Rheumatoid Arthritis

Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.

While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).

The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.

Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.

At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.

Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.

While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.

Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.

"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.

"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.

The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.

Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.

While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).

The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.

Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.

At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.

Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.

While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.

Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.

"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.

"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.

The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.

Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.

While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).

The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.

Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.

At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.

Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.

While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.

Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.

"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.

"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.

The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.

BERLIN – Recent evidence strongly suggests that enthesis-related arthritis in adolescents has two distinct clinical phenotypes, according to Dr. John Ioannou of University College London.

"The traditional view of enthesis-related arthritis has been that peripheral joint involvement and entheseal disease are common at presentation and then sacroiliitis occurs after many years as a late feature. I think that’s a paradigm that has been borne out not to be true. We can confidently shred that up and throw it away," he declared at the annual European Congress of Rheumatology.

The increasing use of MRI in the evaluation of patients who meet revised International League of Associations for Rheumatology diagnostic criteria for enthesis-related arthritis (ERA) has demonstrated that sacroiliitis appears early in the course of the disease in many of them. This early-onset sacroiliitis doesn’t show up on standard radiography, he explained.

ERA is an understudied subtype of juvenile idiopathic arthritis. The true incidence and prevalence of ERA aren’t known. Dr. Ioannou and his coworkers are conducting a long-term observational study at University College London. Analysis of the first 68 patients in the ERA cohort who have undergone MRI scanning indicated that 36, or 62%, had axial disease while the remainder did not.

The axial phenotype of ERA is characterized by a strong association with HLA-B27-positivity; more than 80% of patients with axial ERA were HLA-B27 positive, as was true for only a minority of those with the peripheral ERA phenotype. Extra-articular manifestations of ERA – inflammatory bowel disease and acute anterior uveitis – occurred only in HLA-B27-positive patients with axial disease.

Patients who were unaffected by axial disease had a strong proclivity for ankle arthritis, which was present in 80% of that group, compared with one-fourth of patients with axial ERA.

Fifty-eight of the 68 patients in the ERA cohort are male. Their median age at disease onset was 11 years and 1 month. The median time from disease onset to the appearance of inflammatory spinal symptoms was 2 years and 8 months.

The London experience matches that described by Italian investigators at the University of Florence, who are following a cohort of 59 patients with ERA. Twenty-one of the 59 reported symptoms of inflammatory back pain beginning a median of 1 year and 3 months after onset of ERA. MRI revealed the presence of sacroiliitis in 17 of the 21, all of whom had negative X-rays of the sacroiliac joints. As in the London series, the Italian patients with axial involvement were far more likely to be HLA-B27-positive, while those without axial disease had a greater frequency of ankle arthritis (J. Rheumatol. 2010;37:2395-401).

Twenty-nine of the 68 patients in the London cohort are on anti–tumor necrosis factor (anti-TNF) therapy plus methotrexate or another nonbiologic disease-modifying antirheumatic drug.

"Our anecdotal experience is that anti-TNF therapy tends to work pretty well in patients with ERA, but the remission rate is low. We’ve not been able to discontinue anti-TNF therapy in our patients," Dr. Ioannou noted.

This is consistent with the experience of a Dutch group. They reported that two-thirds of 22 ERA patients treated with an anti-TNF agent had inactive arthritis and enthesis after 15 months; however, none was able to discontinue biologic therapy without flaring of their disease (J. Rheumatol. 2011;38:2258-63).

The pathogenic mechanisms driving the two clinical patterns of ERA aren’t understood yet. Defining those mechanisms will provide a rationale for deciding on the best treatments for patients with one clinical phenotype or the other. At present, treatment is largely based upon extrapolation from data gathered in treating other forms of juvenile idiopathic arthritis or adult ankylosing spondylitis, the rheumatologist said.

Dr. Ioannou reported having no financial conflicts.

BERLIN – Recent evidence strongly suggests that enthesis-related arthritis in adolescents has two distinct clinical phenotypes, according to Dr. John Ioannou of University College London.

"The traditional view of enthesis-related arthritis has been that peripheral joint involvement and entheseal disease are common at presentation and then sacroiliitis occurs after many years as a late feature. I think that’s a paradigm that has been borne out not to be true. We can confidently shred that up and throw it away," he declared at the annual European Congress of Rheumatology.

The increasing use of MRI in the evaluation of patients who meet revised International League of Associations for Rheumatology diagnostic criteria for enthesis-related arthritis (ERA) has demonstrated that sacroiliitis appears early in the course of the disease in many of them. This early-onset sacroiliitis doesn’t show up on standard radiography, he explained.

ERA is an understudied subtype of juvenile idiopathic arthritis. The true incidence and prevalence of ERA aren’t known. Dr. Ioannou and his coworkers are conducting a long-term observational study at University College London. Analysis of the first 68 patients in the ERA cohort who have undergone MRI scanning indicated that 36, or 62%, had axial disease while the remainder did not.

The axial phenotype of ERA is characterized by a strong association with HLA-B27-positivity; more than 80% of patients with axial ERA were HLA-B27 positive, as was true for only a minority of those with the peripheral ERA phenotype. Extra-articular manifestations of ERA – inflammatory bowel disease and acute anterior uveitis – occurred only in HLA-B27-positive patients with axial disease.

Patients who were unaffected by axial disease had a strong proclivity for ankle arthritis, which was present in 80% of that group, compared with one-fourth of patients with axial ERA.

Fifty-eight of the 68 patients in the ERA cohort are male. Their median age at disease onset was 11 years and 1 month. The median time from disease onset to the appearance of inflammatory spinal symptoms was 2 years and 8 months.

The London experience matches that described by Italian investigators at the University of Florence, who are following a cohort of 59 patients with ERA. Twenty-one of the 59 reported symptoms of inflammatory back pain beginning a median of 1 year and 3 months after onset of ERA. MRI revealed the presence of sacroiliitis in 17 of the 21, all of whom had negative X-rays of the sacroiliac joints. As in the London series, the Italian patients with axial involvement were far more likely to be HLA-B27-positive, while those without axial disease had a greater frequency of ankle arthritis (J. Rheumatol. 2010;37:2395-401).

Twenty-nine of the 68 patients in the London cohort are on anti–tumor necrosis factor (anti-TNF) therapy plus methotrexate or another nonbiologic disease-modifying antirheumatic drug.

"Our anecdotal experience is that anti-TNF therapy tends to work pretty well in patients with ERA, but the remission rate is low. We’ve not been able to discontinue anti-TNF therapy in our patients," Dr. Ioannou noted.

This is consistent with the experience of a Dutch group. They reported that two-thirds of 22 ERA patients treated with an anti-TNF agent had inactive arthritis and enthesis after 15 months; however, none was able to discontinue biologic therapy without flaring of their disease (J. Rheumatol. 2011;38:2258-63).

The pathogenic mechanisms driving the two clinical patterns of ERA aren’t understood yet. Defining those mechanisms will provide a rationale for deciding on the best treatments for patients with one clinical phenotype or the other. At present, treatment is largely based upon extrapolation from data gathered in treating other forms of juvenile idiopathic arthritis or adult ankylosing spondylitis, the rheumatologist said.

Dr. Ioannou reported having no financial conflicts.

BERLIN – Recent evidence strongly suggests that enthesis-related arthritis in adolescents has two distinct clinical phenotypes, according to Dr. John Ioannou of University College London.

"The traditional view of enthesis-related arthritis has been that peripheral joint involvement and entheseal disease are common at presentation and then sacroiliitis occurs after many years as a late feature. I think that’s a paradigm that has been borne out not to be true. We can confidently shred that up and throw it away," he declared at the annual European Congress of Rheumatology.

The increasing use of MRI in the evaluation of patients who meet revised International League of Associations for Rheumatology diagnostic criteria for enthesis-related arthritis (ERA) has demonstrated that sacroiliitis appears early in the course of the disease in many of them. This early-onset sacroiliitis doesn’t show up on standard radiography, he explained.

ERA is an understudied subtype of juvenile idiopathic arthritis. The true incidence and prevalence of ERA aren’t known. Dr. Ioannou and his coworkers are conducting a long-term observational study at University College London. Analysis of the first 68 patients in the ERA cohort who have undergone MRI scanning indicated that 36, or 62%, had axial disease while the remainder did not.

The axial phenotype of ERA is characterized by a strong association with HLA-B27-positivity; more than 80% of patients with axial ERA were HLA-B27 positive, as was true for only a minority of those with the peripheral ERA phenotype. Extra-articular manifestations of ERA – inflammatory bowel disease and acute anterior uveitis – occurred only in HLA-B27-positive patients with axial disease.

Patients who were unaffected by axial disease had a strong proclivity for ankle arthritis, which was present in 80% of that group, compared with one-fourth of patients with axial ERA.

Fifty-eight of the 68 patients in the ERA cohort are male. Their median age at disease onset was 11 years and 1 month. The median time from disease onset to the appearance of inflammatory spinal symptoms was 2 years and 8 months.

The London experience matches that described by Italian investigators at the University of Florence, who are following a cohort of 59 patients with ERA. Twenty-one of the 59 reported symptoms of inflammatory back pain beginning a median of 1 year and 3 months after onset of ERA. MRI revealed the presence of sacroiliitis in 17 of the 21, all of whom had negative X-rays of the sacroiliac joints. As in the London series, the Italian patients with axial involvement were far more likely to be HLA-B27-positive, while those without axial disease had a greater frequency of ankle arthritis (J. Rheumatol. 2010;37:2395-401).

Twenty-nine of the 68 patients in the London cohort are on anti–tumor necrosis factor (anti-TNF) therapy plus methotrexate or another nonbiologic disease-modifying antirheumatic drug.

"Our anecdotal experience is that anti-TNF therapy tends to work pretty well in patients with ERA, but the remission rate is low. We’ve not been able to discontinue anti-TNF therapy in our patients," Dr. Ioannou noted.

This is consistent with the experience of a Dutch group. They reported that two-thirds of 22 ERA patients treated with an anti-TNF agent had inactive arthritis and enthesis after 15 months; however, none was able to discontinue biologic therapy without flaring of their disease (J. Rheumatol. 2011;38:2258-63).

The pathogenic mechanisms driving the two clinical patterns of ERA aren’t understood yet. Defining those mechanisms will provide a rationale for deciding on the best treatments for patients with one clinical phenotype or the other. At present, treatment is largely based upon extrapolation from data gathered in treating other forms of juvenile idiopathic arthritis or adult ankylosing spondylitis, the rheumatologist said.

Dr. Ioannou reported having no financial conflicts.

Tofacitinib, an oral Janus kinase inhibitor that blocks signaling for several cytokines that are integral to lymphocyte function, was found to be effective as either a monotherapy or an adjunctive therapy in two industry-sponsored phase III studies of adults with refractory rheumatoid arthritis, which were reported separately online Aug. 9 in the New England Journal of Medicine.

Compared with placebo, two doses of tofacitinib induced clinically meaningful and statistically significant reductions in the signs and symptoms of RA, and improved physical function. However, the drug was no better than placebo at inducing remission.

In the first study, 611 patients who previously had an inadequate response or excess toxicity to at least one nonbiologic or biologic disease-modifying agent were treated for 6 months at 94 medical centers worldwide, said Dr. Roy Fleischmann of the Metroplex Clinical Research Center, Dallas, and his associates in the Oral Rheumatoid Arthritis–Solo (ORAL-Solo) trial.

The study subjects were randomly assigned to receive 5-mg tofacitinib twice daily for 6 months, 10-mg tofacitinib twice daily for 6 months, or placebo twice daily for 3 months followed by 5-mg or 10-mg tofacitinib for 3 months. They were permitted to continue on stable doses of antimalarials and to use NSAIDs and glucocorticoids if needed.

The mean patient age was approximately 50 years, and the mean duration of RA was approximately 8 years. In all, 67% of the subjects were white and 87% were women.

The first efficacy end point was the percentage of patients who met the criteria for an ACR 20 (American College of Rheumatology 20) response, defined as at least a 20% reduction in the number of tender and swollen joints and at least a 20% improvement in three of the following measures: pain, disability, C-reactive protein level, patient’s global assessment of disease, and physician’s global assessment of disease.

At 3 months, 59.8% of patients receiving 5-mg tofacitinib and 65.7% of those receiving 10-mg tofacitinib achieved this end point, a significantly higher percentage than the 26.7% receiving placebo, the investigators said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1109071]).

The second efficacy end point was the percentage of patients who showed improvement in physical function as measured by the HAQ-DI (Health Assessment Questionnaire–Disability Index). Again, significantly more patients in both tofacitinib groups showed significant improvement by week 2 and continued to improve throughout the study, compared with patients in the placebo group. At 3 months, the proportions were 52.9% with 5-mg tofacitinib and 55.7% with 10-mg tofacitinib, compared with 31.7% with placebo.

The third efficacy end point was the percentage of patients who showed significant improvement on the DAS28-4(ESR), a measure of disease activity that includes a 28-joint count and the erythrocyte sedimentation rate. Tofacitinib was not superior to placebo in this outcome measure. At 3 months, the percentage of patients with a DAS28-4(ESR) score less than 2.6, which indicates remission, was 5.6% with 5-mg tofacitinib, 8.7% with 10-mg tofacitinb, and 4.4% with placebo.

Serious adverse events were more common with both doses of tofacitinib than with placebo. Six patients developed seven serious infections, including cellulitis, liver abscess, bronchitis, pyelonephritis, one case of tuberculous pleural effusion in a patient from India, and one case of nondisseminated herpes zoster. Other serious adverse events included heart failure in two patients.

Nonserious adverse events occurred in approximately half of the study subjects, with similar frequencies across the treatment subgroups. In all, 12 patients (2%) discontinued the study drug because of adverse events during the first 3 months, and another 6 (1%) discontinued during the final 3 months of the study.

Neutropenia developed more frequently with the active treatment than with placebo. In addition, tofacitinib raised LDL cholesterol levels, liver aminotransferase levels, and serum creatinine levels.

In the second phase-III study, oral tofacitinib was compared against subcutaneous injections of adalimumab and placebo in 717 patients who were also taking stable doses of methotrexate. These subjects were treated at 115 medical centers worldwide for 1 year, said Dr. Ronald F. van Vollenhoven of the Karolinska Institute, Stockholm, and his associates in the Oral Rheumatoid Arthritis–Standard (ORAL-Standard) trial.

In this study, the patient population also was predominantly female (approximately 80%) and white (approximately 70%), and the mean duration of RA was approximately 8 years.

The study subjects were randomly assigned to receive 5-mg oral tofacitinib twice daily, 10-mg oral tofacitinib twice daily, subcutaneous adalimumab every 2 weeks, or placebo for either 3 months or 6 months. At 3 months, patients in the placebo group who showed an inadequate response were blindly switched to either 5-mg or 10-mg tofacitinib. At 6 months, all patients in the placebo group were blindly switched to 5-mg or 10-mg tofacitinib.

The three efficacy end points were the same as those in the ORAL-Solo study.

At 6 months, the percentages of patients who met criteria for an ACR 20 response were significantly higher with both doses of tofacitinib and with adalimumab than with placebo, and the magnitudes of the treatment effect were similar between tofacitinib and adalimumab (5-mg tofacitinib, 51.5%; 10-mg tofacitinib, 52.6%; adalimumab, 47.2%; placebo, 28.3%).

Similarly, the percentages of patients who showed significant improvement on both the HAQ-DI score and the DAS28-4(ESR) score were significantly higher with both tofacitinib and adalimumab than with placebo, Dr. van Vollenhoven and his colleagues said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1112072]).

As in the ORAL-Solo study, the treatment responses in the ORAL-Standard study were rapid and were sustained throughout the 1-year study period.

Also as in the ORAL-Solo study, serious adverse events – including serious infections such as tuberculosis – were significantly higher with tofacitinib than with either adalimumab or placebo. Notable adverse events included cytopenia, respiratory and urinary tract infections, and gastrointestinal side effects.

Tofacitinib also raised cholesterol and serum creatinine levels. "Given the duration and size of the study, the implications ... for the risk of cardiac events ... could not be assessed. Longer-term monitoring of patients receiving tofacitinib is ongoing," Dr. van Vollenhoven and his associates said.

Both studies were funded by Pfizer. The investigators reported numerous ties to industry sources.

Tofacitinib, an oral Janus kinase inhibitor that blocks signaling for several cytokines that are integral to lymphocyte function, was found to be effective as either a monotherapy or an adjunctive therapy in two industry-sponsored phase III studies of adults with refractory rheumatoid arthritis, which were reported separately online Aug. 9 in the New England Journal of Medicine.

Compared with placebo, two doses of tofacitinib induced clinically meaningful and statistically significant reductions in the signs and symptoms of RA, and improved physical function. However, the drug was no better than placebo at inducing remission.

In the first study, 611 patients who previously had an inadequate response or excess toxicity to at least one nonbiologic or biologic disease-modifying agent were treated for 6 months at 94 medical centers worldwide, said Dr. Roy Fleischmann of the Metroplex Clinical Research Center, Dallas, and his associates in the Oral Rheumatoid Arthritis–Solo (ORAL-Solo) trial.

The study subjects were randomly assigned to receive 5-mg tofacitinib twice daily for 6 months, 10-mg tofacitinib twice daily for 6 months, or placebo twice daily for 3 months followed by 5-mg or 10-mg tofacitinib for 3 months. They were permitted to continue on stable doses of antimalarials and to use NSAIDs and glucocorticoids if needed.

The mean patient age was approximately 50 years, and the mean duration of RA was approximately 8 years. In all, 67% of the subjects were white and 87% were women.

The first efficacy end point was the percentage of patients who met the criteria for an ACR 20 (American College of Rheumatology 20) response, defined as at least a 20% reduction in the number of tender and swollen joints and at least a 20% improvement in three of the following measures: pain, disability, C-reactive protein level, patient’s global assessment of disease, and physician’s global assessment of disease.

At 3 months, 59.8% of patients receiving 5-mg tofacitinib and 65.7% of those receiving 10-mg tofacitinib achieved this end point, a significantly higher percentage than the 26.7% receiving placebo, the investigators said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1109071]).

The second efficacy end point was the percentage of patients who showed improvement in physical function as measured by the HAQ-DI (Health Assessment Questionnaire–Disability Index). Again, significantly more patients in both tofacitinib groups showed significant improvement by week 2 and continued to improve throughout the study, compared with patients in the placebo group. At 3 months, the proportions were 52.9% with 5-mg tofacitinib and 55.7% with 10-mg tofacitinib, compared with 31.7% with placebo.

The third efficacy end point was the percentage of patients who showed significant improvement on the DAS28-4(ESR), a measure of disease activity that includes a 28-joint count and the erythrocyte sedimentation rate. Tofacitinib was not superior to placebo in this outcome measure. At 3 months, the percentage of patients with a DAS28-4(ESR) score less than 2.6, which indicates remission, was 5.6% with 5-mg tofacitinib, 8.7% with 10-mg tofacitinb, and 4.4% with placebo.

Serious adverse events were more common with both doses of tofacitinib than with placebo. Six patients developed seven serious infections, including cellulitis, liver abscess, bronchitis, pyelonephritis, one case of tuberculous pleural effusion in a patient from India, and one case of nondisseminated herpes zoster. Other serious adverse events included heart failure in two patients.

Nonserious adverse events occurred in approximately half of the study subjects, with similar frequencies across the treatment subgroups. In all, 12 patients (2%) discontinued the study drug because of adverse events during the first 3 months, and another 6 (1%) discontinued during the final 3 months of the study.

Neutropenia developed more frequently with the active treatment than with placebo. In addition, tofacitinib raised LDL cholesterol levels, liver aminotransferase levels, and serum creatinine levels.

In the second phase-III study, oral tofacitinib was compared against subcutaneous injections of adalimumab and placebo in 717 patients who were also taking stable doses of methotrexate. These subjects were treated at 115 medical centers worldwide for 1 year, said Dr. Ronald F. van Vollenhoven of the Karolinska Institute, Stockholm, and his associates in the Oral Rheumatoid Arthritis–Standard (ORAL-Standard) trial.

In this study, the patient population also was predominantly female (approximately 80%) and white (approximately 70%), and the mean duration of RA was approximately 8 years.

The study subjects were randomly assigned to receive 5-mg oral tofacitinib twice daily, 10-mg oral tofacitinib twice daily, subcutaneous adalimumab every 2 weeks, or placebo for either 3 months or 6 months. At 3 months, patients in the placebo group who showed an inadequate response were blindly switched to either 5-mg or 10-mg tofacitinib. At 6 months, all patients in the placebo group were blindly switched to 5-mg or 10-mg tofacitinib.

The three efficacy end points were the same as those in the ORAL-Solo study.

At 6 months, the percentages of patients who met criteria for an ACR 20 response were significantly higher with both doses of tofacitinib and with adalimumab than with placebo, and the magnitudes of the treatment effect were similar between tofacitinib and adalimumab (5-mg tofacitinib, 51.5%; 10-mg tofacitinib, 52.6%; adalimumab, 47.2%; placebo, 28.3%).

Similarly, the percentages of patients who showed significant improvement on both the HAQ-DI score and the DAS28-4(ESR) score were significantly higher with both tofacitinib and adalimumab than with placebo, Dr. van Vollenhoven and his colleagues said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1112072]).

As in the ORAL-Solo study, the treatment responses in the ORAL-Standard study were rapid and were sustained throughout the 1-year study period.

Also as in the ORAL-Solo study, serious adverse events – including serious infections such as tuberculosis – were significantly higher with tofacitinib than with either adalimumab or placebo. Notable adverse events included cytopenia, respiratory and urinary tract infections, and gastrointestinal side effects.

Tofacitinib also raised cholesterol and serum creatinine levels. "Given the duration and size of the study, the implications ... for the risk of cardiac events ... could not be assessed. Longer-term monitoring of patients receiving tofacitinib is ongoing," Dr. van Vollenhoven and his associates said.

Both studies were funded by Pfizer. The investigators reported numerous ties to industry sources.

Tofacitinib, an oral Janus kinase inhibitor that blocks signaling for several cytokines that are integral to lymphocyte function, was found to be effective as either a monotherapy or an adjunctive therapy in two industry-sponsored phase III studies of adults with refractory rheumatoid arthritis, which were reported separately online Aug. 9 in the New England Journal of Medicine.

Compared with placebo, two doses of tofacitinib induced clinically meaningful and statistically significant reductions in the signs and symptoms of RA, and improved physical function. However, the drug was no better than placebo at inducing remission.

In the first study, 611 patients who previously had an inadequate response or excess toxicity to at least one nonbiologic or biologic disease-modifying agent were treated for 6 months at 94 medical centers worldwide, said Dr. Roy Fleischmann of the Metroplex Clinical Research Center, Dallas, and his associates in the Oral Rheumatoid Arthritis–Solo (ORAL-Solo) trial.

The study subjects were randomly assigned to receive 5-mg tofacitinib twice daily for 6 months, 10-mg tofacitinib twice daily for 6 months, or placebo twice daily for 3 months followed by 5-mg or 10-mg tofacitinib for 3 months. They were permitted to continue on stable doses of antimalarials and to use NSAIDs and glucocorticoids if needed.

The mean patient age was approximately 50 years, and the mean duration of RA was approximately 8 years. In all, 67% of the subjects were white and 87% were women.

The first efficacy end point was the percentage of patients who met the criteria for an ACR 20 (American College of Rheumatology 20) response, defined as at least a 20% reduction in the number of tender and swollen joints and at least a 20% improvement in three of the following measures: pain, disability, C-reactive protein level, patient’s global assessment of disease, and physician’s global assessment of disease.

At 3 months, 59.8% of patients receiving 5-mg tofacitinib and 65.7% of those receiving 10-mg tofacitinib achieved this end point, a significantly higher percentage than the 26.7% receiving placebo, the investigators said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1109071]).

The second efficacy end point was the percentage of patients who showed improvement in physical function as measured by the HAQ-DI (Health Assessment Questionnaire–Disability Index). Again, significantly more patients in both tofacitinib groups showed significant improvement by week 2 and continued to improve throughout the study, compared with patients in the placebo group. At 3 months, the proportions were 52.9% with 5-mg tofacitinib and 55.7% with 10-mg tofacitinib, compared with 31.7% with placebo.

The third efficacy end point was the percentage of patients who showed significant improvement on the DAS28-4(ESR), a measure of disease activity that includes a 28-joint count and the erythrocyte sedimentation rate. Tofacitinib was not superior to placebo in this outcome measure. At 3 months, the percentage of patients with a DAS28-4(ESR) score less than 2.6, which indicates remission, was 5.6% with 5-mg tofacitinib, 8.7% with 10-mg tofacitinb, and 4.4% with placebo.

Serious adverse events were more common with both doses of tofacitinib than with placebo. Six patients developed seven serious infections, including cellulitis, liver abscess, bronchitis, pyelonephritis, one case of tuberculous pleural effusion in a patient from India, and one case of nondisseminated herpes zoster. Other serious adverse events included heart failure in two patients.

Nonserious adverse events occurred in approximately half of the study subjects, with similar frequencies across the treatment subgroups. In all, 12 patients (2%) discontinued the study drug because of adverse events during the first 3 months, and another 6 (1%) discontinued during the final 3 months of the study.

Neutropenia developed more frequently with the active treatment than with placebo. In addition, tofacitinib raised LDL cholesterol levels, liver aminotransferase levels, and serum creatinine levels.

In the second phase-III study, oral tofacitinib was compared against subcutaneous injections of adalimumab and placebo in 717 patients who were also taking stable doses of methotrexate. These subjects were treated at 115 medical centers worldwide for 1 year, said Dr. Ronald F. van Vollenhoven of the Karolinska Institute, Stockholm, and his associates in the Oral Rheumatoid Arthritis–Standard (ORAL-Standard) trial.

In this study, the patient population also was predominantly female (approximately 80%) and white (approximately 70%), and the mean duration of RA was approximately 8 years.

The study subjects were randomly assigned to receive 5-mg oral tofacitinib twice daily, 10-mg oral tofacitinib twice daily, subcutaneous adalimumab every 2 weeks, or placebo for either 3 months or 6 months. At 3 months, patients in the placebo group who showed an inadequate response were blindly switched to either 5-mg or 10-mg tofacitinib. At 6 months, all patients in the placebo group were blindly switched to 5-mg or 10-mg tofacitinib.

The three efficacy end points were the same as those in the ORAL-Solo study.

At 6 months, the percentages of patients who met criteria for an ACR 20 response were significantly higher with both doses of tofacitinib and with adalimumab than with placebo, and the magnitudes of the treatment effect were similar between tofacitinib and adalimumab (5-mg tofacitinib, 51.5%; 10-mg tofacitinib, 52.6%; adalimumab, 47.2%; placebo, 28.3%).

Similarly, the percentages of patients who showed significant improvement on both the HAQ-DI score and the DAS28-4(ESR) score were significantly higher with both tofacitinib and adalimumab than with placebo, Dr. van Vollenhoven and his colleagues said (N. Engl. J. Med. 2012 Aug. 9 [doi:10.1056/NEJMoa1112072]).

As in the ORAL-Solo study, the treatment responses in the ORAL-Standard study were rapid and were sustained throughout the 1-year study period.

Also as in the ORAL-Solo study, serious adverse events – including serious infections such as tuberculosis – were significantly higher with tofacitinib than with either adalimumab or placebo. Notable adverse events included cytopenia, respiratory and urinary tract infections, and gastrointestinal side effects.

Tofacitinib also raised cholesterol and serum creatinine levels. "Given the duration and size of the study, the implications ... for the risk of cardiac events ... could not be assessed. Longer-term monitoring of patients receiving tofacitinib is ongoing," Dr. van Vollenhoven and his associates said.

Both studies were funded by Pfizer. The investigators reported numerous ties to industry sources.

HOUSTON – Use of a gonadotropin-releasing hormone antagonist showed early promise as a novel therapy for rheumatoid arthritis in a brief, proof-of-concept study that was presented at the annual meeting of the Endocrine Society.

Five days of subcutaneous injections of cetrorelix (Cetrotide) that were aimed at rapidly reducing levels of luteinizing hormone and follicle-stimulating hormone safely improved signs and symptoms of RA and reduced tumor necrosis factor–alpha levels in a 99-patient, placebo-controlled, randomized trial. Larger and longer-term clinical trials of GnRH antagonists as a potential treatment for RA are planned, according to Dr. Anita Kass of Betanien Hospital in Skien, Norway.

All study participants had active RA and were on stable doses of disease-modifying antirheumatic drugs. They were randomized to placebo or subcutaneous cetrorelix dosed at 5 mg on days 1-3 and 3 mg on days 4-5.

Outcomes were assessed on day 5, when LH and FSH levels in the cetrorelix arm were at their nadir. At that time, an ACR 20 (American College of Rheumatology scale, based on a 20% improvement in specified criteria) response was documented in 40% of patients on cetrorelix, compared with 18% of controls. Remission according to the DAS28 (Disease Activity Score, including a 28-joint count) was achieved in 13% of patients on the GnRH antagonist, compared with none on placebo. The erythrocyte sedimentation rate had declined by a mean of 1.06 mm/hour, compared with baseline, in the active treatment group, compared with a 5.04-mm/hour increase in controls.

In addition, the cetrorelix group had a mean 0.58 log pg/mL decrease in TNF-alpha compared with baseline, whereas controls experienced a 0.02 log pg/mL reduction. All of these differences between the cetrorelix and control groups were statistically significant.

The reduction in DAS28 score by day 5 was 0.82 in the cetrorelix group and 0.57 in controls, a trend that didn’t reach significance.

Adverse events in the two study arms did not differ.

Dr. Kass credited the impetus for this line of clinical investigation to earlier work by other investigators at the Weizmann Institute of Science in Rehovot, Israel. They showed that GnRH and GnRH-II are produced by T cells, and that the hormones have roles that extend beyond the reproductive system to include immune system regulation. The hormones trigger T-cell chemotaxis and homing to specific organs (Nat. Med. 2002;8:1421-6).

This proof-of-concept study was supported by the Norwegian Health and Rehabilitation Organization. The presenter reported having no financial conflicts.

HOUSTON – Use of a gonadotropin-releasing hormone antagonist showed early promise as a novel therapy for rheumatoid arthritis in a brief, proof-of-concept study that was presented at the annual meeting of the Endocrine Society.

Five days of subcutaneous injections of cetrorelix (Cetrotide) that were aimed at rapidly reducing levels of luteinizing hormone and follicle-stimulating hormone safely improved signs and symptoms of RA and reduced tumor necrosis factor–alpha levels in a 99-patient, placebo-controlled, randomized trial. Larger and longer-term clinical trials of GnRH antagonists as a potential treatment for RA are planned, according to Dr. Anita Kass of Betanien Hospital in Skien, Norway.

All study participants had active RA and were on stable doses of disease-modifying antirheumatic drugs. They were randomized to placebo or subcutaneous cetrorelix dosed at 5 mg on days 1-3 and 3 mg on days 4-5.

Outcomes were assessed on day 5, when LH and FSH levels in the cetrorelix arm were at their nadir. At that time, an ACR 20 (American College of Rheumatology scale, based on a 20% improvement in specified criteria) response was documented in 40% of patients on cetrorelix, compared with 18% of controls. Remission according to the DAS28 (Disease Activity Score, including a 28-joint count) was achieved in 13% of patients on the GnRH antagonist, compared with none on placebo. The erythrocyte sedimentation rate had declined by a mean of 1.06 mm/hour, compared with baseline, in the active treatment group, compared with a 5.04-mm/hour increase in controls.

In addition, the cetrorelix group had a mean 0.58 log pg/mL decrease in TNF-alpha compared with baseline, whereas controls experienced a 0.02 log pg/mL reduction. All of these differences between the cetrorelix and control groups were statistically significant.

The reduction in DAS28 score by day 5 was 0.82 in the cetrorelix group and 0.57 in controls, a trend that didn’t reach significance.

Adverse events in the two study arms did not differ.

Dr. Kass credited the impetus for this line of clinical investigation to earlier work by other investigators at the Weizmann Institute of Science in Rehovot, Israel. They showed that GnRH and GnRH-II are produced by T cells, and that the hormones have roles that extend beyond the reproductive system to include immune system regulation. The hormones trigger T-cell chemotaxis and homing to specific organs (Nat. Med. 2002;8:1421-6).

This proof-of-concept study was supported by the Norwegian Health and Rehabilitation Organization. The presenter reported having no financial conflicts.

HOUSTON – Use of a gonadotropin-releasing hormone antagonist showed early promise as a novel therapy for rheumatoid arthritis in a brief, proof-of-concept study that was presented at the annual meeting of the Endocrine Society.

Five days of subcutaneous injections of cetrorelix (Cetrotide) that were aimed at rapidly reducing levels of luteinizing hormone and follicle-stimulating hormone safely improved signs and symptoms of RA and reduced tumor necrosis factor–alpha levels in a 99-patient, placebo-controlled, randomized trial. Larger and longer-term clinical trials of GnRH antagonists as a potential treatment for RA are planned, according to Dr. Anita Kass of Betanien Hospital in Skien, Norway.

All study participants had active RA and were on stable doses of disease-modifying antirheumatic drugs. They were randomized to placebo or subcutaneous cetrorelix dosed at 5 mg on days 1-3 and 3 mg on days 4-5.

Outcomes were assessed on day 5, when LH and FSH levels in the cetrorelix arm were at their nadir. At that time, an ACR 20 (American College of Rheumatology scale, based on a 20% improvement in specified criteria) response was documented in 40% of patients on cetrorelix, compared with 18% of controls. Remission according to the DAS28 (Disease Activity Score, including a 28-joint count) was achieved in 13% of patients on the GnRH antagonist, compared with none on placebo. The erythrocyte sedimentation rate had declined by a mean of 1.06 mm/hour, compared with baseline, in the active treatment group, compared with a 5.04-mm/hour increase in controls.

In addition, the cetrorelix group had a mean 0.58 log pg/mL decrease in TNF-alpha compared with baseline, whereas controls experienced a 0.02 log pg/mL reduction. All of these differences between the cetrorelix and control groups were statistically significant.

The reduction in DAS28 score by day 5 was 0.82 in the cetrorelix group and 0.57 in controls, a trend that didn’t reach significance.

Adverse events in the two study arms did not differ.

Dr. Kass credited the impetus for this line of clinical investigation to earlier work by other investigators at the Weizmann Institute of Science in Rehovot, Israel. They showed that GnRH and GnRH-II are produced by T cells, and that the hormones have roles that extend beyond the reproductive system to include immune system regulation. The hormones trigger T-cell chemotaxis and homing to specific organs (Nat. Med. 2002;8:1421-6).

This proof-of-concept study was supported by the Norwegian Health and Rehabilitation Organization. The presenter reported having no financial conflicts.

BERLIN – Rheumatoid arthritis patients who respond favorably to a first course of rituximab and later need retreatment do as well with a follow-up single 1-g intravenous infusion as with the approved dosing regimen consisting of two 1-g infusions given 2 weeks apart, according to a randomized trial presented at the annual European Congress of Rheumatology.

The study findings point the way to a simpler, less costly, and more patient friendly dosing regimen than the one now contained in the product labeling, noted Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Paris.

He presented data from a 2-year, prospective, multicenter, randomized, controlled trial involving 224 patients with moderate to severe RA that was inadequately responsive to antitumor necrosis factor–alpha therapy. All the study subjects had received a first induction cycle of rituximab (Rituxan) at the approved dosage of two 1-g intravenous infusions delivered 2 weeks apart.

The good or moderate response rate at 6 months by EULAR (European League Against Rheumatism) criteria was 71%. At that point, 100 responders were randomized to either open-label retreatment with the licensed regimen of two 1-g infusions 2 weeks apart or the investigational dose consisting of a single 1-g infusion.

Participants were reassessed for disease activity every 8 weeks. Additional retreatment with the assigned regimen was carried out as warranted by return of active RA, defined as a DAS28 (disease activity score based on a 28-joint count) greater than 3.2), as long as at least 6 months had elapsed since the last course of treatment.

The primary study end point was the area under the curve for the DAS28-CRP (C-reactive protein) score at week 104. It averaged 2,761 in the single-infusion retreatment group and was similar at 2,666 in the standard retreatment group, demonstrating the noninferiority of the investigational retreatment regimen.

The median time to a second retreatment was 263 days in the single-infusion group and similar at 255 days in the two-infusion group.

The safety profiles were comparable. Serious adverse events occurred in 29% of single-infusion retreatment patients over the course of the 2-year study, compared with 37% of those who received the approved two-infusion regimen. In all, 2% of patients in the single-infusion group had an IgG level less than 6.82 g/L (the lower limit of normal) at the 2-year mark, compared with 11% in the twin-infusion arm.

The serious infection rate was 7.2 per 100 person-years in the single-infusion group and 1.5 per 100 person-years in those retreated with two 1-g infusions 2 weeks apart.

A caveat regarding this study is that the radiographic or structural effect of the two retreatment strategies wasn’t assessed, the rheumatologist observed.

This clinical trial was supported by Roche. The presenter reported having received research grant support from the sponsor to conduct the study.

BERLIN – Rheumatoid arthritis patients who respond favorably to a first course of rituximab and later need retreatment do as well with a follow-up single 1-g intravenous infusion as with the approved dosing regimen consisting of two 1-g infusions given 2 weeks apart, according to a randomized trial presented at the annual European Congress of Rheumatology.

The study findings point the way to a simpler, less costly, and more patient friendly dosing regimen than the one now contained in the product labeling, noted Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Paris.

He presented data from a 2-year, prospective, multicenter, randomized, controlled trial involving 224 patients with moderate to severe RA that was inadequately responsive to antitumor necrosis factor–alpha therapy. All the study subjects had received a first induction cycle of rituximab (Rituxan) at the approved dosage of two 1-g intravenous infusions delivered 2 weeks apart.

The good or moderate response rate at 6 months by EULAR (European League Against Rheumatism) criteria was 71%. At that point, 100 responders were randomized to either open-label retreatment with the licensed regimen of two 1-g infusions 2 weeks apart or the investigational dose consisting of a single 1-g infusion.

Participants were reassessed for disease activity every 8 weeks. Additional retreatment with the assigned regimen was carried out as warranted by return of active RA, defined as a DAS28 (disease activity score based on a 28-joint count) greater than 3.2), as long as at least 6 months had elapsed since the last course of treatment.

The primary study end point was the area under the curve for the DAS28-CRP (C-reactive protein) score at week 104. It averaged 2,761 in the single-infusion retreatment group and was similar at 2,666 in the standard retreatment group, demonstrating the noninferiority of the investigational retreatment regimen.

The median time to a second retreatment was 263 days in the single-infusion group and similar at 255 days in the two-infusion group.

The safety profiles were comparable. Serious adverse events occurred in 29% of single-infusion retreatment patients over the course of the 2-year study, compared with 37% of those who received the approved two-infusion regimen. In all, 2% of patients in the single-infusion group had an IgG level less than 6.82 g/L (the lower limit of normal) at the 2-year mark, compared with 11% in the twin-infusion arm.

The serious infection rate was 7.2 per 100 person-years in the single-infusion group and 1.5 per 100 person-years in those retreated with two 1-g infusions 2 weeks apart.

A caveat regarding this study is that the radiographic or structural effect of the two retreatment strategies wasn’t assessed, the rheumatologist observed.

This clinical trial was supported by Roche. The presenter reported having received research grant support from the sponsor to conduct the study.

BERLIN – Rheumatoid arthritis patients who respond favorably to a first course of rituximab and later need retreatment do as well with a follow-up single 1-g intravenous infusion as with the approved dosing regimen consisting of two 1-g infusions given 2 weeks apart, according to a randomized trial presented at the annual European Congress of Rheumatology.

The study findings point the way to a simpler, less costly, and more patient friendly dosing regimen than the one now contained in the product labeling, noted Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Paris.

He presented data from a 2-year, prospective, multicenter, randomized, controlled trial involving 224 patients with moderate to severe RA that was inadequately responsive to antitumor necrosis factor–alpha therapy. All the study subjects had received a first induction cycle of rituximab (Rituxan) at the approved dosage of two 1-g intravenous infusions delivered 2 weeks apart.

The good or moderate response rate at 6 months by EULAR (European League Against Rheumatism) criteria was 71%. At that point, 100 responders were randomized to either open-label retreatment with the licensed regimen of two 1-g infusions 2 weeks apart or the investigational dose consisting of a single 1-g infusion.

Participants were reassessed for disease activity every 8 weeks. Additional retreatment with the assigned regimen was carried out as warranted by return of active RA, defined as a DAS28 (disease activity score based on a 28-joint count) greater than 3.2), as long as at least 6 months had elapsed since the last course of treatment.

The primary study end point was the area under the curve for the DAS28-CRP (C-reactive protein) score at week 104. It averaged 2,761 in the single-infusion retreatment group and was similar at 2,666 in the standard retreatment group, demonstrating the noninferiority of the investigational retreatment regimen.

The median time to a second retreatment was 263 days in the single-infusion group and similar at 255 days in the two-infusion group.

The safety profiles were comparable. Serious adverse events occurred in 29% of single-infusion retreatment patients over the course of the 2-year study, compared with 37% of those who received the approved two-infusion regimen. In all, 2% of patients in the single-infusion group had an IgG level less than 6.82 g/L (the lower limit of normal) at the 2-year mark, compared with 11% in the twin-infusion arm.

The serious infection rate was 7.2 per 100 person-years in the single-infusion group and 1.5 per 100 person-years in those retreated with two 1-g infusions 2 weeks apart.

A caveat regarding this study is that the radiographic or structural effect of the two retreatment strategies wasn’t assessed, the rheumatologist observed.

This clinical trial was supported by Roche. The presenter reported having received research grant support from the sponsor to conduct the study.

BERLIN – Multiple tooth loss appears to be a marker for increased risk of subsequent rheumatoid arthritis – and the more missing teeth, the higher the arthritis disease activity and the worse the treatment response, according to studies presented at the annual European Congress of Rheumatology.

Tooth loss is considered a surrogate marker for periodontitis, a common chronic inflammatory process involving the gums and other tooth-supporting structures. Investigators are increasingly interested in exploring a possible causal relationship between this oral disease and chronic diseases elsewhere in the body having a prominent systemic inflammatory component, including coronary artery disease and rheumatoid arthritis (RA).

Dr. Gisela Westhoff reported on 540 patients with early arthritis participating in the ongoing observational CAPEA (Course and Prognosis of Early Arthritis) study. Patients averaged 56 years of age, with a mean symptom duration of 13 weeks at enrollment. A total of 59% were negative for rheumatoid factor and/or positive for anti–citrullinated protein antibody, 67% met current diagnostic criteria for RA, and 87% were on disease-modifying antirheumatic drugs.

At 6 months, 52% of the patients achieved a good response to treatment according to EULAR response criteria. Another 32% had a moderate response, and 16% had no response.

Patients had a mean of 19 teeth at enrollment. In all, 24% of subjects had 10 or fewer teeth, 15% had 11-20, and 22% had 28 or more teeth. Patients missing teeth tended to be older, heavier, and smokers. At 6 months of follow-up, those with 10 or fewer teeth had a significantly greater erythrocyte sedimentation rate, higher tender and swollen joint counts, and a higher Disease Activity Score-28 than did those with more than 10 teeth.

In a multivariate analysis adjusted for age, body mass index, and other potential confounders, patients with 10 or fewer teeth at baseline were 3.8 times as likely to have an insufficient treatment response as those with at least 28 teeth. The only other significant predictor of poor therapeutic response was smoking, which was associated with a 1.7-fold increased likelihood, noted Dr. Westhoff of the German Rheumatism Research Center in Berlin.

In a separate presentation, Dr. Axel Finckh of University Hospital, Geneva, reported that tooth loss was associated with swollen joints in a group of healthy individuals at increased risk of developing RA.

He presented data from an ongoing prospective observational study of 366 first-degree relatives of patients with RA. All were healthy at enrollment, at which time they had a mean of 28 teeth. Six percent had 20 or fewer teeth, 20% had 21-27, and 28% had a full complement of 32 teeth.

Subjects with one or more swollen joints on physical examination had an average of 26 teeth, compared with 29 teeth for those with no swollen joints. In a multivariate analysis, patients with less than 20 teeth were at 8.1-fold greater risk of having at least one swollen joint than those with 32 teeth. Individuals with 20-28 teeth were at 4.1-fold increased likelihood, while those with 28-31 teeth were at 3.6-fold increased risk.

Moreover, participants with less than 20 teeth had an adjusted 5.3-fold increased likelihood of having morning stiffness lasting more than 1 hour for at least 6 weeks than subjects with 32 teeth.

This study was sponsored by the Swiss League Against Rheumatism. Neither Dr. Finckh nor Dr. Westhoff reported having any financial conflicts.

BERLIN – Multiple tooth loss appears to be a marker for increased risk of subsequent rheumatoid arthritis – and the more missing teeth, the higher the arthritis disease activity and the worse the treatment response, according to studies presented at the annual European Congress of Rheumatology.

Tooth loss is considered a surrogate marker for periodontitis, a common chronic inflammatory process involving the gums and other tooth-supporting structures. Investigators are increasingly interested in exploring a possible causal relationship between this oral disease and chronic diseases elsewhere in the body having a prominent systemic inflammatory component, including coronary artery disease and rheumatoid arthritis (RA).

Dr. Gisela Westhoff reported on 540 patients with early arthritis participating in the ongoing observational CAPEA (Course and Prognosis of Early Arthritis) study. Patients averaged 56 years of age, with a mean symptom duration of 13 weeks at enrollment. A total of 59% were negative for rheumatoid factor and/or positive for anti–citrullinated protein antibody, 67% met current diagnostic criteria for RA, and 87% were on disease-modifying antirheumatic drugs.

At 6 months, 52% of the patients achieved a good response to treatment according to EULAR response criteria. Another 32% had a moderate response, and 16% had no response.

Patients had a mean of 19 teeth at enrollment. In all, 24% of subjects had 10 or fewer teeth, 15% had 11-20, and 22% had 28 or more teeth. Patients missing teeth tended to be older, heavier, and smokers. At 6 months of follow-up, those with 10 or fewer teeth had a significantly greater erythrocyte sedimentation rate, higher tender and swollen joint counts, and a higher Disease Activity Score-28 than did those with more than 10 teeth.

In a multivariate analysis adjusted for age, body mass index, and other potential confounders, patients with 10 or fewer teeth at baseline were 3.8 times as likely to have an insufficient treatment response as those with at least 28 teeth. The only other significant predictor of poor therapeutic response was smoking, which was associated with a 1.7-fold increased likelihood, noted Dr. Westhoff of the German Rheumatism Research Center in Berlin.

In a separate presentation, Dr. Axel Finckh of University Hospital, Geneva, reported that tooth loss was associated with swollen joints in a group of healthy individuals at increased risk of developing RA.

He presented data from an ongoing prospective observational study of 366 first-degree relatives of patients with RA. All were healthy at enrollment, at which time they had a mean of 28 teeth. Six percent had 20 or fewer teeth, 20% had 21-27, and 28% had a full complement of 32 teeth.

Subjects with one or more swollen joints on physical examination had an average of 26 teeth, compared with 29 teeth for those with no swollen joints. In a multivariate analysis, patients with less than 20 teeth were at 8.1-fold greater risk of having at least one swollen joint than those with 32 teeth. Individuals with 20-28 teeth were at 4.1-fold increased likelihood, while those with 28-31 teeth were at 3.6-fold increased risk.

Moreover, participants with less than 20 teeth had an adjusted 5.3-fold increased likelihood of having morning stiffness lasting more than 1 hour for at least 6 weeks than subjects with 32 teeth.

This study was sponsored by the Swiss League Against Rheumatism. Neither Dr. Finckh nor Dr. Westhoff reported having any financial conflicts.

BERLIN – Multiple tooth loss appears to be a marker for increased risk of subsequent rheumatoid arthritis – and the more missing teeth, the higher the arthritis disease activity and the worse the treatment response, according to studies presented at the annual European Congress of Rheumatology.

Tooth loss is considered a surrogate marker for periodontitis, a common chronic inflammatory process involving the gums and other tooth-supporting structures. Investigators are increasingly interested in exploring a possible causal relationship between this oral disease and chronic diseases elsewhere in the body having a prominent systemic inflammatory component, including coronary artery disease and rheumatoid arthritis (RA).

Dr. Gisela Westhoff reported on 540 patients with early arthritis participating in the ongoing observational CAPEA (Course and Prognosis of Early Arthritis) study. Patients averaged 56 years of age, with a mean symptom duration of 13 weeks at enrollment. A total of 59% were negative for rheumatoid factor and/or positive for anti–citrullinated protein antibody, 67% met current diagnostic criteria for RA, and 87% were on disease-modifying antirheumatic drugs.

At 6 months, 52% of the patients achieved a good response to treatment according to EULAR response criteria. Another 32% had a moderate response, and 16% had no response.

Patients had a mean of 19 teeth at enrollment. In all, 24% of subjects had 10 or fewer teeth, 15% had 11-20, and 22% had 28 or more teeth. Patients missing teeth tended to be older, heavier, and smokers. At 6 months of follow-up, those with 10 or fewer teeth had a significantly greater erythrocyte sedimentation rate, higher tender and swollen joint counts, and a higher Disease Activity Score-28 than did those with more than 10 teeth.

In a multivariate analysis adjusted for age, body mass index, and other potential confounders, patients with 10 or fewer teeth at baseline were 3.8 times as likely to have an insufficient treatment response as those with at least 28 teeth. The only other significant predictor of poor therapeutic response was smoking, which was associated with a 1.7-fold increased likelihood, noted Dr. Westhoff of the German Rheumatism Research Center in Berlin.

In a separate presentation, Dr. Axel Finckh of University Hospital, Geneva, reported that tooth loss was associated with swollen joints in a group of healthy individuals at increased risk of developing RA.

He presented data from an ongoing prospective observational study of 366 first-degree relatives of patients with RA. All were healthy at enrollment, at which time they had a mean of 28 teeth. Six percent had 20 or fewer teeth, 20% had 21-27, and 28% had a full complement of 32 teeth.

Subjects with one or more swollen joints on physical examination had an average of 26 teeth, compared with 29 teeth for those with no swollen joints. In a multivariate analysis, patients with less than 20 teeth were at 8.1-fold greater risk of having at least one swollen joint than those with 32 teeth. Individuals with 20-28 teeth were at 4.1-fold increased likelihood, while those with 28-31 teeth were at 3.6-fold increased risk.

Moreover, participants with less than 20 teeth had an adjusted 5.3-fold increased likelihood of having morning stiffness lasting more than 1 hour for at least 6 weeks than subjects with 32 teeth.

This study was sponsored by the Swiss League Against Rheumatism. Neither Dr. Finckh nor Dr. Westhoff reported having any financial conflicts.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.

Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.

Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.

Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.

Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.

According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).

Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.

Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.

Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.

The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).

"The level of total pain is comparable no matter which of the groups a patient falls into," he said.

Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.

Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.

BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.

Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.

Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.

Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.

Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.

According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).

Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.

Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.

Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.

The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).

"The level of total pain is comparable no matter which of the groups a patient falls into," he said.

Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.

Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.

BERLIN – Patients with nonradiographic axial spondyloarthritis should be treated as aggressively as patients with ankylosing spondylitis, as the burden of disease is comparable based on clinical disease activity measures, pain levels, and global assessment scores.

Using data from registries and randomized controlled trials, Dr. Joachim Sieper, head of the medical clinic of rheumatology at the Benjamin Franklin University Clinic, Charité Medical University Berlin, compared disease burden in the two patient groups. "The question arises as to whether patients in the earlier phase of disease have a similar level of disease activity, pain, and stiffness as later-stage patients with ankylosing spondylitis," he said at the annual European Congress of Rheumatology.

Dr. Sieper explained that it is known that a delay exists between the onset of symptoms and the final diagnosis of ankylosing spondylitis (AS). Data from the ABILITY 1 trial showed that time to diagnosis was delayed by a mean of 7.2 years in patients with nonradiographic axial spondyloarthritis.

Even when patients have symptoms, diagnosis can take several years, suggesting that referral needs to be considered earlier in patients presenting with symptoms.

Before the onset of structural damage, a diagnosis can be made on the basis of an MRI scan that shows bone inflammation, he explained. "However, we also know that MRI can have limited sensitivity, so we might miss some patients." It is possible, however, to classify these patients on the basis of clinical findings.

According to the new ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axial spondyloarthritis, patients can be divided into those who have already developed radiographic damage as seen in the sacroiliac joints on x-ray, termed AS patients, and those who do not yet have structural damage, termed nonradiographic axial spondyloarthritis (nr axSpA) patients, who require MRI or clinical parameters for diagnosis (Best Pract. Res. Clin. Rheumatol. 2012;26:135-45).

Dr. Sieper analyzed baseline disease activity data derived from spondyloarthritis registries and randomized controlled trials to determine the extent of disease burden between the two classifications of axial SpA patients.

Analysis showed that the ages of patients between the two groups were similar across the databases, at around 35-40 years, as were the levels of human leukocyte antigen-B27 (HLA-B27) positivity. The ratio of females was higher in patients with nr axSpA (around 60%) than in patients with established AS (around 25%). "This is probably because females develop structural damage later, but they still have a similar level of inflammation all the time," he pointed out.

Scores on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) hovered at 6.3-6.5 in both groups. Pain level and patient global assessment were similar in the two groups, according to the registry data and a randomized controlled trial.

The proportion of abnormal C-reactive protein levels was higher in the AS patients than in the nr axSpA patients (68% vs. 36%-38%, depending on the trial).

"The level of total pain is comparable no matter which of the groups a patient falls into," he said.

Nor were there differences between the groups in terms of patient and physician global assessment scores. The Patient’s Global Assessment of Disease Activity on a 0-10 visual analog scale was 5.0 for AS patients and 4.9 for nr axSpA patients, according to one trial.

Dr. Sieper disclosed ties with Abbott, Merck, Pfizer, and UCB.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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