IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Evaluating the patient with vertigo: A complex complaint made simple; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

KEY POINTS

■ Research initiatives support an early, aggressive approach to the diagnosis and treatment of rheumatoid arthritis (RA) based on the observation that disease-modifying therapies can prevent long-term joint damage.

■ The 1987 American College of Rheumatology criteria are the accepted standard for diagnosis but are unable to identify persons with early-stage RA (when treatment may do the most good).

■ The new 2010 proposed criteria define definite RA based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the presence of synovitis, and a score of 6 or higher out of 10 from individual scores in four domains.

■ Improvements in the delivery of care for patients with new-onset RA can be realized through adoption of the principles of early recognition and management outlined in the newly revised criteria for the diagnosis of RA.

Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting in polyarthritis. Joint manifestations typically include pain, swelling, stiffness, and functional limitations. Two of the most important factors contributing to a poor prognosis in patients with RA are a delay in diagnosis and a delay in initiating treatment with disease-modifying antirheumatic drugs (DMARDs). Both factors are greatly impacted by a delay in referring the patient to a rheumatologist. Recognizing the signs and symptoms of early RA is imperative so that the window of opportunity for treatment that has the best chance to minimize disability and optimize outcome is not missed.

Research initiatives support an early, aggressive approach to the diagnosis and treatment of RA based on the observation that DMARDs can prevent long-term joint damage (Figure 1). Early intervention is critically important because RA can progress rapidly and damage joints even in its early stages.1 Because of this, the goal of therapy has shifted to providing earlier treatment of RA. 


The term early RA is not well-defined in the literature, which has resulted in an urgency within the rheumatologic community to look at alternative measures to assist in the early detection of this disease. Concern has grown that the 1987 American College of Rheumatology (ACR) diagnostic criteria for RA lack sensitivity in identifying early-stage 
disease. Many patients presenting with early RA do not meet the 1987 criteria until their disease is more advanced. As a result, these patients are not recognized as having RA, and disease-modifying agents are not started until much later in the course of their disease.


With the current barriers to early diagnosis of RA, generalist clinicians must develop the skills necessary to identify early disease so that rheumatologic referral can be made in a timely manner. In September 2010, proposed changes to the 1987 criteria were published.2 The revised criteria resulted from collaboration between the ACR and the European League Against Rheumatism (EULAR) in order to more clearly define RA. These changes address the limitations of the 1987 ACR classification criteria to promote earlier diagnosis of RA and to differentiate it from other inflammatory joint conditions.2 


BACKGROUND


Rheumatoid arthritis is characterized by inflammatory arthritis that involves multiple joints. Often RA begins gradually and affects the small joints of the hands, wrists, and feet before moving to larger joints. According to the CDC, the prevalence of RA in the United States is approximately 1%, and it constitutes the most common form of chronic inflammatory arthritis.3 If not appropriately managed, RA can lead to substantial physical disability and even to premature death.4 If their condition is left untreated, 20% to 30% of patients with new-onset RA become permanently work-disabled within 2 to 3 years, making RA a major public health concern.5 


The initial course of RA is known to involve a lag time of several months between the onset of symptoms and diagnosis. This lag time is due to delay between the onset of symptoms and the first medical encounter and further delay between the first medical encounter and diagnosis. In a review of medical records from a health maintenance organization in central Massachusetts, Chan and colleagues evaluated 81 patients who received a new diagnosis of RA between 1987 and 1990.6 This review demonstrated that the average time between initial presentation for evaluation of joint pain to confirmation of a diagnosis of RA was 18 weeks.6 


In a prospective follow-up study performed by Fex and colleagues, 113 patients with definite RA and mean disease duration of 11.4 months were followed prospectively over 5 years.7 Radiographs of the hands and feet were obtained annually during the study period. Findings revealed that radiologic damage is significantly progressive during the first 5 years following the onset of joint pain, with the rate of progression being most prominent within the first 
2 years.7 


Since 1987, new therapies for RA have emerged that have been shown to control synovitis and to slow, or even stop, radiographic progression of joint damage.8 Over the past decade, the optimal use of DMARDs and the availability of new biologic agents have enhanced RA management. Additionally, the longer active disease persists without being treated, the less likely the patient is to respond to therapy.9 These findings, as well as evidence confirming early joint damage in the disease course, have emphasized the importance of early intervention. As such, the goal of therapy has shifted to providing earlier treatment to prevent long-term joint damage. 


THE 1987 RA CLASSIFICATION CRITERIA


The 1987 ACR criteria are the accepted standard used by rheumatologists and provide the benchmark for defining established RA.10 These criteria were devised to distinguish patients with established RA from those with a combination of other definite rheumatologic diagnoses. The 1987 criteria were developed from a computerized analysis of 262 patients with RA and 262 control subjects with rheumatic diseases other than RA and include the following:


  • Morning stiffness in and around joints lasting at least 
1 hour

  • Arthritis manifesting as soft tissue swelling of three or more joint areas

  • Arthritis (swelling) of hand (proximal interphalangeal, metacarpophalangeal) or wrist joints

  • Symmetric arthritis (swelling)

  • Rheumatoid nodules

  • Positive test result for serum rheumatoid factor (RF) 

  • Radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints


The presence of at least four of these seven criteria has approximately 90% sensitivity and 90% specificity for established RA.10


LIMITATIONS OF THE CURRENT CRITERIA


When used to diagnose early RA, the 1987 criteria have several important limitations. The most important is 
that they were developed from studies of patients with well-established disease and so they are unable to identify persons with early-stage RA (those for whom treatment may do the most good). A study by Machold and colleagues looked at 108 patients who presented with symptoms of swelling or pain in a single joint for less than 3 months duration and elevated serological inflammatory markers, including leukocytosis and elevations in ESR and C-reactive protein (CRP) levels.11 These patients were assessed every 3 months using clinical evaluation and laboratory testing; radiographs of the hands and feet were taken at the beginning of the study and at 1 year of follow-up. Results confirmed that only 52% of the patients who had RA diagnosed 1 year after presentation using the 1987 criteria had met those criteria at the time of presentation.11 


The physical examination features included in the 1987 criteria also work against the early diagnosis of rheumatoid arthritis. For example, the presence of rheumatoid nodules—which are strongly associated with a positive RF and severe erosive RA—is one of the seven criteria for establishing a diagnosis of RA. In most cases, however, rheumatoid nodules—as with joint deformities—do not appear for months or even years after the onset of synovitis.12 Thus, the absence of nodules is not evidence against the diagnosis of RA. 


Symmetric arthritis and swelling of the hand and wrist joints are also listed in the 1987 criteria for the diagnosis of RA, even though early disease patterns of presentation can be variable in RA. In early disease, asymmetric and even single-joint involvement is often observed. Additionally, involvement of both the upper and lower extremities is characteristic for RA and is more predictive than findings of either the upper or lower extremity alone.13 


Patients with RA demonstrate variability in their initial laboratory test results as well. Connective tissue disorders other than RA can produce a positive rheumatoid factor, making this test less specific for the diagnosis of early RA. For example, a positive RF is common in Sjögren syndrome, lupus erythematosus, and mixed connective tissue disease; and chronic infections, including hepatitis C and endocarditis, can also produce RF antibodies. 


The association of a high titer RF with RA was not fully appreciated at the time that the 1987 criteria were devised. In a prospective follow-up inception cohort, Nell and colleagues measured autoantibodies in 200 patients with very early inflammatory joint disease.14 Patients were included in this study if they met the following criteria: symptom duration less than 3 months, synovitis of at least one joint, and elevated serologic inflammatory markers. The study demonstrated that a high RF titer was associated with a sensitivity of 96% for rheumatoid arthritis and was associated with a high risk for poor outcomes as evidenced by radiographic progression of disease.14 


When the 1987 criteria were developed, testing for anticyclic citrullinated peptide (anti-CCP) antibodies was not possible. Since then, anti-CCP antibodies have gained importance in the diagnosis of RA; they are more specific but less sensitive than RF for diagnosing RA.15 Evidence also suggests that a positive anti-CCP antibody result in conjunction with a positive RF are strong indicators for the diagnosis of RA. In a study by Jansen and colleagues evaluating the diagnostic value of RF antibodies and anti-CCP antibodies, 15,379 patients with peripheral arthritis of two or more joints of less than 3 years duration were evaluated.15 Experienced rheumatologists diagnosed RA in 258 patients and an undifferentiated inflammatory arthritis in 121 patients. In this study, patients who received diagnoses of spondyloarthropathies (such as psoriatic arthritis, reactive arthritis, and ankylosing spondylitis) were excluded. Even though findings suggest that positive RF antibodies and anti-CCP antibodies were independent of one another in the Jansen study,15 strong evidence supports that the optimal criteria for the diagnosis of RA would be a combination of both of these markers. In another study by Schellekens and colleagues, positivity of both the RF and anti-CCP antibodies were found in 50% of patients within the first months following onset of symptoms.16


Finally, radiographic findings of joint erosion as specified in the 1987 criteria may pose limitations for excluding other conditions. Even though joint erosion strongly suggests a diagnosis of RA, it is not necessarily a specific finding. While radiographic presentation and location may vary, erosions can be seen in several inflammatory joint conditions, including gout and psoriatic arthritis. Additionally, erosions are seldom seen in the first 3 months following the onset of symptoms, as noted in a study by Machold and colleagues.1 In this study, erosive disease developed in 63.3% of 55 patients over a 3-year period; 74.3% of those who developed erosive disease had it by the end of the first year, and 97.2% had it by the end of the second year.1 These findings are consistent with those reported by Fex and colleagues, which demonstrated that the rate of radiographic progression was most prominent in the first 2 years following the onset of symptoms.7 


REVISIONS TO THE 1987 CRITERIA 


In September 2010, the collaboration between the American College of Rheumatology and the European League Against Rheumatism produced three phases of recommended changes to the 1987 criteria.2 The first phase, led by EULAR, 
consisted of reviewing existing data collected from patients with early arthritis. This was an attempt to identify patients at high risk for more persistent erosive arthritis considered to be RA by the 1987 criteria. The next phase, led by the ACR, focused on reaching a consensus among practicing rheumatologists to identify the most important factors in predicting the likelihood that a patient will experience chronic joint damage. In phase three, the first two phases were integrated and a scoring system to define disease was established.2 


The new criteria define definite RA based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the presence of synovitis, and a score of 6 or higher out of 10 from individual scores in four domains (Table 1).2 


The first domain refers to any swollen or tender joint found on clinical evaluation and assigns a score between 0 and 5 based on the following criteria:


  • One large joint (0)

  • Two to ten large joints (1)

  • One to three small joints (2)

  • Four to ten small joints (3)

  • Greater than 10 joints with at least one small joint (5).


Categories of joint distribution in this domain are classified according to the location and number of involved joints. Placement into the highest category possible is based on the pattern of joint involvement in which at least one of the involved joints must be a small joint. Large joints refer to shoulders, elbows, hips, knees, and ankles. Small joints refer to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. Joints excluded from this domain include distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints.2


The second domain refers to serologic abnormality and assigns a score between 0 and 3. This is based on the following criteria:


  • Neither RF nor anti-CCP antibody positive (0)

  • At least one test (RF or anti-CCP antibody) low positive titer (2)

  • At least one test high positive titer (3).


Definition of a negative RF refers to international unit (IU) values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay. A low positive refers to IU values that are greater than the ULN but less than 3 times the ULN for the laboratory and assay. High positive refers to IU values that are 3 times the ULN for the laboratory and assay. Where RF information is available only as positive or negative, a positive result should be scored as low positive for RF. Determination of anti-CCP antibody positivity is determined by local laboratory standards.2


The next domain is duration of synovitis. This category assigns a score of either 0 or 1 according to the patient self-report of the duration of signs or symptoms of synovitis. Signs or symptoms refer to pain, swelling, and/or tenderness of joints that are clinically involved at the time of assessment. This is based on the following criteria:


  • Duration of symptoms less than 6 weeks (0)

  • Duration of symptoms 6 weeks or longer (1).


The final domain refers to acute phase response and assigns a score of 0 or 1. This score is based on the results of the ESR and CRP. Scores are assigned based on the following criteria:


  • Neither ESR nor CRP abnormal (0)

  • Abnormal ESR or abnormal CRP (1).
 

RECOMMENDATIONS TO IMPROVE PRACTICE


Rheumatoid arthritis is a persistent, progressive disease that can lead to functional decline, poor quality of life, and even shortened life expectancy. Erosions and radiographic progression of disease occur early, suggesting that the optimal time for treatment is in the early stages of the disease. Thus optimal treatment requires an accurate diagnosis that can distinguish RA from other forms of arthritis. 


The 2010 criteria were officially presented in September 2010. Final approval was quantitatively validated using patient data as well as an external data set. Investigations are now being performed to evaluate the diagnostic and discriminative ability of the new criteria compared with the 1987 criteria. From a provider perspective, the 2010 ACR criteria reinforce the concept that the diagnosis of RA is a clinical one, based almost exclusively on the history and physical examination. No single finding, either on examination or from laboratory testing, is pathognomonic for RA. The new criteria, including patient testing, best apply to patients with at least one joint with definite clinical synovitis and those whose synovitis is not better explained by another inflammatory joint disease. 


The importance of making an accurate diagnosis of RA as early as possible cannot be overemphasized. Clinicians


have a responsibility to incorporate the best available research evidence to facilitate early recognition and management of this disease. Improvements in the delivery of care for patients with new-onset RA can be realized through adoption of the principles of early recognition and management outlined in the newly revised criteria for the diagnosis of RA. 


Evidence indicates that early diagnosis and aggressive management of RA are essential to preserve function and prevent disability. The importance of early rheumatologic referral is critical to ensure that effective treatments are begun when they have the maximum chance of making the biggest differences, while at the same time protecting patients who do not have RA from the potential toxicities of therapies. JAAPA

Linda Sekhon practices rheumatology at the University of Pittsburgh Medical Center and is an assistant professor in the Duquesne University PA program, Pittsburgh, Pennsylvania. The author has indicated no relationships to disclose relating to the content of this article.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Evaluating the patient with vertigo: A complex complaint made simple; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

REFERENCES


1. Machold KP, Stamm TA, Nell VPK, 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(2):342-349. 


2. Aletaha D, Neogi T, Silman SJ, et al. 2010 rheumatoid arthritis classification criteria: an 
American College of Rheumatology/European League Against Rheumatism collaborative 
initiative. Arthritis Rheum. 2010;62(9):2569-2581. 


3. Prevalence of doctor-diagnosed arthritis attributable activity limitation—United States, 2007-2009. MMWR Morb Mortal Wkly Rep. 2010;59(39):1261-1265. 


4. Hochberg MC. Early aggressive DMARD therapy: the key to slowing disease progression in rheumatoid arthritis. Scand J Rheumatol. 1999;28(112 suppl):3-7. 


5. Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(5):1-4. 


6. Chan K-WA, Felson DT, Yood RA, Walker AM. The lag time between onset of symptoms and diagnosis of rheumatoid arthritis. Arthritis Rheum. 1994;37(6):814-820. 


7. Fex E, Jonsson K, Johnson U, Eberhardt K. Development of radiographic damage during the first 5-6 yr of rheumatoid arthritis. A prospective follow-up study of a Swedish cohort. Br J Rheumatol. 1996;35(11):1106-1115. 


8. Savolainen E, Kautianen H, Koivula MK, et al. Change of diagnoses and outcome of patients with early inflammatory joint diseases during a mean 13-month follow-up. Scand J Rheumatol. 2007;36(3):194-197. 


9. Revised RA classification criteria allow for earlier study of treatments. J Musculoskel Med. September 7, 2010. http://www.musculoskeletalnetwork.com/display/article/1145622/1659810. Accessed August 23, 2011.


10. 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(3):315-324. 


11. Machold KP, Stamm TA, Eberl GJ, et al. Very recent onset arthritis—clinical, laboratory, and radiological findings during the first year of disease. J Rheumatol. 2002;29(11):2278-2287. 


12. Ziff M. The rheumatoid nodule. Arthritis Rheum. 1990;33(6):761-767. 


13. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(1):18-24. 


14. Nell VPK, Machold KP, Stamm TA, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005;64:1731-1736. 


15. Jansen ALMA, Horst-Bruinsma I, Schaardenburg D, et al. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol. 2002;29(10):2074-2076. 


16. Schellekens GA, Visser H, De Jong BAW, et al.. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000;43(1):155-163.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Evaluating the patient with vertigo: A complex complaint made simple; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.