Abstract
Objective
Classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP.
Methods
We identified all subjects seen in our Arthritis Center with rheumatoid factor (RF) and anti-CCP tested simultaneously between January 1 and June 30, 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (1) adding anti-CCP, (2) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms ≤ 6 months.
Results
Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF+ and 14% were anti-CCP+ at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up.
The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs. 51% for ACR criteria with a loss in specificity (81% vs. 91%). Sensitivity was greatly improved in subjects with symptoms ≤ 6 months: 25% vs. 63% for ACR criteria with a decrease in specificity.
Conclusion
The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms ≤ 6 months and could be used for classification of subjects for RA in clinical studies.
Keywords: Rheumatoid arthritis, cyclic citrullinated peptide, classification, early RA
INTRODUCTION
The past decade has seen extensive advances in knowledge regarding the epidemiology, pathophysiology, and treatment of rheumatoid arthritis (RA). Early aggressive treatment of RA with disease modifying anti-rheumatic drugs (DMARDs) and biologic agents decreases the development of radiographic erosions [1, 2], decreases disease-related disability [3-5], and increases the rate of disease remission [6, 7]. The opportunity to impact the natural history of RA is most pronounced in the first months after symptom onset.
The current American College of Rheumatology (ACR, previously American Rheumatism Association) criteria were developed initially in 1957 by a subcommittee of five expert rheumatologists with a goal of appropriately classifying RA patients and providing a homogenous population for inclusion into clinical studies and trials [8, 9]. The 1957 criteria classified subjects into four groups: possible RA, probable RA, definite RA, and in 1958, a fourth category, classical RA was added [9]. In 1987 the criteria were revised, with simplification of the description of “definite RA” to those individuals with four out of seven criteria (Table 1). These revised criteria were developed through the examination of subjects with longstanding RA (mean duration of symptoms of 7.7 years) [10] and are the current standard for the selection of subjects for clinical research studies and trials.
Table 1.
Criteria sets investigated for classification of RA
| 1987 ACR Criteria |
1987 ACR Criteria + anti-CCP |
CCP 7 Criteria |
CCP 6 Criteria |
|
|---|---|---|---|---|
| 1. morning stiffness > 1 hr* | ✓ | ✓ | ✓ | ✓ |
| 2. arthritis ≥ 3 joints* | ✓ | ✓ | ✓ | ✓ |
| 3. hand arthritis* | ✓ | ✓ | ✓ | ✓ |
| 4. symmetric arthritis* | ✓ | ✓ | ✓ | ✓ |
| 5. rheumatoid nodules | ✓ | ✓ | ||
| 6. RF + | ✓ | ✓ | ✓ | ✓ |
| 7. radiographic changes | ✓ | ✓ | ✓ | |
| 8. anti-CCP + | ✓ | ✓ | ✓ | |
| # criteria required | ≥4 out of 7 | ≥4 out of 8 | ≥3 out of 7 | ≥3 out of 6 |
Arthritis symptoms ≥ 6 weeks
Over the past 10 years, more sensitive and specific laboratory tests for the identification of RA have been developed, specifically, antibodies to citrullinated proteins. These autoantibodies, directed against citrullinated residues of proteins including keratin and filaggrin, are present in the blood of the majority of RA subjects with established disease and their presence is associated with more severe, erosive disease [11-20]. Utilizing this new knowledge, a better test for the detection of antibodies to cyclic citrullinated peptides (CCP) was developed [18]. In early inflammatory arthritis, the specificity of anti-CCP antibody for rheumatoid arthritis has ranged from 90-97%, compared to RF, which ranges from 80-90% [17, 21-23]. While the sensitivity of anti-CCP antibodies in early RA is comparable to that of RF, the detection of either RF or anti-CCP has significantly improved sensitivity for RA diagnosis compared to either laboratory test alone [22].
The 1987 ACR criteria have a sensitivity of 91-94% and specificity of 89% for the classification of established RA [24]. They include characteristics that are rare in new onset RA, such as radiographic erosive changes and rheumatoid nodules. Studies have shown that the 1987 ACR criteria are suboptimal when identifying subjects with early RA (employing a range of arthritis symptom duration from 4 weeks to 2 years), with sensitivity ranging from 40-90% and specificity from 50-90% [24-28]. With mounting evidence of the importance of early diagnosis and aggressive treatment, there is a need for criteria with the ability to appropriately diagnose and classify subjects with early and established RA [29].
We hypothesized that the inclusion of anti-CCP antibody results into the existing 1987 ACR Criteria for the Classification of RA would increase their sensitivity, and that further adjustments to the existing criteria would improve particularly upon the identification of individuals with early RA. We evaluated the performance characteristics of newly revised sets of classification criteria for RA.
MATERIALS AND METHODS
Subject identification
We identified all subjects evaluated by staff rheumatologists at the Brigham and Women's Hospital Arthritis Center between January 1st and June 30th 2004 who had serum anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) measured on the same day. Subjects diagnosed with juvenile rheumatoid arthritis (JRA) or juvenile idiopathic arthritis (JIA) with age of onset at 16 or younger were excluded.
Laboratory measurements
Anti-CCP and RF measurements were performed in the hospital Clinical Immunology Laboratory. Second generation anti-CCP titers were measured using an enzyme linked immunosorbent assay (ELISA) from the Axis-Shield Corporation. RF titers were determined by nephelometry [22]. The cutoff for positivity was 5 U/mL for anti-CCP and 10 IU/mL for RF.
Data collection
All data available in the Brigham and Women's electronic medical record, including office notes, referral letters, laboratory results, and diagnostic reports, were reviewed. The records were independently reviewed by 4 rheumatology reviewers (KB, KC, KL, PS) in the years 2006 and 2007. The date of the RF and anti-CCP request was defined as the baseline date, and the duration of arthritis symptoms up to the baseline date were recorded. Each subject's medical record at the baseline visit was also evaluated for the presence of components of the 1987 Revised Criteria for the Classification of RA [10] (Table 1). The first four were noted as positive if they had been present for at least six weeks at the time of the initial visit when anti-CCP and RF tests were ordered. We also collected additional information including:
results of serum anti-CCP test (2nd generation anti-CCP titer > 5 U/mL = positive)
date of onset of arthritis symptoms
arthritis symptom duration (months)
the rheumatologist's diagnosis at the baseline visit
the rheumatologist's diagnosis at the first follow-up visit
the rheumatologist's diagnosis at the most recent follow-up visit
Diagnosis was classified as definite RA, possible/probable RA, or not RA based on the wording used by the treating rheumatologist at the most recent follow-up visit. All patients clearly diagnosed with RA were included as such. All patients clearly felt not to have RA (usually given an alternate diagnosis) by the rheumatologist were labeled as not RA. All patients thought to have possible or probable RA by the treating rheumatologist (terminology included “likely inflammatory arthritis”, “possible mild RA”, “new onset polyarthritis”), were assigned a definition of possible/probable RA. To standardize and verify our interpretations, an initial group of 79 subject records were independently reviewed by three rheumatologists. Disagreements were resolved by consensus among all reviewers.
Lastly, in 2007 we identified the most-recent follow-up visit for each subject in our electronic medical records and noted the rheumatologist's diagnosis at that time. Each of the above criteria was considered positive if documented as present at any time since symptom onset to the date that RF and anti-CCP were ordered. Criteria were negative if documented as such at any time since symptom onset or no documentation of a positive finding through the date that RF and anti-CCP were ordered. If a criterion was not documented, it was considered missing. The presence or absence of erosions on hand and foot radiographs were determined from documentation either by the rheumatologist from studies at other institutions and/or radiographs performed and interpreted by the Radiology department at Brigham and Women's Hospital. We included radiographic joint erosions, but not “bony decalcification localized in or most marked adjacent to the involved joints” as per the 1987 ACR criteria [10], as the latter is more subject to interpretation and we did not have access to original radiographs in all cases.
Our goals were to investigate the effects of adding anti-CCP to the existing ACR criteria, and of replacing existing criteria to maximize sensitivity and specificity for the classification of both early and longstanding RA. As nodules and erosions are late RA manifestations, we investigated the effect of removing them from the criteria. Thus, we tested the following three revisions of the 1987 ACR criteria: (1) addition of anti-CCP testing (1987 ACR Criteria + Anti-CCP), (2) replacement of rheumatoid nodules with anti-CCP as a criterion (CCP 7 criteria), (3) replacement of rheumatoid nodules and erosions as criteria with anti-CCP (CCP 6 criteria) (Table 1). We compared the sensitivity and specificity of the 1987 ACR criteria to our three sets of modified criteria and compared these to the rheumatologists' diagnosis at the most recent follow-up visit. Partners' Institutional Review Board approved of all aspects of this study.
Statistical analysis
The sensitivities and specificities of the sets of criteria for the classification of RA were calculated using 2 × 2 tables using the rheumatologist's diagnosis at most recent follow-up as the standard. For each of the 3 sets of revised criteria, we chose the cutoff that maximized sensitivity and specificity on ROC curves. The following formulas were used for the calculations: Sensitivity= (number of subjects classified as RA by criteria)/(number of subjects diagnosed with RA by the rheumatologist at the most recent follow-up); Specificity= (number of subjects classified as not having RA by criteria)/(number of subjects diagnosed as not RA by the rheumatologist at most recent follow-up)
The data were also stratified by duration of arthritis symptoms at baseline of six months or less (short duration), or more than six months (long duration). In our primary analyses, we included subjects who had been diagnosed at the most recent visit by their rheumatologists as having either definite RA, or not RA and we excluded those subjects who were labeled as possible or probable RA. In the sensitivity analyses of our new criteria sets, we investigated the effects of including these subjects either with the individuals with definite RA or with those without RA. We analyzed the data using the SAS software package version 9.1 (SAS Institute, Cary, NC, USA).
RESULTS
Three hundred and ninety one subjects were identified and their medical records were reviewed. Ninety-nine subjects were excluded, 20 with JRA and 79 with no follow-up visit. Thus, 292 subjects were included in this analysis. The mean age of the subjects was 54 years; 82% were women, and the mean duration of symptoms was 4.1 years. Seventeen percent of subjects were RF positive and 14% were anti-CCP positive at initial testing (Table 2).
Table 2.
Characteristics of all subjects
| Criteria | All, n (%) | SHORT (symptoms <6 mos), n (%) |
LONG (symptoms >6 mos), n (%) |
|---|---|---|---|
| N | 292 | 79 (27) | 213 (73) |
| Female | 239 (82) | 64 (81) | 175 (82) |
|
Mean age at onset of arthritis symptoms, years (min-max) |
50 (17-87) | 55 (20-87) | 47 (17-81) |
|
Mean age at baseline, years (min-max) |
54 (19-88) | 55 (20-88) | 53 (19-88) |
|
Mean duration of follow-up: Baseline to 1st follow-up visit, months (min-max) |
2.8 (0.1 – 26.3) | 2.5 (0.1 – 21.4) | 2.9 (0.1 – 26.3) |
|
Mean duration of follow-up: baseline to most recent visit, months (min-max) |
9.3 (0.1-34.9) | 8.5 (0.1-31.7) | 9.5 (0.1-34.9) |
|
| |||
| Morning stiffness > 1 hour* | 111 (38) | 30 (38) | 81 (38) |
| Arthritis of ≥3 joint areas* | 126 (43) | 30 (38) | 96 (45) |
| Arthritis of hand joints* | 139 (48) | 37 (47) | 102 (48) |
| Symmetric arthritis* | 123 (42) | 31 (39) | 92 (42) |
| Rheumatoid factor positive | 50 (17) | 14 (18) | 36 (17) |
|
| |||
| Rheumatoid nodules+ | 4 (8) | 0 | 4 (11) |
| Radiographic erosions✦ | 35 (16) | 3 (6) | 32 (20) |
|
| |||
| Anti-CCP positive | 40 (14) | 9 (11) | 33 (15) |
|
Initial rheumatologist diagnosis | |||
| Not RA | 150 (51) | 41 (52) | 109 (51) |
| Possible/probable RA | 100 (34) | 36 (56) | 64 (30) |
| Definite RA | 42 (14) | 2 (3) | 40 (19) |
|
Rheumatologist diagnosis at most recent follow-up | |||
| Not RA | 170 (58) | 50 (63) | 120 (56) |
| Possible/probable RA | 44 (15) | 13 (16) | 31 (15) |
| Definite RA | 78 (27) | 16 (20) | 62 (29) |
Arthritis symptoms for ≥ 6 weeks at initial visit
Documented in 50 subjects, percentages reflect % of documented cases
Documented in 210 subjects, percentages reflect % of documented cases
When stratified by arthritis symptom duration of six months or less or more than six months, findings of radiographic erosions and rheumatoid nodules differed greatly between the two groups. All documented findings of rheumatoid nodules were among subjects with arthritis symptoms of greater than six months, although seldom were nodules specifically noted. Similarly, 91% of documented radiographic erosions were found in that group. Patients with arthritis symptoms of six months or less were also slightly older (Table 2).
Forty-two subjects (14%) had definite RA according to their rheumatologist at the baseline visit. At the next visit, a mean of 2.8 months later, 30 additional individuals were diagnosed with RA. Eighteen of these subjects had an initial diagnosis of possible/probable RA and 12 were thought not to have RA. Of the 18 subjects initially diagnosed as possible/probable RA and subsequently diagnosed as RA at the next visit, 33% were anti-CCP positive and 44% were RF positive. In comparison, of the 30 subjects who were initially diagnosed as possible/probable RA and subsequently diagnosed as not RA in the next follow-up visit, none were anti-CCP positive and 7% were RF positive (Table 3). Of the 12 subjects who were initially diagnosed as not having RA and subsequently diagnosed with RA at the next visit, 42% were anti-CCP positive and 33% were RF positive. In comparison, of the 127 subjects who maintained a diagnosis of not RA, 6% were anti-CCP positive and 8% were RF positive (Table 3).
Table 3.
Rheumatologist diagnosis at baseline and at next visit for all subjects and their anti-CCP and RF status
| Diagnosis at baseline, n=292 |
Diagnosis at next- follow-up, n=292 |
n | Anti-CCP+, n (%) |
RF+, n (%) |
|---|---|---|---|---|
| RA n=42 |
RA | 39 | 16 (41) | 18 (46) |
| Possible/probable | 1 | 0 | 0 | |
| Not RA | 2 | 0 | 0 | |
|
| ||||
| Possible/Probable RA n=100 |
RA | 18 | 6 (33) | 8 (44) |
| Possible/probable | 52 | 6 (12) | 7 (13) | |
| Not RA | 30 | 0 | 2 (7) | |
|
| ||||
| Not RA n=150 |
RA | 12 | 5 (42) | 4 (33) |
| Possible/probable | 11 | 2 (18) | 2 (18) | |
| Not RA | 127 | 7 (6) | 9 (7) | |
There were three subjects initially diagnosed as RA who had their diagnoses at next follow-up changed. Two of these subjects were thought to not have RA in follow-up, and one was diagnosed as possible/probable RA. These subjects were all negative for anti-CCP and RF (Table 3).
Compared to the rheumatologists' diagnosis at the most recent follow-up, a mean of 9 months after the baseline date when RF and anti-CCP were checked, the 1987 ACR criteria had a sensitivity of 51% and specificity of 91% for the classification of RA for all subjects. Adding anti-CCP to the existing criteria resulted in an improvement in sensitivity from 51 to 55% with no change in specificity (Table 4). Our CCP 6 and 7 criteria, removing nodules and then removing nodules and erosions, however, had increased sensitivity compared to the ACR criteria for all subjects (77% and 74% compared to 51%), as well as for the classification of subjects with both early and longer standing RA symptoms (63% for each compared to 25% for those with early symptoms, and 81% or 77% compared to 58% for the ACR criteria among those with longer duration of symptoms). For all of our newly revised sets of criteria, there was a decrement in the specificity to 70-80%, compared to the ACR criteria.
Table 4.
Performance characteristics for criteria stratified by duration of arthritis symptoms*
| Criteria | Sensitivity (%) | Specificity (%) |
|---|---|---|
| All subjects, n = 248 | ||
| 1987 ACR Criteria | 51 | 91 |
| 1987 ACR Criteria + Anti-CCP | 55 | 91 |
| CCP 7 Criteria | 77 | 79 |
| CCP 6 Criteria | 74 | 81 |
|
Subjects with arthritis symptoms ≤ 6 months, n = 66 | ||
| 1987 ACR Criteria | 25 | 86 |
| 1987 ACR Criteria + Anti-CCP | 44 | 86 |
| CCP 7 Criteria | 63 | 72 |
| CCP 6 Criteria | 63 | 72 |
|
Subjects with arthritis symptoms > 6 months, n = 182 | ||
| 1987 ACR Criteria | 58 | 93 |
| 1987 ACR Criteria + Anti-CCP | 58 | 93 |
| CCP 7 Criteria | 81 | 82 |
| CCP 6 Criteria | 77 | 85 |
Calculation for specificity performed using only individuals diagnosed as “not RA” by the rheumatologist at most recent follow-up
In sensitivity analyses, we added the subjects who were diagnosed with possible/probable RA by their rheumatologists to those defined as not RA and then to those defined as definite RA (Tables 5 and 6, web-only tables). The sensitivities observed remained similar regardless of the definitions employed.
Table 5.
Performance characteristics for sets of criteria stratified by duration of arthritis symptoms with possible/probable subjects included with definite RA subjects
| Criteria | Sensitivity (%) | Specificity (%) |
|---|---|---|
| All subjects, n=292 | ||
| 1987 ACR Criteria | 51 | 83 |
| Anti-CCP Revised 6 Criteria | 74 | 72 |
|
Subjects with arthritis symptoms ≤ 6 months, n=79 | ||
| 1987 ACR Criteria | 25 | 79 |
| Anti-CCP Revised 6 Criteria | 63 | 65 |
|
Subjects with arthritis symptoms > 6 months, n=213 | ||
| 1987 ACR Criteria | 58 | 85 |
| Anti-CCP Revised 6 Criteria | 77 | 75 |
Table 6.
Performance characteristics for sets of criteria stratified by duration of arthritis symptoms with possible/probable group included with not RA subjects
| Criteria | Sensitivity (%) | Specificity (%) |
|---|---|---|
| All subjects, n=292 | ||
| 1987 ACR Criteria | 50 | 91 |
| Anti-CCP Revised 6 Criteria | 70 | 81 |
|
Subjects with arthritis symptoms ≤ 6 months, n=79 | ||
| 1987 ACR Criteria | 34 | 86 |
| Anti-CCP Revised 6 Criteria | 62 | 72 |
|
Subjects with arthritis symptoms > 6 months, n=213 | ||
| 1987 ACR Criteria | 55 | 93 |
| Anti-CCP Revised 6 Criteria | 73 | 85 |
DISCUSSION
In this study, including anti-CCP in the classification criteria for RA improved upon the sensitivity of the 1987 ACR criteria without affecting the specificity in all subjects and in subjects with arthritis symptoms of ≤ 6 months. This is consistent with previous studies that have reported that detection of either RF or anti-CCP can improve sensitivity of the diagnosis of RA compared to either test alone [22]. Additionally, we have found that removing rheumatoid nodules alone (CCP 7 Criteria) or both rheumatoid nodules and erosions (CCP 6 Criteria), while substituting anti-CCP, adds further sensitivity, with loss of specificity. For subjects with arthritis symptoms of 6 months or less, our CCP 6 Criteria significantly improved upon the sensitivity for classifying early RA subjects compared to the 1987 ACR criteria from 25% to 63% with a decrement in specificity from 86 to 72%. For subjects with arthritis symptoms suggestive of RA lasting > 6 months, the CCP 6 and 7 Criteria systems we investigated also performed better than the ACR criteria with an increase in sensitivity and a decrease in specificity. In sensitivity analyses (Tables 5 and 6, web-only tables), the sensitivity and specificity of our newly revised criteria sets remained high.
Several recent editorials have called for the addition of anti-CCP into a newly revised classification criteria for RA [30, 31]. Aletaha and colleagues have highlighted the need for criteria that “are useful for the state of the disease at which physicians most frequently need the help of criteria, namely, very early in the course [32].” The actual definition and terminology of new onset RA has not yet been established. The Norfolk Arthritis Register has examined individuals with “inflammatory polyarthritis,” defined as swelling in two or more joints for 4 weeks or longer, or less than 2 years [33]. Studies published from the Leiden Early Arthritis Center studied patients with “undifferentiated arthritis.” Duration of arthritis symptoms were between 3 weeks and 2 years [34]. With these studies in mind, we chose arthritis symptoms of 6 months or less for classifying early RA.
In our study population, the widely used 1987 Criteria performed poorly compared to previous studies with a sensitivity of 51% in all subjects and as low as 25% in subjects with early RA. This lower sensitivity likely reflects a higher proportion of subjects in our study population with early or undifferentiated arthritis, for whom the ACR criteria in past studies have been shown to be less sensitive [24-28]. Using physician diagnosis at the latest visit (an average of 9 months since the initial visit) as a point of comparison, may also explain the lower sensitivity and specificity of the 1987 ACR criteria compared to previous studies. This conferred the advantage of time to the rheumatologist who had more information for accurate diagnosis. We used this diagnosis to assess the performance of our revised sets of criteria. However, the rheumatologist had arrived at this diagnosis in part based on the current ACR criteria and anti-CCP results. Visser and colleagues attempted to avert the circularity of using either the physician diagnosis or the ACR criteria by employing arthritis outcome at two years as a gold standard. The authors noted that this outcome is also not free from the influence of the classification criteria, insomuch as they inform rheumatologists' decisions to start DMARDs [28]. DMARDs in turn affect erosions and arthritis outcomes. Until a definitive diagnostic test for the diagnosis of RA is developed, RA research will continue to require tolerance of a degree of circularity.
The impact of the decreased specificity in the CCP 6 Criteria from 91% in the ACR criteria to 81% for all subjects and from 86 to 72% in subjects with arthritis symptoms of ≤ 6 months could result in misclassification of patients with short duration of arthritis symptoms who do not in fact have RA. The implications of adopting new criteria for the classification of RA and early RA for clinical studies are far-reaching and must be addressed by the ACR, and panels of experts and trialists. Potentially, this misclassification could bias results of clinical trials toward the null. On the other hand, slightly lower specificity and increased sensitivity could increase subject inclusion and generalizability of trial results.
This was a retrospective medical record review and our data is limited by what is recorded by the physician at each visit. Rheumatoid nodules were infrequently documented. The low prevalence of nodules in RA with current treatments may contribute to low priority on the part of rheumatologists to assess and document nodules.
This study was conducted in a large tertiary care center where pre-test probability for disease may be higher. The tertiary care center setting may also explain the large variation in the length of follow-up (0.1 to 35 months). Our patients are not part of an early RA cohort. Rather, they presented with a variety of arthritis symptoms and were thought to potentially have or be developing RA. A subset of our subjects were seen for second opinions and thus were followed for a shorter period of time and then returned to their outside rheumatologist for further care. Others were lost to follow-up or were thought not to have a rheumatic illness and returned to their primary care physician for further management. Given this real-life situation, we cannot exclude that anti-CCP antibodies, rheumatoid factor, or other symptoms later developed in those judged not to have rheumatic disease by the treating rheumatologist, and not followed in our center long-term. However, there was no significant difference in length of follow-up in those who were anti-CCP positive and those who were negative at the initial visit (8.1 vs. 9.5 months, p=0.43). There was also no significant difference between length of follow-up between subjects diagnosed with definite RA, possible/probable RA and not RA (p=0.26).
Many advances have occurred in the management of RA over the past 20 years. Biologic agents can slow the progression of the disease and induce remission. The discovery and development of the anti-CCP assay has allowed for improvements in diagnoses. Anti-CCP antibodies may also be involved in the pathogenesis of the disease [35, 36]. As we move toward a new paradigm of early aggressive treatment of RA, it is important to re-evaluate our mechanisms for identifying subjects with RA for inclusion into clinical studies. It is time to revise the 1987 ACR Classification Criteria for RA to account for changes in technology and knowledge, and to develop more sensitive criteria for the classification of early RA. Further research and validation of our newly proposed criteria is needed.
ACKNOWLEDGMENTS
Many thanks to Drs. Elizabeth Karlson and Daniel Solomon for their valuable input and ideas and to Holly Fossel for her support with data management.
FUNDING
Supported by NIH grants T32 AR007530, K12 HD051959, P60 AR047782. Dr. Costenbader is the recipient of an Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award and a Katherine Swan Ginsburg Memorial Award.
Footnotes
DISCLOSURES
All authors declare that the answer to the questions on your competing interest form are all “No” and therefore have nothing to declare.
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to be published in the Annals of the Rheumatic Diseases editions and any other BMJPGL products http://ard.bmjjournals.com/ifora/license.pdf
REFERENCES
- 1.Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-repo M, Hakala M, et al. Retardation of Joint Damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease modifying antirheumatic drugs. Arthritis & Rheumatism. 2004;50(7):2072–2081. doi: 10.1002/art.20351. [DOI] [PubMed] [Google Scholar]
- 2.Stenger AAME, Van Leeuwen MA, Houtman PM, Bruyn GAW, Speerstra F, Barendsen BC, et al. Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. British Journal of Rheumatology. 1998;37:1157–1163. doi: 10.1093/rheumatology/37.11.1157. [DOI] [PubMed] [Google Scholar]
- 3.Munro R, Hampson R, McEntegart A, Thomson EA, Madhok R, Capell H. Improved functional outcome in patients with early rheumatoid arthritis treated with intramuscular gold: results of a five year prospective study. Ann Rheum Dis. 1998;57(2):88–93. doi: 10.1136/ard.57.2.88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Puolakka K, Kautiainen H, Mottonen T, Hannonen P, Korpela M, Julkunen H, et al. Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial. Arthritis Rheum. 2004;50(1):55–62. doi: 10.1002/art.11436. [DOI] [PubMed] [Google Scholar]
- 5.van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with “second-line” antirheumatic drugs. A randomized, controlled trial. Ann Intern Med. 1996;124(8):699–707. doi: 10.7326/0003-4819-124-8-199604150-00001. [DOI] [PubMed] [Google Scholar]
- 6.Makinen H, Kautiainen H, Hannonen P, Mottonen T, Leirisalo-repo M, Laasonen L, et al. Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. J Rheumatol. 2007;34:316–321. [PubMed] [Google Scholar]
- 7.Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004;43(7):906–14. doi: 10.1093/rheumatology/keh199. [DOI] [PubMed] [Google Scholar]
- 8.Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA. Proposed diagnostic criteria for rheumatoid arthritis. Bulletin on Rheumatic Diseases. 1956;VII(4):121–124. [PubMed] [Google Scholar]
- 9.Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA. Revision of diagnostic criteria for rheumatoid arthritis. Bulletin on Rheumatic Diseases. 1958;IX(4):175–176. 1958. [PubMed] [Google Scholar]
- 10.Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
- 11.Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis. 2006;65(4):453–8. doi: 10.1136/ard.2005.041376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.del Val del Amo N, Ibanez Bosch R, Fito Manteca C, Gutierrez Polo R, Loza Cortina E. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: relation with disease aggressiveness. Clin Exp Rheumatol. 2006;24(3):281–6. [PubMed] [Google Scholar]
- 13.Forslind K, Ahlmen M, Eberhardt K, Hafstrom I, Svensson B. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP) Ann Rheum Dis. 2004;63(9):1090–5. doi: 10.1136/ard.2003.014233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Machold KP, Stamm TA, Nell VPK, Pflugbeil S, Aletaha D, Steiner G, et al. Very recent onset rheumatoid arthritis: Clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology. 2007;46:342–349. doi: 10.1093/rheumatology/kel237. [DOI] [PubMed] [Google Scholar]
- 15.Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, Dubois A, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis. 2003;62(2):120–6. doi: 10.1136/ard.62.2.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Panchagnula R, Rajiv SR, Prakash J, Chandrashekara S, Suresh KP. Role of anticyclic citrullinated peptide in the diagnosis of early rheumatoid factor-negative suspected rheumatoid arthritis: is it worthwhile to order the test? J Clin Rheumatol. 2006;12(4):172–5. doi: 10.1097/01.rhu.0000230483.66042.28. [DOI] [PubMed] [Google Scholar]
- 17.Quinn MA, Gough AK, Green MJ, Devlin J, Hensor EM, Greenstein A, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford) 2006;45(4):478–80. doi: 10.1093/rheumatology/kei203. [DOI] [PubMed] [Google Scholar]
- 18.Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000;43(1):155–63. doi: 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
- 19.Vencovsky J, Machacek S, Sedova L, Kafkova J, Gatterova J, Pesakova V, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis. 2003;62(5):427–30. doi: 10.1136/ard.62.5.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Schur PH. Anti-Cyclic Citrullinated Antibodies: Diagnostic, Predictive, and Monitoring Value in RA. International Journal of Advances in Rheumatology. 2005;3(3):77–83. [Google Scholar]
- 21.Ates A, Karaaslan Y, Aksaray S. Predictive value of antibodies to cyclic citrullinated peptide in patients with early arthritis. Clin Rheumatol. 2007;26(4):499–504. doi: 10.1007/s10067-006-0309-z. [DOI] [PubMed] [Google Scholar]
- 22.Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis. 2003;62(9):870–4. doi: 10.1136/ard.62.9.870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797–808. doi: 10.7326/0003-4819-146-11-200706050-00008. [DOI] [PubMed] [Google Scholar]
- 24.Saraux A, Berthelot JM, Chales G, Le Henaff C, Thorel JB, Hoang S, et al. Ability of the American College of Rheumatology 1987 criteria to predict rheumatoid arthritis in patients with early arthritis and classification of these patients two years later. Arthritis Rheum. 2001;44(11):2485–91. doi: 10.1002/1529-0131(200111)44:11<2485::aid-art428>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
- 25.Harrison BJ, Symmons DP, Barrett EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. American Rheumatism Association. J Rheumatol. 1998;25(12):2324–30. [PubMed] [Google Scholar]
- 26.Hulsemann JL, Zeidler H. Diagnostic evaluation of classification criteria for rheumatoid arthritis and reactive arthritis in an early synovitis outpatient clinic. Ann Rheum Dis. 1999;58(5):278–80. doi: 10.1136/ard.58.5.278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Taylor HG, Dawes PT. The utility of the 1987 revised ARA criteria for rheumatoid arthritis in early synovitis. Br J Rheumatol. 1991;30(4):319. doi: 10.1093/rheumatology/30.4.319. [DOI] [PubMed] [Google Scholar]
- 28.Visser H, Cessie S.l., Vos K, Breedveld FC, Hazes JMW. How to diagnose rheumatoid arthritis early: A prediction model for persistent (erosive) arthritis. Arthritis & Rheumatism. 2002;46(2):357–365. doi: 10.1002/art.10117. [DOI] [PubMed] [Google Scholar]
- 29.Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146(6):406–15. doi: 10.7326/0003-4819-146-6-200703200-00005. [DOI] [PubMed] [Google Scholar]
- 30.Inanc M. Very early ‘rheumatoid’ arthritis cohorts: limited by selection. Rheumatology. 2007;46:185–187. doi: 10.1093/rheumatology/kel342. [DOI] [PubMed] [Google Scholar]
- 31.Symmons DP. Classification criteria for rheumatoid arthritis--time to abandon rheumatoid factor? Rheumatology (Oxford) 2007;46(5):725–6. doi: 10.1093/rheumatology/kel418. [DOI] [PubMed] [Google Scholar]
- 32.Aletaha D, Breedveld FC, Smolen JS. The need for new classification criteria for rheumatoid arthritis. Arthritis & Rheumatism. 2005;52(11):3333–3336. doi: 10.1002/art.21410. [DOI] [PubMed] [Google Scholar]
- 33.Bukhari M, Thomson W, Naseem H, Bunn D, Silman A, Symmons D, et al. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: Results from the Norfolk Arthritis Register. Arthritis Rheum. 2007;56(9):2929–2935. doi: 10.1002/art.22868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.van der Helm-van Mil AH, le Cessie S, van Dongen H, Breedveld FC, Toes RE, Huizinga TW. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 2007;56(2):433–40. doi: 10.1002/art.22380. [DOI] [PubMed] [Google Scholar]
- 35.Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 2004;6(4):R303–8. doi: 10.1186/ar1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005;64(12):1731–6. doi: 10.1136/ard.2005.035691. [DOI] [PMC free article] [PubMed] [Google Scholar]