February, 2006 - CRA Journal Club Review by Dr. B. BISSONNETTE
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Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis
Auteurs : V P K Nell, K P Machold, T A Stamm, G Eberl, H Heinzl, M Uffmann, J S Smolen, G Steiner - Annals of the Rheumatic Diseases, déc. 2005, vol. 64, no 12, p. 1731 - 1736
Dr. B. Bissonnette
M.D., FRCPC |
Editorial:
By Dr. B. Bissonnette In order to prevent its progression, emphasis has recently been placed on the early detection and treatment of rheumatoid arthritis (RA). But because many of the inflammatory joint diseases present with similar symptoms, diagnosis can be a challenge. Moreover, the criteria established in 1987 for RA often aren’t met in the early stages. Thus the instigation of early DMARD treatment appears to be even more desirable because erosions can occur within the first months. Rather than waiting for all criteria to be met, it becomes essential to attempt to rapidly anticipate the potential for damage from this disease.
According to the 1987 criteria established by the American Rheumatism Association, the only serological marker for the disease remains the rheumatoid factor (RF). It is associated with the more aggressive forms of the disease, especially when present in high titers. But it is often absent when symptoms first appear.
| Here, the authors have studied the value of the rheumatoid factor (RF), anti-CCP autoantibodies (cyclic citrullinated peptide) and the anti-RA33 autoantibodies (directed against the heterogeneous nuclear ribonucleoprotein A2) in the early diagnosis of RA as well as their prognostic value.
The prospective follow-up inception cohort included 200 patients recruited within the Austrian Early Arthritis Action registry, based on the following inclusion criteria: early (< 3 months) symptoms, synovitis in at least one joint, sedimentation > 20mm per hour and CRP > 5 mg/l. Patients had to be reexamined over a minimum 6-month period.
The autoantibodies were initially measured and analyzed according to a decisional tree model aimed at determining the added diagnostic and prognostic value of anti-CCP and anti-RA33 as compared with rheumatoid factor alone. To do this, an ROC (receiver operator curve) analysis was designed.
DAS-28 was used to measure the disease activity. For patients with rheumatism, X-rays of the extremities were taken annually and modified Larsen scores were used.
The ROC curve analysis demonstrated that over and above an FR of 50 U/ml, the anti-CCP and/or anti-RA33 had no additional diagnostic value. The presence of erosion with rheumatoid patients followed for at least one year was the major outcome variable of the study to judge the prognostic value of autoantibodies.
After one year, 102 of the 200 patients were considered as rheumatoid. The curve of joint destruction progression was more abrupt with those who had high titer RF and/or anti-CCP compared to sero-negatives.
If initial DAS-28 scores were the same, the improvement was nonetheless greater in sero-negatives during the course of the disease. In contrast, the presence of anti-RA33 underlined a better sustained therapeutic response, in fact, superior to that observed when the three autoantibodies were negative.
Because 45% of the 102 patients who developed an RA and only 4% of the 98 others were RF positive, it seemed unnecessary to “push” the serology. Whereas amongst the 150 remaining patients, the anti-CCP antibodies revealed 14 other patients with RA, while only 2 patients without RA proved to be positive. This gives an initial seropositivity of 59% in rheumatoids and 6% in non-rheumatoids. In the 134 sero-negatives from both groups the anti-RA33 revealed 13 seropositives, but they were also found in 9 non-rheumatoids.
This study allows for the identification of patients who would benefit from a more in-depth initial serology. The higher cost of determining anti-CCPs could be counterbalanced by the fact that it is unnecessary to repeat them (very few sero-conversions) and by limiting research to those who have an RF inferior to 50.
The conclusions of this study corroborate those of previous studies undertaken in other centres that proposed a “redefinition” of seropositivity at 50 U/ml. It has the added advantage of including an important number of patients presenting with very early inflammatory arthropathy.
References:
Nielen MM, van der Horst AR van Schaardenburg D, et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann Rheum Dis 2005;64:1199-204
Jansen Al, van der Hosrt-Bruinsma I, van Schaardenburg D et al. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis and undifferentiated arthritis in patients with early arthritis. J Rheumatol 2002;29:2074-2076
Learning Objectives :
- Determine the diagnostic and prognostic values of diverse autoantibodies ( rheumatoid factor, anti CCP, anti RA33 ) in very early inflammatory arthritis.
- Determine in which situation a more elaborate antibody profile might be worthwhile.
ABSTRACT
BACKGROUND: Early treatment prevents progression of joint damage in rheumatoid (RA), but diagnosis in arthritisearly disease is impeded by lack of appropriate diagnostic criteria.
OBJECTIVE: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis.
METHODS: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone.
RESULTS: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional fordiagnostic value. Remarkably, RF >or=50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF >or=50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease.
CONCLUSIONS: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.
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CRA Forum : February, 2006 Journal Club Review by Dr. B. BISSONNETTE
Topic: Review
