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EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
ScienceDirect Available online at www.indianjrheumatol.com and www.sciencedirect.com
Original Article
Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India Vinod Ravindran a,*, Ahlam Abdulaziz a, Palli Valappil Bhargavan b a
Department of Rheumatology, bDepartment of Internal Medicine, MES Medical College, Perinthalmanna 679338, Kerala, India
article info
abstract
Article history:
Objectives: In this prospective study following were evaluated (i) whether the 2010 ACR/
Received 29 January 2014
EULAR criteria would include patients who were classified as early rheumatoid arthritis
Accepted 31 March 2014
(RA) according to the 1987 ACR criteria, and (ii) outcome by classification when followed
Available online xxx
prospectively of those patients who initially remained unclassified i.e. had undifferentiated arthritis (UA).
Keywords:
Methods: Eligible cohort (all patients with at least one clinically swollen joint) consisted of
Rheumatoid arthritis
134 patients, 120 out of which had clinical diagnosis of RA. On the eligible cohort both 1987
Classification criteria
and the 2010 criteria were applied simultaneously at the beginning of the study and 1 year
Sensitivity
later.
Indian
Results: Out of 134 eligible patients 102 were classified as RA based on 1987 criteria. A total
Early arthritis
of 82 (80%) out of 102 patients were seropositive for RA, i.e. positive for either rheumatoid factor (RF) or anti-citrullinated peptide antibody (ACPA). According to the 2010 criteria, 86 (84%) out of the 102 patients were classified as having RA and 16 did not have RA. Among the 82 seropositive patients, only 1 (1.21%) patient was classified as not having RA whereas, among 20 patients who had seronegative (both for RF and ACPA) RA, 15 (75%) patients were not classified as RA according to the 2010 criteria. Sensitivity and specificity of the 2010 criteria was 96.67% and 92.86%, respectively, compared with 85% and 85.71% by 1987 criteria. 25% of initial UA patients were reclassified as RA by the 2010 criteria at 1 year. Conclusions: The 2010 criteria did not identify a substantial proportion of seronegative RA classified by the 1987 criteria. Therefore due care must be taken when applying the new criteria to patients with arthritis who are seronegative. Clinicians should be aware and alert regarding the possibility of UA patients fulfilling classification criteria for RA over time. Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
* Corresponding author. Tel.: þ91 4933 298300. E-mail address: [email protected] (V. Ravindran). http://dx.doi.org/10.1016/j.injr.2014.03.004 0973-3698/Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
2
1.
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
Introduction
In recent years it has become evident that early treatment of rheumatoid arthritis (RA) results in better long term outcome. As a consequence, in 2010, the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) jointly developed new classification criteria for identifying patients with early RA.1 The 2010 ACR/EULAR criteria have some important differences from the 1987 ACR criteria2; radiographic damage and rheumatoid nodules were excluded as they signify established and long standing disease. Morning stiffness was eliminated because of its lack of specificity for RA, while acute-phase reactants and a leveldependent consideration of auto-antibodies, including anticitrullinated peptide antibodies (ACPA), were included in the 2010 criteria. Given the differences in comparison with the 1987 criteria, understanding the performance of the 2010 criteria has been a focus of several studies mainly from the USA and European countries.3 Very limited data exists from the Asian countries4,5 and so far no published data exists regarding the performance of the new criteria on Indian patients with arthritis. This is important and highly relevant, as populations identified by the 2010 criteria for future studies are likely to be different from those classified by the 1987 criteria even among Indian patients, and thus, the results of clinical trials and cohort studies may not be easily comparable with the existing literature.6 Ascertaining the degree of overlap between the criteria in Indian patients who are ethnically different will help establish the extent to which previous research can be generalised to patients classified under the new system. The primary objectives of the present prospective study were (i) to assess whether the 2010 ACR/EULAR criteria would include patients who are classified as RA according to the 1987 ACR criteria, and (ii) to ascertain the outcome by classification when followed prospectively of those patients who initially remain unclassified i.e. had undifferentiated arthritis (UA)7 by re-classifying. We also assessed the sensitivity, specificity etc. of the 2010 ACR/EULAR criteria.
2.
Methods
2.1.
Patients
Between 1st October 2011 to 31st March 2012 all consecutive adult (age 18e75 years) patients (1) presenting with joint symptoms of less than one year duration and, (2) having history of joint(s) swelling were included in this study carried out at our tertiary care institution. Those patients who had at least one swollen joint on clinical examination formed the “eligible cohort”. In this cohort 1987 ACR and 2010 ACR/EULAR criteria were applied simultaneously to classify patients as either RA or as undifferentiated arthritis (UA). Relevant classification and diagnostic criteria were used to classify patients into other disease categories as and when appropriate and these patients were excluded from further analysis. To calculate the sensitivity and specificity and other performance parameters of the 2010 ACR/EULAR criteria; clinical
diagnosis of RA by experienced rheumatologist (expert opinion) with the initiation of synthetic disease modifying anti-rheumatic drugs (DMARDs) was deemed the “reference standard” in keeping with other studies.5,8 Patients were followed up for at least one year. At the end of one year from the enrolment those patients who were initially classified as UA were further subjected to an assessment by both 1987 and 2010 criteria. The protocol for this study was approved by institutional ethics committee of the institution. This study conforms to the provisions of the World Medical Association’s Declaration of Helsinki. Informed consent was obtained from all patients.
2.2.
Assessments
Data on demographics and clinical features were recorded. Standard 44 joints were assessed and clinical examination including a search for rheumatoid nodules and other extraarticular manifestations were performed by a single experienced rheumatologist at the initial visit. Laboratory investigations included rheumatoid factor (RF), anticyclic citrullinated peptide antibody (ACPA), erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and radiographs of hands and feet; to enable appropriate application of both criteria. Relevant investigations were repeated at the end of one year for patients initially classified as UA.
2.3.
Statistics
Differences in means were assessed using a two tailed, unpaired Student’s t test. Proportions were compared using c2 test. All tests were two tailed, and p < 0.05 was considered significant. Data management and analyses were carried out using the statistical package for social sciences, version 17.0.
3.
Results
3.1.
Patients (Fig. 1)
A total of 156 patients were assessed. Of these 22 were excluded as they did not have any swollen joint on clinical examination. These patients had following diagnosis for their joint symptoms; tenosynovitis (n ¼ 2), gout (n ¼ 4), SLE (n ¼ 4), psoriatic arthritis (n ¼ 5), spondyloarthropathy (n ¼ 3) and osteoarthritis (n ¼ 4). Of the remaining 134 patients (eligible cohort) who all had at least one clinically swollen joint, 120 (90%) were clinically diagnosed to have RA and were initiated on DMARDs (mainly a combination of methotrexate, hydroxychloroquine along with tapering course of oral glucocorticoids). These 120 (90%) patients therefore constituted the reference standard with the clinical diagnosis of RA. On the eligible cohort of 134 patients when 1987 ACR classification criteria were applied; 102 (76%) patients were classified as having RA and 32 (24%) as UA. When on the eligible cohort (n ¼ 134) 2010 ACR/EULAR criteria were applied; 116 (87%) patients were classified as having RA and 18 UA (13%) (Fig. 1). On following these patients prospectively for one year; none of the patients with the diagnosis of
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
3
Fig. 1 e Flow chart of patients in early arthritis cohort to compare 1987 and 2010 classification criteria for rheumatoid arthritis (RA) and outcome of undifferentiated arthritis (UA).
RA by either classification criteria or clinically were lost to follow up.
joints, levels of ESR and CRP between 82 seropositive and 20 seronegative patients (data not shown).
3.2. Does 2010 criteria identify all patients diagnosed as RA on basis of 1987 criteria
3.3. Classification outcome of initial undifferentiated arthritis patients
The mean age of 102 patients classified as RA by 1987 ACR criteria was 48.1 6 years and 87% patients were women. The mean symptom duration was 6.6 4.2 months. The mean numbers of swollen and tender joints were 8 5.7 and 7.2 5.4 respectively. Rheumatoid factor was positive in 67 patients and 55 patients were ACPA positive. A total of 82 (80%) out of 102 patients were thus seropositive for RA, i.e. positive for either RF or ACPA. According to the 2010 ACR/EULAR criteria, 86 (84%) out of these 102 patients were classified as having RA and 16 did not have RA. Among the 82 seropositive patients, only 1 (1.21%) patient was classified as not having RA whereas, among 20 patients who had seronegative RA, 15 (75%) patients were not classified as RA according to the 2010 criteria. The most frequent “scores” according to 2010 ACR/EULAR in these 102 patients were: “8” (n ¼ 36) followed by “7” (n ¼ 30) (among seropositive patients, n ¼ 82) and “4” (n ¼ 10) followed by “5” (n ¼ 6) (among seronegative patients, n ¼ 20). There were no significant differences in the demographic and clinical characteristics including age, sex, number of swollen and tender
After 1 year of follow up a total of 14 out of 134 patients were lost to follow up. In the UA category; out of original 32 UA patients according to 1987 ACR criteria 3 were lost to follow up and of the remaining 29 UA patients a further 10 (34%) were now classified as having RA based on 1987 ACR criteria (Fig. 1); this was due to presence of rheumatoid nodules (n ¼ 2), radiographic changes (n ¼ 5) and rheumatoid factor positivity (n ¼ 3). Radiographic changes were erosions and unequivocal periarticular osteopenia as per the ACR 1987 criteria. However it is important to note that 2 and 3 patients had all three or two aforementioned new features respectively. In contrast; out of original 18 UA patients according to 2010 ACR/EULAR criteria 6 were lost to follow up and of the remaining 12 UA patients a further 3 (25%) were now classified as having RA based on 1987 ACR criteria (Fig. 1), this was due to rheumatoid factor positivity in all three. More (but not statistically significant) patients still remained classified as UA when 2010 ACR/EULAR criteria were reapplied to aforementioned groups (Fig. 1).
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
4
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
3.4. Comparative performance of the classification criteria in this cohort (Table 1) When the performance of both classification criteria was assessed against the clinical diagnosis of RA as mentioned in the methods we found that compared to the 1987 ACR criteria, the 2010 ACR/EULAR criteria had better sensitivity and specificity (85 vs. 96.67% and 85.71 vs. 92.86%, respectively) (Table 1). The positive predictive values (PPVs) were equal, and the negative predictive values and the positive likelihood ratios were better by the 2010 criteria compared to 1987 criteria (99.15 vs. 98.08%, 76.47 vs. 40% and 13.53 vs. 5.95%, respectively) (Table 1).
4.
Discussion
The impetus for developing the new 2010 ACR/EULAR classification criteria was to facilitate recognition of RA at an earlier stage compared with the 1987 ACR criteria, thereby enabling earlier enrolment into the studies. It is quite likely that similar to 1987 ACR criteria over time the new criteria would also be used by clinicians in their routine clinical care as an aid to “diagnose” RA. However, concerns have been raised about several different aspects of the utility of the new criteria.6 In the present study one of the primary objectives was to assess whether the newly developed 2010 ACR/EULAR criteria would include patients who are classified as RA according to the 1987 ACR criteria. In our study the 2010 ACR/EULAR criteria did not identify a substantial proportion of seronegative early RA (classified by the 1987 ACR criteria). Our results are similar to other studies such as from the Netherlands in which 11.3% patients who fulfilled the 1987 ACR criteria did not fulfil the 2010 ACR/EULAR criteria and 97.5% of these “1987 only” patients were seronegative for both RF and ACPA.9 Similarly in a study from Japan among seronegative patients the 2010 criteria had a sensitivity of only 15.8%.5 According to the new criteria, to be classified as RA in seronegative patients the number of affected joints should be 10 or more with at least one small joint. In our study all seronegative patients who were classified as RA according to 1987 ACR criteria but not according to the 2010 ACR/EULAR criteria had less than 10 affected joints. Therefore due care must be taken when
Table1 e Comparison of performance of 1987 vs. 2010 criteria for RA.
Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Positive likelihood ratio Negative likelihood ratio
2010 ACR/EULAR criteria
1987 ACR criteria
96.67 92.86 99.15
85.00 85.71 98.08
76.47
40.00
13.53 00.04
05.95 00.18
applying the new criteria to the patients with early arthritis who are seronegative for RF or ACPA and have small number of swollen joints. The second “primary objectives” of our study was to assess the outcome by classification on prospective follow-up up of patients who were initially classified as UA. For clinicians it is important to be aware and alert regarding the possibility of initially undifferentiated patients fulfilling both the old and new classification criteria over time. Whereas for the 1987 ACR criteria this could result from the development of rheumatoid nodules and radiographic damage; for the 2010 ACR/EULAR criteria apart from ‘1’ more point if the duration is more than 6 weeks it could also result from many more joints being affected. Positivity for RF may affect the 1987 criteria and RF and/or ACPA positivity would affect the 2010 criteria and also if a change takes place in the titers of RF or ACPA. In our study at baseline 24% and 13% patients were not classifiable according to 1987 ACR and 2010 ACR/EULAR criteria respectively reflecting the enhanced sensitivity of the later criteria over former for RA. Similar to a recent study10 our initial 2010 ACR/EULAR UA patients had milder (but not statistically significant) disease (data not shown). This might be a possible reason for higher number of patient being lost to follow up. The lack of persistent disease also did not allow reclassification as RA in this group. Aforementioned results highlight the fact that though UA patients with poor prognostic factors are likely to be classified as RA, careful clinical observation of patient with UA is necessary. The use of validated predictive tool to allow individualised treatment decisions for patients with UA has also been recommended.6,7,11 In our small cohort we also compared the performance of both criteria against a reference standard of clinical diagnosis of RA with the initiation DMARDs. We found that the 2010 ACR/EULAR criteria demonstrated high sensitivity of 96.67% and slightly lower specificity of 92.86%. These results are in keeping with a recent systematic review3 which reported pooled sensitivity and specificity for initiation of any DMARDs as 0.80 (95% CI 0.79e0.82) and 0.65 (95% CI 0.61e0.68) respectively and pooled sensitivity and specificity for diagnosis of RA based on expert opinion as 0.88 (95% CI 0.86e0.90) and 0.48 (95% CI 0.45e0.52) respectively. Given the large heterogenecity in populations wide variation in the specificities ranging from 0.38 or 0.97 was found for the diagnosis of RA based on expert opinion (i.e. clinical diagnosis).3 This systematic review of 34 studies involving more than 10,000 patients found a wide variation in the performance of the new criteria but in general found higher sensitivity and lower specificity. Due to a relatively lower specificity in the present study and in several other studies4,5,8,9 it is presumed that it will incorrectly label those as having RA when in fact they may have another type of inflammatory arthritis. The importance of a thorough evaluation for confounding illnesses is stressed by these results. Clinicians need to be aware of this when applying the new criteria for classifying their patients for any purpose. It is also noteworthy that in the same systematic review compared with 1987 ACR criteria, the 2010 ACR/EULAR RA criteria have been found to have a range of 6% lower and 27% higher sensitivity and 30% lower to 10% higher specificity.3
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
Apart from relatively smaller number of patients there are some other limitations to the present study. One of these was the “reference standard” of clinical diagnosis of RA. However as we used both expert opinion (by rheumatologist with >10 years of clinical experience) and initiation of any DMARDs in accordance with several other published studies; we believe the risk of misdiagnosis to be non-existent. Other potential limitation of this study was the referral bias arising from ours being a tertiary care institution. It is likely therefore that many of the patients were more likely to have RA, and the positive predictive values might have been estimated higher than what it really is. However all parameters of the diagnostic performance of the 2010 ACR/EULAR criteria in our study fall within the reported ranges of these parameters in the recently published systematic review3 of >30 studies involving >10,000 patients. In conclusion in this first study of the performance of 2010 ACR/EULAR classification criteria for RA from India we have found that though 2010 ACR/EULAR criteria had a high sensitivity it did not identify a substantial proportion of seronegative RA classified by the 1987 criteria. Our result also underscores the need for constant clinical evaluation of patients classified as UA for its potential prognostic and therapeutic implications. Our study adds to the emerging body of knowledge from Asian countries in this particular subject area.
Author contributions VR: Conceptualized, designed, performed, analysed and manuscript preparation. AA: Data management, analysed and manuscript preparation. PVB: Conceptualized, designed, analysed and manuscript preparation.
Conflicts of interest All authors have none to declare.
5
references
1. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580e1588. 2. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315e324. 3. Radner H, Neogi T, Smolen JS, Aletaha D. Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature reveiw. Ann Rheum Dis. 2014;73:114e123. 4. Jung SJ, Kang Y, Ha YJ, et al. Application of the 2010 ACR/ EULAR classification criteria for rheumatoid arthritis in Korean patients with undifferentiated arthritis. Scand J Rheumatol. 2012;41:192e195. 5. Kaneko Y, Kuwana M, Kameda H, et al. Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria. Rheumatology. 2011;50:1268e1274. 6. Zeidler H. The need to better classify and diagnose early and very early rheumatoid arthritis. J Rheumatol. 2012;39:212e217. 7. van der Helm-van Mil AH, Detert J, le Cessie S, et al. Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: moving toward individualized treatment decision-making. Arthritis Rheum. 2008;58:2241e2247. 8. Cader MZ, Filer A, Hazlehurst J, et al. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis. 2011;70:949e955. 9. van der Linden MP, Knevel R, Huizinga TW, et al. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League against Rheumatism criteria. Arthritis Rheum. 2011;63:37e42. 10. Krabben A, Huizinga TWJ, van der helm-van Mil AHM, et al. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Ann Rheum Dis. 2012;71:238e241. 11. Huizinga TW, van der Helm-van Mil AHM. Quantitative approach to early rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2011;69:116e121.
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
ScienceDirect Available online at www.indianjrheumatol.com and www.sciencedirect.com
Original Article
Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India Vinod Ravindran a,*, Ahlam Abdulaziz a, Palli Valappil Bhargavan b a
Department of Rheumatology, bDepartment of Internal Medicine, MES Medical College, Perinthalmanna 679338, Kerala, India
article info
abstract
Article history:
Objectives: In this prospective study following were evaluated (i) whether the 2010 ACR/
Received 29 January 2014
EULAR criteria would include patients who were classified as early rheumatoid arthritis
Accepted 31 March 2014
(RA) according to the 1987 ACR criteria, and (ii) outcome by classification when followed
Available online xxx
prospectively of those patients who initially remained unclassified i.e. had undifferentiated arthritis (UA).
Keywords:
Methods: Eligible cohort (all patients with at least one clinically swollen joint) consisted of
Rheumatoid arthritis
134 patients, 120 out of which had clinical diagnosis of RA. On the eligible cohort both 1987
Classification criteria
and the 2010 criteria were applied simultaneously at the beginning of the study and 1 year
Sensitivity
later.
Indian
Results: Out of 134 eligible patients 102 were classified as RA based on 1987 criteria. A total
Early arthritis
of 82 (80%) out of 102 patients were seropositive for RA, i.e. positive for either rheumatoid factor (RF) or anti-citrullinated peptide antibody (ACPA). According to the 2010 criteria, 86 (84%) out of the 102 patients were classified as having RA and 16 did not have RA. Among the 82 seropositive patients, only 1 (1.21%) patient was classified as not having RA whereas, among 20 patients who had seronegative (both for RF and ACPA) RA, 15 (75%) patients were not classified as RA according to the 2010 criteria. Sensitivity and specificity of the 2010 criteria was 96.67% and 92.86%, respectively, compared with 85% and 85.71% by 1987 criteria. 25% of initial UA patients were reclassified as RA by the 2010 criteria at 1 year. Conclusions: The 2010 criteria did not identify a substantial proportion of seronegative RA classified by the 1987 criteria. Therefore due care must be taken when applying the new criteria to patients with arthritis who are seronegative. Clinicians should be aware and alert regarding the possibility of UA patients fulfilling classification criteria for RA over time. Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
* Corresponding author. Tel.: þ91 4933 298300. E-mail address: [email protected] (V. Ravindran). http://dx.doi.org/10.1016/j.injr.2014.03.004 0973-3698/Copyright ª 2014, Indian Rheumatology Association. All rights reserved.
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
2
1.
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
Introduction
In recent years it has become evident that early treatment of rheumatoid arthritis (RA) results in better long term outcome. As a consequence, in 2010, the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) jointly developed new classification criteria for identifying patients with early RA.1 The 2010 ACR/EULAR criteria have some important differences from the 1987 ACR criteria2; radiographic damage and rheumatoid nodules were excluded as they signify established and long standing disease. Morning stiffness was eliminated because of its lack of specificity for RA, while acute-phase reactants and a leveldependent consideration of auto-antibodies, including anticitrullinated peptide antibodies (ACPA), were included in the 2010 criteria. Given the differences in comparison with the 1987 criteria, understanding the performance of the 2010 criteria has been a focus of several studies mainly from the USA and European countries.3 Very limited data exists from the Asian countries4,5 and so far no published data exists regarding the performance of the new criteria on Indian patients with arthritis. This is important and highly relevant, as populations identified by the 2010 criteria for future studies are likely to be different from those classified by the 1987 criteria even among Indian patients, and thus, the results of clinical trials and cohort studies may not be easily comparable with the existing literature.6 Ascertaining the degree of overlap between the criteria in Indian patients who are ethnically different will help establish the extent to which previous research can be generalised to patients classified under the new system. The primary objectives of the present prospective study were (i) to assess whether the 2010 ACR/EULAR criteria would include patients who are classified as RA according to the 1987 ACR criteria, and (ii) to ascertain the outcome by classification when followed prospectively of those patients who initially remain unclassified i.e. had undifferentiated arthritis (UA)7 by re-classifying. We also assessed the sensitivity, specificity etc. of the 2010 ACR/EULAR criteria.
2.
Methods
2.1.
Patients
Between 1st October 2011 to 31st March 2012 all consecutive adult (age 18e75 years) patients (1) presenting with joint symptoms of less than one year duration and, (2) having history of joint(s) swelling were included in this study carried out at our tertiary care institution. Those patients who had at least one swollen joint on clinical examination formed the “eligible cohort”. In this cohort 1987 ACR and 2010 ACR/EULAR criteria were applied simultaneously to classify patients as either RA or as undifferentiated arthritis (UA). Relevant classification and diagnostic criteria were used to classify patients into other disease categories as and when appropriate and these patients were excluded from further analysis. To calculate the sensitivity and specificity and other performance parameters of the 2010 ACR/EULAR criteria; clinical
diagnosis of RA by experienced rheumatologist (expert opinion) with the initiation of synthetic disease modifying anti-rheumatic drugs (DMARDs) was deemed the “reference standard” in keeping with other studies.5,8 Patients were followed up for at least one year. At the end of one year from the enrolment those patients who were initially classified as UA were further subjected to an assessment by both 1987 and 2010 criteria. The protocol for this study was approved by institutional ethics committee of the institution. This study conforms to the provisions of the World Medical Association’s Declaration of Helsinki. Informed consent was obtained from all patients.
2.2.
Assessments
Data on demographics and clinical features were recorded. Standard 44 joints were assessed and clinical examination including a search for rheumatoid nodules and other extraarticular manifestations were performed by a single experienced rheumatologist at the initial visit. Laboratory investigations included rheumatoid factor (RF), anticyclic citrullinated peptide antibody (ACPA), erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and radiographs of hands and feet; to enable appropriate application of both criteria. Relevant investigations were repeated at the end of one year for patients initially classified as UA.
2.3.
Statistics
Differences in means were assessed using a two tailed, unpaired Student’s t test. Proportions were compared using c2 test. All tests were two tailed, and p < 0.05 was considered significant. Data management and analyses were carried out using the statistical package for social sciences, version 17.0.
3.
Results
3.1.
Patients (Fig. 1)
A total of 156 patients were assessed. Of these 22 were excluded as they did not have any swollen joint on clinical examination. These patients had following diagnosis for their joint symptoms; tenosynovitis (n ¼ 2), gout (n ¼ 4), SLE (n ¼ 4), psoriatic arthritis (n ¼ 5), spondyloarthropathy (n ¼ 3) and osteoarthritis (n ¼ 4). Of the remaining 134 patients (eligible cohort) who all had at least one clinically swollen joint, 120 (90%) were clinically diagnosed to have RA and were initiated on DMARDs (mainly a combination of methotrexate, hydroxychloroquine along with tapering course of oral glucocorticoids). These 120 (90%) patients therefore constituted the reference standard with the clinical diagnosis of RA. On the eligible cohort of 134 patients when 1987 ACR classification criteria were applied; 102 (76%) patients were classified as having RA and 32 (24%) as UA. When on the eligible cohort (n ¼ 134) 2010 ACR/EULAR criteria were applied; 116 (87%) patients were classified as having RA and 18 UA (13%) (Fig. 1). On following these patients prospectively for one year; none of the patients with the diagnosis of
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
3
Fig. 1 e Flow chart of patients in early arthritis cohort to compare 1987 and 2010 classification criteria for rheumatoid arthritis (RA) and outcome of undifferentiated arthritis (UA).
RA by either classification criteria or clinically were lost to follow up.
joints, levels of ESR and CRP between 82 seropositive and 20 seronegative patients (data not shown).
3.2. Does 2010 criteria identify all patients diagnosed as RA on basis of 1987 criteria
3.3. Classification outcome of initial undifferentiated arthritis patients
The mean age of 102 patients classified as RA by 1987 ACR criteria was 48.1 6 years and 87% patients were women. The mean symptom duration was 6.6 4.2 months. The mean numbers of swollen and tender joints were 8 5.7 and 7.2 5.4 respectively. Rheumatoid factor was positive in 67 patients and 55 patients were ACPA positive. A total of 82 (80%) out of 102 patients were thus seropositive for RA, i.e. positive for either RF or ACPA. According to the 2010 ACR/EULAR criteria, 86 (84%) out of these 102 patients were classified as having RA and 16 did not have RA. Among the 82 seropositive patients, only 1 (1.21%) patient was classified as not having RA whereas, among 20 patients who had seronegative RA, 15 (75%) patients were not classified as RA according to the 2010 criteria. The most frequent “scores” according to 2010 ACR/EULAR in these 102 patients were: “8” (n ¼ 36) followed by “7” (n ¼ 30) (among seropositive patients, n ¼ 82) and “4” (n ¼ 10) followed by “5” (n ¼ 6) (among seronegative patients, n ¼ 20). There were no significant differences in the demographic and clinical characteristics including age, sex, number of swollen and tender
After 1 year of follow up a total of 14 out of 134 patients were lost to follow up. In the UA category; out of original 32 UA patients according to 1987 ACR criteria 3 were lost to follow up and of the remaining 29 UA patients a further 10 (34%) were now classified as having RA based on 1987 ACR criteria (Fig. 1); this was due to presence of rheumatoid nodules (n ¼ 2), radiographic changes (n ¼ 5) and rheumatoid factor positivity (n ¼ 3). Radiographic changes were erosions and unequivocal periarticular osteopenia as per the ACR 1987 criteria. However it is important to note that 2 and 3 patients had all three or two aforementioned new features respectively. In contrast; out of original 18 UA patients according to 2010 ACR/EULAR criteria 6 were lost to follow up and of the remaining 12 UA patients a further 3 (25%) were now classified as having RA based on 1987 ACR criteria (Fig. 1), this was due to rheumatoid factor positivity in all three. More (but not statistically significant) patients still remained classified as UA when 2010 ACR/EULAR criteria were reapplied to aforementioned groups (Fig. 1).
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
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3.4. Comparative performance of the classification criteria in this cohort (Table 1) When the performance of both classification criteria was assessed against the clinical diagnosis of RA as mentioned in the methods we found that compared to the 1987 ACR criteria, the 2010 ACR/EULAR criteria had better sensitivity and specificity (85 vs. 96.67% and 85.71 vs. 92.86%, respectively) (Table 1). The positive predictive values (PPVs) were equal, and the negative predictive values and the positive likelihood ratios were better by the 2010 criteria compared to 1987 criteria (99.15 vs. 98.08%, 76.47 vs. 40% and 13.53 vs. 5.95%, respectively) (Table 1).
4.
Discussion
The impetus for developing the new 2010 ACR/EULAR classification criteria was to facilitate recognition of RA at an earlier stage compared with the 1987 ACR criteria, thereby enabling earlier enrolment into the studies. It is quite likely that similar to 1987 ACR criteria over time the new criteria would also be used by clinicians in their routine clinical care as an aid to “diagnose” RA. However, concerns have been raised about several different aspects of the utility of the new criteria.6 In the present study one of the primary objectives was to assess whether the newly developed 2010 ACR/EULAR criteria would include patients who are classified as RA according to the 1987 ACR criteria. In our study the 2010 ACR/EULAR criteria did not identify a substantial proportion of seronegative early RA (classified by the 1987 ACR criteria). Our results are similar to other studies such as from the Netherlands in which 11.3% patients who fulfilled the 1987 ACR criteria did not fulfil the 2010 ACR/EULAR criteria and 97.5% of these “1987 only” patients were seronegative for both RF and ACPA.9 Similarly in a study from Japan among seronegative patients the 2010 criteria had a sensitivity of only 15.8%.5 According to the new criteria, to be classified as RA in seronegative patients the number of affected joints should be 10 or more with at least one small joint. In our study all seronegative patients who were classified as RA according to 1987 ACR criteria but not according to the 2010 ACR/EULAR criteria had less than 10 affected joints. Therefore due care must be taken when
Table1 e Comparison of performance of 1987 vs. 2010 criteria for RA.
Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Positive likelihood ratio Negative likelihood ratio
2010 ACR/EULAR criteria
1987 ACR criteria
96.67 92.86 99.15
85.00 85.71 98.08
76.47
40.00
13.53 00.04
05.95 00.18
applying the new criteria to the patients with early arthritis who are seronegative for RF or ACPA and have small number of swollen joints. The second “primary objectives” of our study was to assess the outcome by classification on prospective follow-up up of patients who were initially classified as UA. For clinicians it is important to be aware and alert regarding the possibility of initially undifferentiated patients fulfilling both the old and new classification criteria over time. Whereas for the 1987 ACR criteria this could result from the development of rheumatoid nodules and radiographic damage; for the 2010 ACR/EULAR criteria apart from ‘1’ more point if the duration is more than 6 weeks it could also result from many more joints being affected. Positivity for RF may affect the 1987 criteria and RF and/or ACPA positivity would affect the 2010 criteria and also if a change takes place in the titers of RF or ACPA. In our study at baseline 24% and 13% patients were not classifiable according to 1987 ACR and 2010 ACR/EULAR criteria respectively reflecting the enhanced sensitivity of the later criteria over former for RA. Similar to a recent study10 our initial 2010 ACR/EULAR UA patients had milder (but not statistically significant) disease (data not shown). This might be a possible reason for higher number of patient being lost to follow up. The lack of persistent disease also did not allow reclassification as RA in this group. Aforementioned results highlight the fact that though UA patients with poor prognostic factors are likely to be classified as RA, careful clinical observation of patient with UA is necessary. The use of validated predictive tool to allow individualised treatment decisions for patients with UA has also been recommended.6,7,11 In our small cohort we also compared the performance of both criteria against a reference standard of clinical diagnosis of RA with the initiation DMARDs. We found that the 2010 ACR/EULAR criteria demonstrated high sensitivity of 96.67% and slightly lower specificity of 92.86%. These results are in keeping with a recent systematic review3 which reported pooled sensitivity and specificity for initiation of any DMARDs as 0.80 (95% CI 0.79e0.82) and 0.65 (95% CI 0.61e0.68) respectively and pooled sensitivity and specificity for diagnosis of RA based on expert opinion as 0.88 (95% CI 0.86e0.90) and 0.48 (95% CI 0.45e0.52) respectively. Given the large heterogenecity in populations wide variation in the specificities ranging from 0.38 or 0.97 was found for the diagnosis of RA based on expert opinion (i.e. clinical diagnosis).3 This systematic review of 34 studies involving more than 10,000 patients found a wide variation in the performance of the new criteria but in general found higher sensitivity and lower specificity. Due to a relatively lower specificity in the present study and in several other studies4,5,8,9 it is presumed that it will incorrectly label those as having RA when in fact they may have another type of inflammatory arthritis. The importance of a thorough evaluation for confounding illnesses is stressed by these results. Clinicians need to be aware of this when applying the new criteria for classifying their patients for any purpose. It is also noteworthy that in the same systematic review compared with 1987 ACR criteria, the 2010 ACR/EULAR RA criteria have been found to have a range of 6% lower and 27% higher sensitivity and 30% lower to 10% higher specificity.3
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004
i n d i a n j o u r n a l o f r h e u m a t o l o g y x x x ( 2 0 1 4 ) 1 e5
Apart from relatively smaller number of patients there are some other limitations to the present study. One of these was the “reference standard” of clinical diagnosis of RA. However as we used both expert opinion (by rheumatologist with >10 years of clinical experience) and initiation of any DMARDs in accordance with several other published studies; we believe the risk of misdiagnosis to be non-existent. Other potential limitation of this study was the referral bias arising from ours being a tertiary care institution. It is likely therefore that many of the patients were more likely to have RA, and the positive predictive values might have been estimated higher than what it really is. However all parameters of the diagnostic performance of the 2010 ACR/EULAR criteria in our study fall within the reported ranges of these parameters in the recently published systematic review3 of >30 studies involving >10,000 patients. In conclusion in this first study of the performance of 2010 ACR/EULAR classification criteria for RA from India we have found that though 2010 ACR/EULAR criteria had a high sensitivity it did not identify a substantial proportion of seronegative RA classified by the 1987 criteria. Our result also underscores the need for constant clinical evaluation of patients classified as UA for its potential prognostic and therapeutic implications. Our study adds to the emerging body of knowledge from Asian countries in this particular subject area.
Author contributions VR: Conceptualized, designed, performed, analysed and manuscript preparation. AA: Data management, analysed and manuscript preparation. PVB: Conceptualized, designed, analysed and manuscript preparation.
Conflicts of interest All authors have none to declare.
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references
1. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580e1588. 2. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315e324. 3. Radner H, Neogi T, Smolen JS, Aletaha D. Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature reveiw. Ann Rheum Dis. 2014;73:114e123. 4. Jung SJ, Kang Y, Ha YJ, et al. Application of the 2010 ACR/ EULAR classification criteria for rheumatoid arthritis in Korean patients with undifferentiated arthritis. Scand J Rheumatol. 2012;41:192e195. 5. Kaneko Y, Kuwana M, Kameda H, et al. Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria. Rheumatology. 2011;50:1268e1274. 6. Zeidler H. The need to better classify and diagnose early and very early rheumatoid arthritis. J Rheumatol. 2012;39:212e217. 7. van der Helm-van Mil AH, Detert J, le Cessie S, et al. Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: moving toward individualized treatment decision-making. Arthritis Rheum. 2008;58:2241e2247. 8. Cader MZ, Filer A, Hazlehurst J, et al. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis. 2011;70:949e955. 9. van der Linden MP, Knevel R, Huizinga TW, et al. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League against Rheumatism criteria. Arthritis Rheum. 2011;63:37e42. 10. Krabben A, Huizinga TWJ, van der helm-van Mil AHM, et al. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Ann Rheum Dis. 2012;71:238e241. 11. Huizinga TW, van der Helm-van Mil AHM. Quantitative approach to early rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2011;69:116e121.
Please cite this article in press as: Ravindran V, et al., Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis in a prospective early arthritis cohort in Kerala, India, Indian Journal of Rheumatology (2014), http://dx.doi.org/10.1016/ j.injr.2014.03.004