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  1. Re:Clarification of the role of ultrasonography, magnetic resonance imaging and conventional radiography in the ACR/EULAR 2010 rheumatoid arthritis classification criteria - comment to the article by Aletaha et al.

    Dear Editor,

    We thank Dr. Ostergaard for the comment on the mentioned article on the ACR/EULAR classification criteria. As co-authors on that manuscript, we confirm that all points mentioned by the authors are correct:
    - Only patients with a clinical synovitis, which is not clearly better explained by another disease entity are eligible for testing.
    - MRI and US may be used to determine a more complete joint involvement AFTER the patient has been found eligible.
    - Classification is usually a procedure in early disease. However, some problems may occur in the rare scenario of classification attempts in late disease, as patients may have become inactive. For those patients with a long history, but without a documentation of the domains, a standard radiograph may be used (as correctly mentioned in the e-letter).
    - In case a patient with established/late disease brings documentation on the domains that show active classifiable disease in the past, classification can also be made retrospectively.
    Although these issues are mentioned in the manuscript, we agree that it is certainly very important to re-emphasize, as they are critical to a correct classification. In this regard it is also very important to again stress that the classification criteria do include several aspects of isease activity, and that therefore, if a patient is then well treated, they will become negative again. This is, similar to the previous criteria, NOT indicating that this patient does not have classified rheumatoid arthritis anymore.
    Although, the construct of the new criteria will hopefully be a basis for classification of RA in the extended future, there is the possibility of amending these as new evidence is generated. This includes long term implications of MRI/US findings in patients with clear conventional radiographs, such as possibly evidenced by newer studies, some of which are cited by Dr Ostergaard.

    One main objective of the classification committee was to provide criteria, which are to be usable world-wide, considering possible limited access to new imaging techniques or other, more advanced diagnostic tests, such as ACPA. The latter were therefore not asked for exclusively in the classification system. This thought on general feasibility should be kept in mind, even as hopefully convincing new evidence for new diagnostic markers comes along.

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  2. Clarification of the role of ultrasonography, magnetic resonance imaging and conventional radiography in the ACR/EULAR 2010 rheumatoid arthritis classification criteria - comment to the article by Aletaha et al.

    Dear Editor,

    With large enthusiasm I read the paper on the 2010 ACR/EULAR RA classification criteria,[1,2] which in the interest of our patients allow earlier diagnosis of rheumatoid arthritis (RA). I congratulate the authors for their hard and successfull work, which I am sure will benefit our patients.
    Being interested in imaging methods and the way they can assist rheumatologists in improving the care of patients with RA, I have attended several presentations and/or discussions by various authors of the manuscript, incl. Professors Aletaha and Smolen. From these presentations/discussions the roles of imaging in the new criteria were clear and unambiguous. However, the published manuscript is less explicit on some areas, and the roles of imaging may seem more limited than the authors explained orally, eventhough it seems unlikely that the criteria have been changed. This has led to some confusion in the imaging field, which needs to be resolved.

    To recapitulate, classification as definite RA is based on presence of definite clinical synovitis (swelling at clinical examination) in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score at least 6(of a possible 10) from the individual scores in 4 domains: number/site of involved joints(score range:0-5), serologic abnormality (range 0-3), elevated acute-phase response(range:0-1), and symptom-duration(range:0-1).[1,2]
    It was very clear from the above-mentioned presentations/discussions (but not from the paper) that joint involvement by detection of joint inflammation(synovitis) by MRI or US counted in the scoring in the "joint involvement domain". For example, this means that a patient with 2 clinically swollen small joints, in which MRI or US confirms the 2 swollen small joints but also detects 3 additional small joints with obvious synovitis (as assessed by MRI/US), will have a total of 5 involved joints and a resulting score of 3 in the "joint involvement domain".

    It should be emphasized that the initial requirement of "presence of synovitis in at least 1 joint", which allows the patient to enter the score-based algorithm, can only be achieved by detection of swelling by clinical (not imaging) examination.

    Concerning radiography, the above-mentioned presentations included an illustration describing that patients with "typical RA erosion on conventional radiographs" on top of fulfilling the 2 initial criteria (synovitis in at least 1 joint and absence of an alternative diagnosis better explaining synovitis), sufficed for fulfilling the RA criteria. The paper does not include a such figure but states "patients with erosive disease typical of RA with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA".

    A role of MRI and US in the diagnosis of RA is supported by the fact that MRI/US are much more sensitive for detection of synovitis than clinical examination, that MRI/US can detect subclinical inflammation in patients in clinical remission,[3,4] and that such findings are predictors of subsequent radiographic erosive progression in early RA,[5-9] and of development of RA in undifferentiated arthritis.[10] However, the purpose of this letter is not to argue for the virtues of MRI and US, but solely to make sure that the roles of imaging in th new RA criteria are made totally clear.

    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;69:1580-8.

    2. Aletaha D, Neogi T, Silman AJ et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.

    3. Brown AK, Quinn MA, Karim Z et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006;54:3761-73.

    4. Gandjbakhch F, Conaghan PG, Ejbjerg B et al. Synovitis and osteitis are very frequent in rheumatoid arthritis clinical remission: Results from an MRI study of 294 patients in clinical remission or low disease activity state. J Rheumatol 2010;(In Press).

    5. Brown AK, Conaghan PG, Karim Z et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008;58:2958-67.

    6. Haavardsholm EA, Boyesen P, Ostergaard M et al. Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis 2008;67:794-800.

    7. Hetland ML, Ejbjerg B, Horslev-Petersen K et al. MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis 2009;68:384-90.

    8. Hetland ML, Stengaard-Pedersen K, Junker P et al. Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial. Ann Rheum Dis 2010;69:1789-95.

    9. Boyesen P, Haavardsholm EA, Ostergaard M et al. MRI in early rheumatoid arthritis: synovitis and bone marrow oedema are independent predictors of subsequent radiographic progression. Ann Rheum Dis 2010; Online First, published on August 31, 2010 as 10.1136/ard.2009.123950.

    10. Duer-Jensen A, Horslev-Petersen K, Hetland ML et al. MRI bone edema is an independent predictor of development of rheumatoid arthritis in patients with early undifferentiated arthritis. Arthritis Rheum 2010;62:S55-S56.

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  3. Anti-CCP report: clinicians should be aware!

    Dear Sir

    The article describing '2010 Rheumatoid Arthritis Classification Criteria' is very informative and contains much useful practical guidance. However there are factual errors regarding the measurement of ACPA/CCP which ought to be corrected.

    With a high specificity anti CCP is very useful for early diagnosis of rheumatoid arthritis. [1, 2, 3] While the definition of positivity is understandably vague given the lack of correlation and standardization of assays, the discussion of the reporting of CCP in 'IU' is an error which will lead clinicians to believe that there is meaningful standardisation of testing.

    Although Rheumatoid factor (RF) assay standardization is still suboptimal, it can be reported in 'IU' when using assays such as nephelometry, turbidimetry, EIA (enzyme linked immunoassay) since IRP is available to calibrate against (WHO, NIBSC code- W1066). [4, 5]
    In contrast, at least (11) assays are available for detecting anti CCP in the UK yet currently there is no current IRP for anti-CCP nor is there consistency in reporting of units. Stating that there are 'IU' for anti CCP measurement can unintentionally lead to the assumption that one CCP result is equivalent, and comparable with another. How could a clinician be assured that what is "high-titre" in one assay is not "low-titre" in another?

    Some manufacturers report in arbitrary U/ml. [6, 7, 8, 9, 10]. Some calibrations are heterologous and made against an immunoglobulin standard lyophilized human immunoglobulin G, A, and M (WHO, NIBSC code-67/086) [4, 5]. The units are not truly anti-CCP IU; they are essentially still arbitrary units and do not prove equivalence between assays or imply standardisation.

    Guidelines often require clinical management decisions on the basis of diagnostic tests. This article has rightly pointed out that pathogenetic and prognostic perspective of RA is found to be different depending upon the positivity of ACPA. Therefore input from experts in laboratory testing is essential to ensure the recommendations are robust and achievable in real-life testing and in the knowledge of the true performance characteristics of a "test". [4] Since anti-CCP is an important assay, future development of IRP is required to enable standardised decision making on the basis of test equivalence across centres and methods. Furthermore, if such tests are to be used, there should be a recommendation for appropriate quality assurance such as participation in 'External Quality Assurance' programmes to ensure equivalence of testing across geographical networks and time.

    References

    1. Bas S, Perneger T V, Seitz M, et al. Diagnostic tests for rheumatoid arthritis: Comparison of anti-cyclic citrullinated peptide antibodies, anti-keratin antibodies and IgM rheumatoid factors. Rheumatology 2002;41:809-814.

    2. Forslind K, Ahlm?n M, Eberhardt K, et al. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis 2004;63:1090-1095.

    3. Zendman A J W, Venrooij W J van, Pruijn G J M. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006; 45:20-25.

    4. http://www.who.int/bloodproducts/publications/Final_Prep_Stds_Nov2004.pdf

    5. http://www.who.int/bloodproducts/catalogue/ImmuJan10.pdf

    6. http://www.aesku.com/

    7. http://www.eurodiagnostica.com/

    8. http://www.phadia.co.uk/upload/Autoimmunity/Products/Files/Product_Catalogue_AI_2010.pdf

    9. http://www.axis-shield.com/assets/Diastat_Anti-CCP_Brochure.pdf

    10. http://www.euroimmun.com

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