerable groups.

The researchers said the findings are limited by reliance on coded information from claims and limited information on actual use of medications. The study was primarily sponsored by the Food and Drug Administration and the Department of Health and Human Services. Dr. Grijalva did not have any financial disclosures, but eight of the study investigators reported multiple associations with pharmaceutical companies.