Measures of RA Progression Remain Flawed Predictors of Outcomes

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.

CHICAGO – The disease activity score outcome in rheumatoid arthritis should be used with caution as a treatment target when the clinical aim is to prevent radiographic progression. The DAS may show that a patient is in remission when in fact the disease is still active.

The van der Heijde/Sharp score is also flawed in that the total mean change is less meaningful than is the probability of progression of rheumatoid arthritis (RA) and may be misleading, said Dr. Edward Keystone.

"The change in the mean Sharp score point is of some importance, but not nearly as important as the proportion of people who are progressing, or those particularly rapid progressors," said Dr. Keystone, professor of medicine at the University of Toronto. In general, a large change in Sharp score points is needed to reduce physical function, noting that a change in 2 points per year will be significant over a decade, he said.

"If you change by 3 [points] a year, in 10 years you’re going to have disability."

Joint space narrowing may be more predictive than are erosions of radiographic progression. "Most methotrexate-inadequate responders, despite the fact that they’re clinically active, may still have less radiographic progression," Dr. Keystone said at the Midwest Rheumatology Summit.

"So how good is methotrexate, in patients failing methotrexate?" he said. "That’s the question."

Remission is the clinical target in RA, but its measurement is complex. True remission is a state of low-disease activity in patients who are not progressing, said Dr. Keystone. Unfortunately, there is dissociation between clinical and radiographic outcomes, and radiographic progression may occur in patients in clinical remission. Patients with active disease may likewise not progress radiographically.

The composite indices defining remission allow for a significant degree of clinical synovitis, and residual synovitis detected with sensitive imaging might explain the progression in structural damage, even in clinical remission (Arthritis Rheum. 2006;4:3761-73).

Joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ.

As for patients with clinical disease activity who do not progress radiographically, Dr. Keystone said that the concept comes from the ACR 20 nonresponders.

"People who do not make an ACR 20 are still responders," said Dr. Keystone. It’s the difference in patient-derived vs. physician-derived outcomes, he said. In established disease, ACR 20 nonresponders to biologics do not seem to progress radiographically but may still improve.

"Why do most people not achieve an ACR 20? It’s not the swollen and tender joint. It’s usually the patient-derived outcome. ... That’s the problem: The patient says ‘I’m not better.’ Therefore when you look at the ACR 20 data, he’s a nonresponder."

Early disease can present conundrums as well.

In the PREMIER study, methotrexate was clinically identical to monotherapy adalimumab. Nevertheless, a 10-point Sharp score change was observed with methotrexate alone, vs. a 5-point Sharp score change with adalimumab monotherapy (Arthritis Rheum. 2006;54:26-37).

"Clinically, they looked alike, but radiographically, adalimumab monotherapy was much better in reducing the Sharp score." However, he said, the mean change in total Sharp score reflects the Total Sharp Score change only of those patients progressing. "And rheumatologists make decisions on the basis of probability, not mean change in [total Sharp score]," he said. The mean change in total Sharp score means less than the probability of progression, and may lead you astray, he said.

The 52-week results from the JESMR (Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan) study found that combination therapy of etanercept plus methotrexate resulted in better clinical and radiographic outcomes than etanercept monotherapy, even in patients with active rheumatoid arthritis and despite methotrexate treatment. (Rheumatology 2011;38:1585-92). This led to the conclusion that methotrexate should be continued at the commencement of etanercept therapy even in patients with rheumatoid arthritis who showed an inappropriate response to methotrexate as demonstrated by changes in radiographic progression.

However, only four patients were rapid progressors, said Dr. Keystone, leading him to conclude that it may not be so bad to stop methotrexate, because the probability of being a rapid progressor is not very high.

In early rheumatoid arthritis, radiographic progression influences disability in a short time, according to results of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) (Ann. Rheum. Dis. 2008;67:1267-70).

The PREMIER study found a relationship between structural damage, as reflected in the total Sharp score and disability, as measured by the Health Assessment Questionnaire (HAQ) (J. Rheumatol. 2010;37:2237-46). The trial quantified the meaning of progression of joint damage to physical function in early rheumatoid arthritis as a noticeable change in physical function would occur with an approximate 100-unit change in total Sharp score.

Radiographic progression results in disability early in disease, said Dr. Keystone, but a substantial change in total Sharp score is needed to have a noticeable change in physical function in both early and established disease.

Furthermore, joint space narrowing is more predictive of disability than erosion, as demonstrated by the 5-year HAQ (Rheumatology 2004;43:79-84).

"Joint space narrowing determines unemployment," said Dr. Keystone. It has a greater effect than do erosions on disability.

Finally, he said that timing of response is predictive of long-term outcome. The disease state achieved at 12 weeks is a predictor of long-term outcome. The U.S. is the last country in the world to adopt Treat to Target, as described in the EULAR treatment recommendations (Ann. Rheum. Dis. 2010;69:964-75).

It is not just the target achieved, it\'s the time to reach the target that’s important, said Dr. Keystone.

"People who have a lot of pain, a lot of disability at baseline, they often take longer than people who are in the lower disease state. And it’s patient-derived outcomes that made the difference," said Dr. Keystone. "The sicker you are, the worse you are in terms of what the difference or the cost of delay is."

The Foundation for Osteoporosis Research and Education, a CME accredited provider, acknowledged commercial support for this meeting from Abbott, Amgen, Centocor, Genentech, Human Genome Science, and UCB. Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.