Remission Entrenched as RA Management Goal

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.

Remission has become an accepted goal in the management of rheumatoid arthritis, but its definition remains in flux.

About a year ago, a panel assembled jointly by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published two provisional definitions of remission in rheumatoid arthritis (RA) for clinical trials: a Simplified Disease Activity Index (SDAI) score of 3.3 or less; or no more than 1 tender and 1 swollen on a 28-joint examination, a C reactive protein (CRP) level of 1 mg/dL or less, and a patient global assessment score of 1 or less on a 0-10 scale (Arthritis Rheum. 2011;63:573-86; Ann. Rheum. Dis. 2011;70:404-13).

The ACR/EULAR panel explicitly said that their definitions of remission were intended for use only in clinical trials for the time being, and the group did not yet endorse their use in routine clinical practice, in part because the definitions had not yet been tested in that setting, and in part because in clinical practice data on acute phase reactants, such as CRP, "are frequently not immediately available."

Dr. David T. Felson, professor of medicine and epidemiology at Boston University as well as first author on the ACR/EULAR remission paper, noted in an interview that "We studied data from clinical trials to develop these remission criteria, and trial patients are not generalizable to those in practice, nor are their assessments as comprehensive."

But even with the new definitions not formally designed for routine practice, their designation by a combined ACR and EULAR panel appears to have helped solidify remission as the benchmark goal for management of most RA patients, capping a decade-long trend. It’s already well accepted that remission is achievable in "at least half" of patients with new-onset RA, noted Dr. James R. O’Dell and Dr. Ted R. Mikuls in an editorial that accompanied the publication of the provisional definition (Arthritis Rheum. 2011;63:587-9). The remission rate in patients with long-standing RA is much lower, more on the order of perhaps 10%, Dr. O’Dell said in an interview.

Noted Dr. Daniel E. Furst: "When I started working on rheumatoid arthritis, we used the word remission with the hope that some day it would be possible. Because of advances in treatment, over the last 10 years it has become possible, and consequently it is totally appropriate that we aim for remission."

The provisional definitions that the panel set for clinical trials serve as "a reasonable set of criteria" for routine practice, said Dr. Furst, who is Carl M. Pearson professor in rheumatology at the University of California, Los Angeles and a member of the ACR/EULAR panel.

"I do this all the time. It requires physicians to routinely quantify patient responses, which is not common right now, but it will become more common. The need for a lab test [measurement of CRP] as part of the definition makes it a little more difficult to use because it usually takes some time to get the blood-test result. What I do is a CDAI [Clinical Disease Activity Index, the sum of tender and swollen joint counts, and physician and patient global assessments] at the same time that I’m obtaining the other results that take time. That’s more practical to do in everyday practice," he said in an interview.

"Right now, my associates and I generally use a DAS28, but we’re rethinking that," in part prompted by the new remission definitions, said Dr. O’Dell, who is Larson professor of medicine and chief of rheumatology at the University of Nebraska in Omaha. "DAS28 is an imperfect measure. I can have a patient with a very low [ESR] of 2 [mm/hr] and their DAS28 will look pretty good until they have three or four swollen joints. But the flip side is I can have a patient who is doing terrific, with no swollen joints, and their [ESR] is 25. Since the ARC/EULAR definition, we have thought about whether we should do more CDAI or SDAI. [ESR] and CRP give information in a different way than what we get from joints, but they often aren’t available in real time.

"The ACR Quality Measures Committee will issue a white paper in late spring on the disease activity measures that it thinks are feasible and that clinicians can use, including the CADI, SDAI, DAS28, RAPID3 [Routine Assessment of Patient Index Data 3], and PAS [Patient Activity Score]. It’s far more important that physicians measure a patient’s disease activity with some scale than which scale you use," he said in an interview. "If you don’t want to do 28-joint counts, then do a RAPID3. The ACR/EULAR panel set its remission criteria for trials, but for routine practice there should be more flexibility" for physicians to use the scale that best fits their approach to practice, Dr. O’Dell said. "The RAPID3 is much easier to do and is available in real time, and is very good. It’s not quite as good as some others, but if that’s what you use, you’ll do fine."

Assessing the ACR/EULAR Criteria’s Performance

In addition to not having been derived from patients in routine practice, the ACR/EULAR definitions of remission may also show variability from physician to physician, and unstable reproducibility within individual patients.

Last November, researchers from the Arthritis and Rheumatology Clinics of Kansas in Wichita and their collaborators published an analysis that applied the ACR/EULAR provisional remission definition to patients in two cohorts: 1,341 patients from the Department of Veteran’s Affairs, and 1,153 patients in a cohort assembled at the Arthritis and Rheumatology Clinics of Kansas. The two ACR/EULAR criteria identified about 5%-10% of patients as being in remission at any one time, depending on the cohort and specific definition applied, they reported (Arthritis Rheum. 2011;63:3204-15).

However, the probability of a specific patient being in remission at two or more visits ranged from 2%-5%. The analysis also showed "substantial evidence to indicate that inter-rater reliability is poor with respect to the examination of tender and swollen joints." The authors estimated that the probability of remission using the ACR/EULAR definitions in these two cohorts could vary by twofold depending solely on the physician examiner and independent of disease activity.

The researchers concluded that "problems with reliability and agreement limit the usefulness of these criteria in the individual patient." But several rheumatologists interviewed noted that variability among physicians in scoring swollen and tender joint counts is expected. The finding simply underscores that the best way to serially monitor joint status in a patient is for the same physician to do it every time. They also commented that the low rates of remission seen in this study highlight just how challenging it is to maintain RA patients at a very low level of disease activity.

"These criteria were developed for clinical trials, and I agree that they’re reasonable for trials," said Dr. Frederick Wolfe, the senior author on this study and a member of the ACR/EULAR definition panel. "Until now, there were lots of different ideas of what was remission, which limited its use. We wanted to make a standard for remission [in trials], and did a pretty good job. But in the clinic, physicians know more than they can get from questionnaires," he said in an interview.

For example, Dr. Wolfe cited a study he and his associates ran in which patients were asked what influenced their global self rating. "We found that some patients who all physicians would agree were in remission gave themselves poor scores because they had pain in other regions, mostly back pain, or because of fatigue, or other things" not related to RA. "In clinical practice, we’d ask patients to ignore that, or to explain their high global self-assessment score, so in the clinic you can decide whether patients are in remission," said Dr. Wolfe, director of the National Databank for Rheumatic Diseases in Wichita, Kan.

For measuring RA activity in routine practice, Dr. Wolfe said that he favors the CDAI "as an overall measure of disease activity." He also endorsed patient-centered measures of pain, such as the Health Assessment Questionnaire (HAQ), global self-assessment, RAPID3, and the PAS.

A more positive assessment of the ACR/EULAR definitions in clinical practice came from a recent study that applied them to a cohort of 535 RA patients at Brigham and Women’s Hospital in Boston followed for 2 years by serial joint radiographs. The authors examined the ability of the definitions to predict good radiographic and functional outcomes over time in these clinical-practice patients. They found that 30 patients (6%) of the 535 met the four-part ACR/EULAR definition of remission at baseline, while 26 (5%) met the CDAI definition, 37 (7%) met a SDAI definition of remission, and 106 (20%) met a DAS28-CRP definition. The best of these measures for predicting freedom from radiographic joint progression during 2 years of follow-up was the CDAI, with a positive likelihood ratio of 2.8, followed closely by the four-part ACR/EULAR definition, with a positive likelihood ratio of 2.7. The ratio for SDAI was 2.1, and for DAS28-CRP 1.5 (Ann. Rheum. Dis. 2011 Oct. 12 [doi:10.1136/ard.2011.154625]).

"Our findings strengthen the applicability of the ACR/EULAR criteria in clinical practice," the researchers concluded, and also noted that "the findings might have been different in a patient population of early RA patients." The cohort they examined had been diagnosed with RA for a median of 11 years, with 75% diagnosed for 4 years or longer.

The authors also said "a significant proportion of patients who do not fulfill the remission criteria still experience a good outcome of their disease, especially for radiographic joint damage. ... A byproduct of more stringent remission criteria as a treatment target will be more patients in low disease activity with good disease outcome, potentially risking overtreatment."

Several other assessments of the remission criteria in other data sets are on the way, Dr. O’Dell said. "I’ve heard of them, and people are talking about them," and these reports will likely appear in the literature over the next year. Advance word is that the remission criteria "stood up very well," Dr. O’Dell added.

Is Remission the Right Goal?

The last comment from the Brigham and Women’s group raises the important question of whether remission is the best target for most RA patients or is low disease activity enough.

"About 10%-20% of patients in trials reach remission according to the new definitions. Newly diagnosed patients tend to have disease that is more responsive to treatment, so that the proportion achieving remission is likely to be higher, but probably not reaching 40%," said Dr. Felson. "In trials, regimens will target" the new ARC/EULAR definition, "but I’m less sure about this as a target for patients [in routine practice]. It may be difficult for many patients to reach this threshold, even with optimal current treatment."

For the time being, in patients with an established RA diagnosis using MRI or ultrasound to pick up inflammation that is not clinically apparent "is not practical," said Dr. O’Dell. One area where joint imaging may be especially helpful is in patients who are doing well on treatment and can be considered for tapering down treatment. Studies are now looking at whether ultrasound or MRI can identify patients who are good candidates for dose reductions, Dr. O’Dell said.

"Remission, whether you define it with the new definition or an older one, is necessary for the long-term health of patients," said Dr. Furst. "The goal is preventing x-ray damage, and allowing patients to have optimal long-term function and quality of life. That’s what remission criteria are all about: They give physicians a measuring stick for telling how well a patient is doing" with respect to these long-term treatment goals. "There is always a balance between achieving these goals and making sure the patient is not harmed" by aggressive treatment. The ACR/EULAR criteria "emphasize the need to quantify patient response, and in that sense they are slowly changing practice," Dr. Furst said.

"There is no doubt that there is increasing movement toward treating to a target, but most rheumatologists don’t believe that remission is the right goal for every patient." said Dr. O’Dell. "We’d love to have remission, but sometimes it’s more problematic than it’s worth. What we don’t know is the long-term difference between a patient who is barely in remission compared with one who is close but not in remission. How far should we push it? If the patient is not having trouble with treatment, then we should definitely push it. If a patient is on 20 mg/week of methotrexate and is nearly there, then trying 25 mg of methotrexate/week is clearly the right thing to do in most patients. But if the patient is not at remission but also is not always tolerating 20 mg/week, if they don’t feel good the day after their dose, what’s the right answer? We don’t know; it’s clinical judgment."

Dr. Felson, Dr. O’Dell and Dr. Wolfe said they had no disclosures. Dr. Furst said that he has financial relationships with Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Gilead, GlaxoSmithKline, Merck, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma.