Induction-Maintenance Treatment Succeeds in Early RA

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.

LONDON – An induction and maintenance treatment model works well for many patients with rheumatoid arthritis who start on potent, combined therapy very early in the course of their disease, based on 78-week follow-up of more than 200 patients in a randomized, controlled study.

The results showed that most patients who, within a few months of their onset of RA, began a regimen that combined the tumor necrosis factor (TNF) inhibitor adalimumab with methotrexate and who then reached a low level of disease activity after 22-26 weeks on the combined regimen could then switch to methotrexate monotherapy and remain at a low disease-activity state for the following year, Dr. Paul Emery and his associates reported in a poster at the annual European Congress of Rheumatology. Nearly half of the patients who began on the adalimumab plus methotrexate regimen reached a low disease activity state after 26 weeks.

The finding has important implications for the necessary duration of treatment with a TNF inhibitor, a member of the expensive class of biologic RA drugs.

"The key finding is that if you start patients on a biologic drug first, they do not take the biologic for life. You can probably stop [the biologic] in the majority of patients. The key is to treat patients when their disease is still completely reversible, hit them as hard as you can safely, and then hope to withdraw the biologic and [still] have a profound effect" on their disease that would not be possible if the biologic treatment was withheld until later, Dr. Emery said in an interview.

"It is an oncologic approach of induction and maintenance. The usual paradigm has been to use the cheap drugs" (disease-modifying antirheumatic drugs like methotrexate) first, and then, for the patients who failed to respond, to treat with a TNF inhibitor. But that approach delays treatment with the biologic until later in the course of RA. And at that point, withdrawal of the TNF inhibitor is harder because patients would then be left on just the drug (methotrexate) to which they had already failed to respond, he said.

Further analysis of the data collected in this study also holds the promise of finding demographic or clinical features to identify the patients who would best respond to initial combined therapy with a TNF inhibitor and methotrexate, followed by withdrawal of the biologic drug.

"We could use biomarkers to personalize [treatment], to target this approach to patients" who will likely succeed with induction and maintenance, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal medicine at the University of Leeds (England). He plans to "define the subpopulation of very early RA patients who are capable of achieving and sustaining optimal therapeutic outcomes with early initiation of adalimumab and methotrexate, followed by biologic-free treatment.

Additional related issues that require further study include identifying what is the maximum level of disease activity that patients can have at the end of TNF-inhibitor treatment and still remain in a state of low disease activity. Another issue is whether patients who have disease recurrence when they are switched from combined treatment to methotrexate monotherapy can then restart the TNF inhibitor and still have a good response the second time.

The new analysis used data that were collected in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab Combination Therapy in Patients with Early RA) trial, conducted at 175 sites in 20 countries worldwide, including more than 50 U.S. centers. Between December 2006 and September 2010, the investigators randomized 1,032 patients with recently diagnosed RA to treatment with either adalimumab plus methotrexate or placebo plus methotrexate. Researchers administered 40 mg adalimumab once every other week, and they titrated methotrexate to a maximum dosage of 20 mg/week.

The analysis reported by Dr. Emery and his associates focused on patients who initially received the combined active treatment. Within that treatment group, they selected the 44% of patients who, at week 22-26, achieved a state of low disease activity, defined as a DAS28 (disease activity score based on a 28-joint count) less than 3.2. They randomized 102 of these patients to continue on methotrexate monotherapy and 105 patients to remain on combined therapy with methotrexate and adalimumab. These patients averaged 50 years of age, nearly three-quarters were women, 90% were white, and, at the time they entered the study, they had been diagnosed with RA for an average of 4 months.

The study’s primary end point was a DAS28-CRP (based on C-reactive protein) score of less than 3.2, and radiographic changes on the modified total Sharp score of 0.5 or less at week 78 of the study, after spending 1 year on the randomized, maintenance therapies. The percentage of patients who met this criterion was 55% in those who were treated with methotrexate monotherapy for 1 year and 70% among those who were kept on the dual regimen, a statistically significant difference.

But other, less stringent measures of disease activity showed fairly good maintenance with methotrexate monotherapy. For example, the percentage of patients at 78 weeks with low disease activity based on a DAS28-CRP score of less than 3.2 was 81% in the methotrexate monotherapy group and 91% among the patients on both active drugs. Of the patients on methotrexate alone, 84% had an SDAI (Simplified Disease Activity Index) of 11 or less at 78 weeks, as did 92% of those on methotrexate plus adalimumab. There was no radiographic progression in 81% of the patients in the monotherapy arm at 78 weeks and in 89% of the patients on both drugs. An ACR 50 (American College of Rheumatology scale showing a 50% improvement) response was recorded at 78 weeks in 80% of patients on methotrexate only and in 89% of patients on methotrexate plus adalimumab.

"On the whole, patients on methotrexate [monotherapy] did extremely well and maintained their responses," Dr. Emery said. These are "the first global, randomized, controlled data on discontinuation of a TNF inhibitor after successful achievement of stable, low disease activity. The data suggest that for a large proportion of very early RA patients, a 26-week course of adalimumab and methotrexate, followed by 52 weeks of methotrexate monotherapy, may be a viable option to allow for the achievement of good outcomes."

The study is funded by Abbott, the company that markets adalimumab (Humira). Dr. Emery said that he has received research support from and has been a consultant to Abbott, Bristol-Myers Squibb, Merck, Pfizer, and Roche.