This month, the ACR and the European League Against Rheumatism (EULAR) will release new rheumatoid arthritis (RA) classification criteria. The criteria have been endorsed by both organizations and will be published in the September 2010 issue of Arthritis & Rheumatism, available online by mid-August.
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The criteria were first presented in a well organized, fast-paced, and densely packed session at the ACR Annual Scientific Meeting in October 2009. There, members of the ACR–EULAR task force premiered the results of the ambitious three-year collaborative effort to develop updated RA classification criteria. Their data- and consensus-driven process has yielded a new approach with an emphasis on identifying patients with a relatively short duration of symptoms who may benefit from early initiation of disease-modifying antirheumatic drug (DMARD) therapy or entry into clinical trials of promising new agents.
Why New Criteria?
This effort was undertaken to update the ACR RA classification criteria published in 1987. As noted by the authors, the 1987 criteria were derived by discriminating patients with established RA from those with other definite rheumatologic diagnoses; therefore, they are not helpful in identifying patients who would benefit from early intervention. Identifying RA at later stages is easy, remarked Paul Emery, MA, MD, professor of rheumatology and head of the academic section of MSK Disease at the Leeds Institute of Molecular Medicine at the University of Leeds, United Kingdom, in his 2009 ACR meeting presentation about the need for new RA criteria. The problem is that classification using the 1987 criteria only occurs after nodules and radiographic changes are apparent. Research in the intervening decades has established that RA is characterized by “an evolving phenotype, and this evolution can actually be interrupted,” he noted. This is the goal of newer RA therapies—preventing patients with RA from reaching a chronic, erosive disease state.
Having uniform criteria to classify patients with early disease facilitates clinical trials that investigate the efficacy of early interventions in preventing later-stage RA. “If our job as rheumatologists is to prevent disease,” Dr. Emery reminded his audience, “then early therapy is essential.”
Alan J. Silman, MD, from the Arthritis Research Campaign in Chesterfield, United Kingdom, and a member of the task force, summarized the history of RA classification criteria at the annual meeting session. The 1987 ACR Criteria, following earlier efforts such as the 1956 ARA criteria, 1961 Rome criteria, and 1966 New York criteria, was the first classification to use an analytical approach. The 1987 ACR Criteria “were not designed to work when we most need them,” he said. To address this need, a joint task force of the ACR and EULAR was formed and developed criteria in the phased approach described below. Importantly, the focus of this endeavor was not on developing diagnostic criteria or informing primary care referral.
Phase One: Data Analysis
As the task force began its work, said Dr. Silman, its assignment was to use available data to statistically develop rules that could best differentiate subgroups of patients with newly presenting, undifferentiated inflammatory synovitis at sufficiently high risk of persistent and/or erosive disease from those with lower risk. For ethical reasons, a natural history study would have been out of the question. “Nobody now waits for someone to develop erosive disease before they start DMARD therapy,” he noted.
Because its charge was to identify those patients who would benefit from early initiation of treatment, the task force decided to use initiation of methotrexate (MTX) as the gold standard against which variables would be measured. If physicians had started patients on MTX, this meant that, in their clinical judgment, these patients were at risk for developing persistent or erosive RA. This approach avoided the circularity that would occur if the 1987 criteria were used as the gold standard.
Daniel Aletaha, MD, MSc, of the Medical University of Vienna, Austria, also a member of the task force, described the scientific challenges of the three-step data analysis of Phase One in his presentation entitled, “Developing New RA Classification Criteria: Learning from an Early Disease Cohort.” Investigators from nine centers gave the task force access to their early arthritis patient cohorts. With a total of 3,115 included patients, the cohorts yielded a large field of variables, with substantial variation. For instance, the average duration of symptoms at presentation ranged from 1.2 to 7 months, and the percentage of patients who were rheumatoid factor seropositive ranged from 13–40%. “This heterogeneity was one of the great strengths of the analysis because the [differences between the cohorts support] the generalizability of the results we generated,” Dr. Aletaha explained.
Step 1 of the data analysis began with what Dr. Aletaha called “a cloud of variables.” The team performed univariate regression analysis to look at each variable’s effect on MTX treatment at one year. Some of the variables, such as age, gender, and involvement of large joints, were eliminated as not predictive of persistent disease. Step 2 involved performing a principle component analysis to identify sets of variables that represented a similar theme. Each of these groupings, or factors, was given a name: metatarsalphalangeal (MTP) involvement, wrist involvement, hand–finger tenderness, acute phase response, proximal interphalangeal (PIP) involvement, and serology. The final multivariate regression analysis, Step 3, then yielded the independent associations of the key variables that would need to be considered in a final set of criteria.
After this three-step analysis, the Phase One effort had identified key variables and provided the relative weights of those variables to inform the final criteria. Among the findings:
- The importance of the hands as signified by swelling of the PIP, MCP, and wrist regions, with an independent contribution of tenderness;
- Symmetrical involvement did not have a significant effect over unilateral involvement; and
- Abnormal acute phase response, especially C-reactive protein values, had a considerable effect.
Phase Two: The Probability of RA
During Phase Two, the aim was to reach consensus on those patient factors that clinicians use to determine the patients’ probability of developing persist or erosive RA, according to task force member Gillian A. Hawker, MD, MSc, of the Women’s College Hospital, Toronto. In Phase Two, a 24-member expert panel was assembled, including task force leaders and other ACR and EULAR members, academicians and clinicians, and men and women. Each panel member submitted three to five patient-case scenarios based on real patients with undifferentiated inflammatory arthritis seen in their practices. They ranked their cases on a five-point Likert scale according to the probability that the patient would develop RA. From a total of 86 cases they received, the task force chose 30, which they simplified, anonymized, and disseminated to members of the panel. These panel members were then asked to rank all cases in descending order, from highest to lowest probability of RA, given the variables that had been identified in Phase One.
When the panel convened in Chicago in May 2009, they were shown a scatterplot of their rankings of the cases to initiate discussions about differences of opinion. During this meeting, the panel identified four domains associated with an increasing probability of developing RA: joint involvement, serology, duration of synovitis, and acute phase reactants. These later became the key domains in a 10-point score. Consensus panel discussions also generated what they considered “mandatory requirements” to fulfill the classification of RA: evidence of synovitis in at least one joint, as validated by an expert clinician or imaging, and signs or symptoms that could not be explained by other diseases or conditions.
To evaluate the weights, and thus the scores, attached to each of the categories within the four domains, the panel used a series of paired discrete choices and a novel decision analytic software, 1000 Minds. Those weights then determined the scores assigned to each category; these category scores were then summed to produce an overall patient score, which represented the patient’s probability of developing persistent or erosive RA (from 0, very low probability, to 100, very high probability). The program deduced that involvement of more than 10 joints, including small joints, had a very strong impact on a patient’s score of probable RA. The next highest influence was high positive serology, following by longer duration of synovitis and positive acute phase response. The results of the consensus meeting were remarkably congruent with findings from the Phase One analysis, said Dr. Hawker.
The task force presented its preliminary results at the 2009 EULAR meeting in Copenhagen. Following revisions in response to feedback, the panel refined their definitions of synovitis, joint involvement, high- and low-titer serology, and acute phase reactants, and determined the strategy for classification of patients with erosive changes. They then rescored the original case scenarios using a 100-point scale to verify rank order. In their final phase, they derived cut points for definite RA (60 out of 100 or 6 out of 10) and simplified the scoring system, from a 100-point to a 10-point scale.
At the end of her October 2009 presentation at the ACR annual meeting, Dr. Hawker walked her audience through both a tree algorithm and the 10-point classification scale, both of which are now available as part of the published criteria and on the ACR website at www.rheumatology.org/practice. Later, during the question-and-answer period, presenters urged audience members to test the criteria in a prospective manner. “Once the criteria are published, our call to everyone is to go back to their own cohorts and test these new criteria in all possible ways,” said Dr. Aletaha.
Michael E. Weinblatt, MD, co-director of clinical rheumatology at Brigham and Women’s Hospital in Boston, wrapped up the session with high praise for the task force’s work. He noted that the criteria will set the stage for earlier identification and treatment of disease. “For the first time, [the classification criteria] now appreciate the diversity of a heterogeneous disease and will improve patient care,” he said.
Gretchen Henkel is a freelance journalist based in California.