To the Editor:

We read with great interest 2 recent articles (1, 2) on the American College of Rheumatology N (ACR-N) index (3). Using the early rheumatoid arthritis trial data, Drs. Siegel and Zhen claim that discriminative power between therapies is increased by the ACR-N and especially ACR-N area under the curve (AUC) (1). Dr. Boers argues that the ACR-N AUC reflects an AUC of relative improvement from baseline, crediting improvements achieved at earlier visits at each subsequent evaluation (2).

The multiplicative approach of the ACR-N AUC exaggerates response differences and, in fact, translates earlier efficacy into better efficacy. In contrast, in the context of absolute measures, AUC analyses are helpful, and not misleading. Continuous activity scales, such as the Disease Activity Score in 28 joints (DAS28) (4), allow cross-sectional assessment of individuals and patient populations at any point in time (5). More importantly, keeping the level of disease activity below a certain cutoff value has allowed for testing and confirming the benefits of tight control (6). This would hardly have been possible using the ACR or ACR-N criteria. Ideally, criteria should be easy to understand, transposable into clinical practice, and have validity and usefulness in a world of changing requirements and treatment approaches. For the ACR-N, all of these aspects do not apply. Moreover, the ACR-N does not help in addressing the most burning current question: what is the proportion of patients in whom low disease activity or remission is achieved?

We have recently introduced the Simplified Disease Activity Index (SDAI), the numerical sum of 5 core set variables (7). In developing novel criteria for low disease activity and remission, we found that the current DAS28 remission criteria allow for >10 swollen joints (8), as also seen by others (9, 10). In contrast, the remission cutoff for the SDAI is ≤3.3, which allows no patient to be considered to have disease remission if there are >2 tender or swollen joints. We have also recently validated the Clinical Disease Activity Index (CDAI), which is based on the SDAI but does not include measurement of acute-phase reactants (11). Based on the same data we used to derive the SDAI criteria (8), we have determined that a CDAI of ≤2.8 corresponded to remission, a CDAI of ≤10 to low disease activity, a CDAI of ≤22 to moderate disease activity, and a CDAI of >22 to high disease activity. It is this knowledge about the presence or absence of low disease activity or remission that is needed today; conceptually and practically, there is no way to define such criteria with the ACR-N.

Table 1 shows an example of 2 patients. Patient 1 has an ACR50 (12) response and an ACR-N of 65%, but considerable residual disease activity by virtue of the individual measures. The SDAI and the CDAI accordingly classify this patient as having moderate disease activity at the end point, while the DAS28 assigns the category of remission. Patient 2 achieves an ACR70 and an ACR-N of 83%, moderate disease activity (>3.2) by the DAS28, but remission by the SDAI and CDAI (0 swollen and 1 tender joint, normal C-reactive protein level). These examples not only show the importance of looking at absolute disease activity to make judgments about disease states, but also indicate that weighting of variables in an index can cause a problem.

Table 1. Two examples illustrating calculation of various indices and the difficulty of their interpretation*
 Patient 1Patient 2
BaselineEnd point% improvementBaselineEnd point% improvement
  • *

    SJC = swollen joint count; TJC = tender joint count; PGA = patient global assessment; VAS = visual analog scale; EGA = evaluator global assessment; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; DAS28 = Disease Activity Score in 28 joints; SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; ACR = American College of Rheumatology.

SJC, 0–281857250100
TJC, 0–28201956183
PGA, 10-cm VAS6.92.2685.70.591
EGA, 10-cm VAS6.23.4455.10.296
Pain, 10-cm VAS9.53.6625.50.686
CRP, mg/dl6.50.5922.40.579
ESR, mm/hour54296724438
ACR 20/50/70 50  70 
ACR-N 65  83 

Rheumatologists today do not care about ACR20 or other minimal responses and do not wish to learn if a new drug or regimen allows a large proportion of patients to achieve minimal responses; they want to know the proportions of patients in whom low disease activity is achieved. Useful scoring systems should validly reflect this quest to achieve low disease activity and remission, regardless of the patient's level of disease activity at enrollment. Any other approach will lead us back into the darkness of the tunnel.

  • 1
    Siegel JN, Zhen BG. Use of the American College of Rheumatology N (ACR-N) index of improvement in rheumatoid arthritis: argument in favor. Arthritis Rheum 2005; 52: 163741.
  • 2
    Boers M. Use of the American College of Rheumatology N (ACR-N) index of improvement in rheumatoid arthritis: argument in opposition. Arthritis Rheum 2005; 52: 16425.
  • 3
    Schiff M, Weaver A, Keystone E, Moreland L, Spencer-Green G. Comparison of ACR response, numeric ACR, and ACR AUC as measures of clinical improvement in RA clinical trials [abstract]. Arthritis Rheum 1999; 42 Suppl 9: S81.
  • 4
    Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 448.
  • 5
    Van Riel PL, van Gestel AM. Clinical outcome measures in rheumatoid arthritis. Ann Rheum Dis 2000; 59 Suppl 1: i2831.
  • 6
    Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364: 2639.
  • 7
    Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42: 24457.
  • 8
    Aletaha D, Ward MM, Machold KP, Nell VP, Stamm T, Smolen JS. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum 2005; 52: 262536.
  • 9
    Landewe RB, van der Heijde DM, van der Linden S, Boers M. 28-joint counts invalidate the DAS28-remission definition due to the omission of the lower extremity joints: a comparison with the DAS-remission. Ann Rheum Dis 2005. E-pub ahead of print.
  • 10
    Makinen H, Kautiainen H, Hannonen P, Sokka T. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis 2005; 64: 14103.
  • 11
    Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res 2005; 7: R796806.
  • 12
    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminaey definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 72735.

Daniel Aletaha MD*, Josef S. Smolen MD*, * Medical University of Vienna Vienna, Austria.