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Rheumatology Advance Access originally published online on July 13, 2006
Rheumatology 2006 45(9):1055-1057; doi:10.1093/rheumatology/kel187
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIAL

The measurement of outcome and the rheumatoid arthritis core set to lift the prejudice of the ‘thaumaturgus cliché’

L. Bertinotti, F. Nacci and M. Matucci-Cerinic

Division of Medicine I & Rheumatology, AOUC, University of Florence, Italy

Correspondence to: M. Matucci-Cerinic, MD, PhD, Viale Pieraccini 18, 50139 Firenze (Italy). E-mail: cerinic{at}unifi.it

For many decades in the past century, the lack of drugs specifically designed to treat rheumatic diseases kept rheumatology in a long ‘lethargy’, where the doctor felt more like a ‘thaumaturgus’ — miracle worker — with limited therapeutic possibilities.

One of the most ancient needs for the physician has always been the ability to measure the efficacy of the therapy he prescribes. However, this primary necessity cannot be separated by the patient's main need ‘to feel better, to feel good’. Nevertheless, patient's and physician's point of view sometimes do not completely match: physicians give great value to activity indices of the disease, while patients do not consider fundamental the metric parameters that doctors use, and their only leitmotif is to improve their state of health. In modern terms, the problem is how to unify the efficacy/outcome together with patient's need and, in particular, his ‘quality of life’.

Moreover, quantitative measurements of activity of the rheumatic diseases have been unsatisfactory because of poor sensitivity and specificity [for example, rheumatoid factor, erythrocyte sedimentation rate (ESR) and antinuclear antibodies], and the lack of univocal ‘gold standard’ assessment of the status of a single patient [1].

At the end of the 1980s, experts perceived the need of evidenced-based medicine (EBM) and the status quo of the rheumatologist and his capacity to measure activity and outcome began to change. Clinical trials started to be designed with a more accurate, reliable and reproducible evaluation of the results. To assess outcome, a great deal of work was done reconsidering the old methods that in the past consisted only of the physician's point of view based on clinical signs, inflammatory parameters, radiographic aspects and, sometimes marginally, patient's point of view.

Today, the awareness of the patient's needs and the heavy burden of rheumatoid arthritis (RA) for the social security system for the patient and his family have led the rheumatologists to develop more precise measures to allow a correct evaluation of their treatments, with the inclusion of both patient's and doctor's point of view [2].

In the early 1990s, the standardization of clinical trials in RA was reconsidered by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) as well as during the Outcome Measures in Rheumatoid Arthritis Clinical Trial (OMERACT) consensus conference. In the consensus, the ‘core data set of outcome measures’ were established to make a clinical trial feasible and acceptable worldwide [3]. On the basis of five types of criteria of validity (construct, face, content, criterion and discriminant) [4], using a consensual–statistical accordance among the selected experts, seven disease activity measures were proposed: (i) tender joint count, (ii) swollen joint count, (iii) patient's assessment of pain, (iv) patient's global assessment of disease activity, (v) physician's global assessment of disease activity, (vi) patient's assessment of physical function and (vii) ESR or C-reactive protein (CRP) evaluation, for trials of DMARDs, with a duration >1 yr [3]. Other disease activity measures, such as joint count scores, previously largely used in trials, were excluded because of redundancy or poor sensitivity to RA activity variations. Also, X-ray changes were discouraged in clinical trials of brief duration (<1 yr), although they are still an easy, cheap and reproducible measure of outcome in RA long-lasting trials and in observational studies. Radiographic changes reflect articular inflammation over time and correlate with disability [5]. It was recommended to count the number of painful and tender joints (points 1 and 2) and to use visual analogue scales (VAS) or Likert descriptive scale (point 3, 4 and 5). Point 6 could be assessed by several instruments (e.g. health assessment questionnaire (HAQ), arthritis impact measurement scale (AIMS), and McMaster and Toronto Arthritis patient preference disability questionnaire (MACTAR) [3] and point 7 always by ESR (Westergren method) or CRP [3].

The leading work of OMERACT and ACR inspired several studies in the following literature studying different aspects of RA. Indeed, OMERACT has approached multitude of questions, such as the validation of an MRI score [6], the clinimetric revision of quality of life instruments [7], the social and economic aspects of rheumatic diseases [8, 9], the core efficacy end points that should be established in the clinical trials [10] and the patient's viewpoint as integral part of end points of the studies [11]. Recently, it also addressed the evaluation of the effects of new biological therapies [12] and pharmacovigilance [13, 14]. Various works have established the superior statistical power of the combined method (physician's and patient's viewpoint) proposed at the OMERACT conference [15], and many efforts are now done to value the opinion of patients about their disease status, such as the recent International Classification of Functioning, Disability and Health Comprehensive Core Set [16].

Based on the same core set (ACR core set) parameters, the ACR20 criteria were derived, that is, improvement criteria based on a minimum 20% improvement of both tender and swollen joint counts, in addition to three of the other five measures of ACR core data set [2]. Finally, OMERACT reviewed also previous radiological evaluating methods (indices of damage), such as Larsen, Larsen/Rau, Sharp, Sharp/van der Heijde and Simple Erosion Narrowing Score (SENS) [17], proposed an ongoing standardization of the interpretation of X-rays [18] and considered new potential imaging methods like ultrasound [19] and MRI [20].

The alternative to ACR core set are the response criteria developed by the European League Against Rheumatism (EULAR) [21], which produce continuous, instead of dichotomous (‘yes or not’), variables given in ACR criteria. The response criteria specifically developed to evaluate DMARD therapy and classify patients as non-moderate, or good responders, proved to be of comparable validity to ACR20 [22]. In the EULAR response criteria, the Disease Activity Score (DAS) [23, 24], which derives RA activity by combining swollen joints, tender joints, acute phase reactants and general health status, is included. Also the simplified form of the DAS, DAS28, derived by a 28 tender joint and 28 swollen joint count, ESR and a general health assessment, may be used to calculate EULAR response criteria [24].

Recently, a revised form of ACR20, ACR-N, which, like DAS and EULAR response criteria, generates a continuous variable, has been proposed to recognize the worsening of RA patients’ status [25].

Besides, a self-administered Rheumatoid Arthritis Disease Activity Index (RADAI), a patient-derived DAS without objective assessment tools [26], was proposed in substitution of physician-derived scales [27], but is still not unanimously accepted [28].

Despite the existence of all these different scales and absence of a really worldwide standardization, the pivotal requirement remains, to date, the exact definition not only of RA activity and remission but also of the patient perception of the disease in order to provide a correct and univocal interpretation of the outcome. In fact, this is not a secondary aspect in the planning of a clinical trial as this must give the real efficacy of a drug with a multifaceted outcome. However, the perception of the physician about the correctness and real efficacy of the proposed criteria of outcome still remains an important issue.

In the present issue of this journal, Aletaha et al. [29] have designed a study to evaluate the perception of values of individual core set measures by clinical rheumatologists in order to understand how much it was differing across measures and across physicians. With this method they evaluated the different perception of the most frequent outcome measures by international experts. Clearly, they demonstrate that some outcome measures, such as ESR and global assessment scales, are regarded less stringently than others, such as CRP and joints counts. This implies that different measures, in the core data set, differently drive the physician's judgement of RA activity. Very important is the fact that physicians tend to assume that patients rate RA activity higher than their physicians. Thus, the data clearly demonstrate that measures used in the RA core set need to be better harmonized to make the evaluation of the physician more accurate and precise.

The effort made by the Austrian colleagues testifies the advancement of the evaluation of the core set measures for RA. This attitude is thus contributing to further improve the role that the rheumatologist plays today in the evolving field of medicine, eventually lifting the cliché of a ‘thaumaturgus’ and acquiring a new habitus of a doctor dealing with sophisticated targeted therapies that need a reliable evidence-based measurement of activity.

In conclusion, the identification of the best RA core data set of measures is still in progress. Recent works suggest that some factors, such as intercultural differences, or interindividual perception of disease activity status and mainly patient judgement, could largely vary the interpretation of the outcome measurement. Nevertheless, in the future new armaments will enforce the rheumatologist's equipment. Outcome measures defined by absolute values distributed in a Gaussian shape, such as DAS and DAS28 [24] or, more probably, their simpler evolutions, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) [30], might be transferred from clinical trials to everyday clinical practice, permitting a feasible, accurate and reproducible method to evaluate RA status, course, response to therapy and, hopefully, remission state in every single patient, allowing physicians to plan the best treatment. Furthermore, SDAI and, better, CDAI can help patients to better understand their disease activity status, because they produce an intuitive response (single number) [30].

The ongoing impulse to raise patient's awareness of disease, of course, will encourage self-assessment questionnaires, like the ongoing Patient-Reported-Outcomes Measurements Information System (PROMIS) project, which represents a renewal of the old patient-reported outcomes (HAQ, Short Form-36) using a revolutionary data processing (computerized adaptive testing) to produce an individually calibrated test shaped on the single patient abilities [31].

Finally, in addition to well-known parameters (i.e. the recent use of anti-cyclical citrullinated peptide antibodies) and the described outcome scores that will permit an individual assessment in everyday practice, there are new interesting ‘works in progress’.

The circulating pro- and anti-inflammatory cytokine network has been shown to identify biologically based subsets of arthritis that may be helpful in identifying a prognostic profile [32].

In RA, the therapeutic response with serum cytokine changes has recently led to the proposal of a new multivariant assessment of arthritis patients with a cytokine activity index (CAI). [33]. In the future, biomarker-based disease activity assessments such as these may provide rheumatologists more biological insights into clinical outcomes and help support the ongoing progression towards evidenced-based treatment in the clinic.

Formula

The authors have declared no conflicts of interest.

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Accepted 21 April 2006


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