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Assessment of rheumatoid arthritis activity in clinical trials and clinical practice

Josef S Smolen, MD
Daniel Aletaha, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


Approaches to the management of rheumatoid arthritis (RA) have evolved as an increasing number of effective disease-modifying antirheumatic drugs (DMARDs) have become available. The early introduction of DMARDs has become standard of care, and depends upon early diagnosis [1]. Such early diagnosis is facilitated by the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis classification criteria [2].

The goals of DMARD use are not only to ameliorate the symptoms and signs of active RA, but also to prevent structural joint damage and avoid functional impairment or enable its restoration. The development of new antirheumatic therapies, including biologic and synthetic agents targeted against specific components of the immunoinflammatory system, has required the availability of instruments that permit the assessment of disease activity and the response to therapy. Regardless of whether patients are evaluated in the context of a clinical trial or longitudinal clinical practice, the successful application of DMARD therapy requires that the goals of therapy be specified in advance and that the specific choice of DMARDs be revisited on a regular basis [3,4].

Clinical indicators employed in the assessment of RA activity are discussed here. The roles of both individual variables (eg, swollen joint counts and acute phase reactant measurements) and composite indices for disease activity assessment are considered, as are definitions of remission and criteria for clinically significant responses. Although much of the discussion centers on clinical trial outcome measures, we also provide recommendations for clinical practice.

A number of other topic reviews are related to the discussion of RA disease activity and complement the information provided here. As examples:

The clinical features of RA, including the importance of distinguishing disease activity from structural joint damage are discussed elsewhere. (See "Clinical manifestations of rheumatoid arthritis".)


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Literature review current through: Sep 2016. | This topic last updated: Feb 28, 2016.
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  1. Combe B, Landewe R, Lukas C, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007; 66:34.
  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. Ann Rheum Dis 2010; 69:1580.
  3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73:492.
  4. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016; 75:3.
  5. van Leeuwen MA, van der Heijde DM, van Rijswijk MH, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis. A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants. J Rheumatol 1994; 21:425.
  6. van Leeuwen MA, van Rijswijk MH, Sluiter WJ, et al. Individual relationship between progression of radiological damage and the acute phase response in early rheumatoid arthritis. Towards development of a decision support system. J Rheumatol 1997; 24:20.
  7. Welsing PM, van Gestel AM, Swinkels HL, et al. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum 2001; 44:2009.
  8. Aletaha D, Machold KP, Nell VP, Smolen JS. The perception of rheumatoid arthritis core set measures by rheumatologists. Results of a survey. Rheumatology (Oxford) 2006; 45:1133.
  9. Drossaers-Bakker KW, de Buck M, van Zeben D, et al. Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis Rheum 1999; 42:1854.
  10. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 2005; 7:R796.
  11. Aletaha D, Ward MM, Machold KP, et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum 2005; 52:2625.
  12. Smolen JS, Van Der Heijde DM, St Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006; 54:702.
  13. Smolen JS, Aletaha D. Patients with rheumatoid arthritis in clinical care. Ann Rheum Dis 2004; 63:221.
  14. Aletaha D, Smolen J, Ward MM. Measuring function in rheumatoid arthritis: Identifying reversible and irreversible components. Arthritis Rheum 2006; 54:2784.
  15. Smolen JS, Aletaha D, Grisar JC, et al. Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials. Ann Rheum Dis 2010; 69:1058.
  16. Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum 2005; 52:1020.
  17. Devlin RD, Reddy SV, Savino R, et al. IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures. J Bone Miner Res 1998; 13:393.
  18. Kobayashi K, Takahashi N, Jimi E, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 2000; 191:275.
  19. Kudo O, Sabokbar A, Pocock A, et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003; 32:1.
  20. Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106:1481.
  21. Ragab AA, Nalepka JL, Bi Y, Greenfield EM. Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells. Am J Physiol Cell Physiol 2002; 283:C679.
  22. Redlich K, Hayer S, Ricci R, et al. Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest 2002; 110:1419.
  23. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289:1504.
  24. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52:3381.
  25. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364:263.
  26. Smolen JS, Sokka T, Pincus T, Breedveld FC. A proposed treatment algorithm for rheumatoid arthritis: aggressive therapy, methotrexate, and quantitative measures. Clin Exp Rheumatol 2003; 21:S209.
  27. Molenaar ET, Voskuyl AE, Dijkmans BA. Functional disability in relation to radiological damage and disease activity in patients with rheumatoid arthritis in remission. J Rheumatol 2002; 29:267.
  28. Aletaha D, Funovits J, Breedveld FC, et al. Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment. Arthritis Rheum 2009; 60:1242.
  29. Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis 2013; 72:64.
  30. Radner H, Smolen JS, Aletaha D. Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs. Arthritis Res Ther 2014; 16:R56.
  31. Smolen JS, Han C, van der Heijde DM, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis 2009; 68:823.
  32. Aletaha D, Smolen JS. The definition and measurement of disease modification in inflammatory rheumatic diseases. Rheum Dis Clin North Am 2006; 32:9.
  33. Scott DL, Panayi GS, van Riel PL, et al. Disease activity in rheumatoid arthritis: preliminary report of the Consensus Study Group of the European Workshop for Rheumatology Research. Clin Exp Rheumatol 1992; 10:521.
  34. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum 1993; 36:729.
  35. Boers M, Tugwell P, Felson DT, et al. World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials. J Rheumatol Suppl 1994; 41:86.
  36. Tugwell P, Bombardier C. A methodologic framework for developing and selecting endpoints in clinical trials. J Rheumatol 1982; 9:758.
  37. van der Heijde DM, van't Hof MA, van Riel PL, et al. Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis 1992; 51:177.
  38. Goldsmith CH, Boers M, Bombardier C, Tugwell P. Criteria for clinically important changes in outcomes: development, scoring and evaluation of rheumatoid arthritis patient and trial profiles. OMERACT Committee. J Rheumatol 1993; 20:561.
  39. Hart LE, Tugwell P, Buchanan WW, et al. Grading of tenderness as a source of interrater error in the Ritchie articular index. J Rheumatol 1985; 12:716.
  40. Prevoo ML, van Riel PL, van 't Hof MA, et al. Validity and reliability of joint indices. A longitudinal study in patients with recent onset rheumatoid arthritis. Br J Rheumatol 1993; 32:589.
  41. Prevoo ML, van 't Hof MA, Kuper HH, et al. 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; 38:44.
  42. Fuchs HA, Pincus T. Reduced joint counts in controlled clinical trials in rheumatoid arthritis. Arthritis Rheum 1994; 37:470.
  43. Smolen JS, Breedveld FC, Eberl G, et al. Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. Arthritis Rheum 1995; 38:38.
  44. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000; 39:655.
  45. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999; 353:259.
  46. van Tuyl LH, Britsemmer K, Wells GA, et al. Remission in early rheumatoid arthritis defined by 28 joint counts: limited consequences of residual disease activity in the forefeet on outcome. Ann Rheum Dis 2012; 71:33.
  47. Carlsson AM. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain 1983; 16:87.
  48. Scott J, Huskisson EC. Vertical or horizontal visual analogue scales. Ann Rheum Dis 1979; 38:560.
  49. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs 2005; 14:798.
  50. Studenic P, Smolen JS, Aletaha D. Near misses of ACR/EULAR criteria for remission: effects of patient global assessment in Boolean and index-based definitions. Ann Rheum Dis 2012; 71:1702.
  51. Dawes PT, Fowler PD, Clarke S, et al. Rheumatoid arthritis: treatment which controls the C-reactive protein and erythrocyte sedimentation rate reduces radiological progression. Br J Rheumatol 1986; 25:44.
  52. Mallya RK, de Beer FC, Berry H, et al. Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 1982; 9:224.
  53. Plant MJ, Williams AL, O'Sullivan MM, et al. Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis. Arthritis Rheum 2000; 43:1473.
  54. Crowson CS, Rahman MU, Matteson EL. Which measure of inflammation to use? A comparison of erythrocyte sedimentation rate and C-reactive protein measurements from randomized clinical trials of golimumab in rheumatoid arthritis. J Rheumatol 2009; 36:1606.
  55. Schulz KF, Grimes DA. Multiplicity in randomised trials I: endpoints and treatments. Lancet 2005; 365:1591.
  56. van der Heijde DM, van 't Hof M, van Riel PL, van de Putte LB. Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol 1993; 20:579.
  57. Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 1968; 37:393.
  58. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42:244.
  59. 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; 52:1637.
  60. Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum 2007; 56:3226.
  61. van der Heijde D, Klareskog L, Boers M, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis 2005; 64:1582.
  62. Mäkinen H, Kautiainen H, Hannonen P, Sokka T. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis 2005; 64:1410.
  63. Balsa A, de Miguel E, Castillo C, et al. Superiority of SDAI over DAS-28 in assessment of remission in rheumatoid arthritis patients using power Doppler ultrasonography as a gold standard. Rheumatology (Oxford) 2010; 49:683.
  64. Smolen JS, Aletaha D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum 2011; 63:43.
  65. Wong AL, Harker JO, Park GS, Paulus HE. Longitudinal measurement of RA disease activity in a clinical practice setting: Usefulness of the SDAI. Arthritis Rheum 2004; 50:S386.
  66. Soubrier M, Zerkak D, Gossec L, et al. Which variables best predict change in rheumatoid arthritis therapy in daily clinical practice? J Rheumatol 2006; 33:1243.
  67. American College of Rheumatology Committee to Reevaluate Improvement Criteria. A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum 2007; 57:193.
  68. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011; 63:573.
  69. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011; 70:404.
  70. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005; 23:S100.
  71. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23:137.
  72. Scott DL, Pugner K, Kaarela K, et al. The links between joint damage and disability in rheumatoid arthritis. Rheumatology (Oxford) 2000; 39:122.
  73. Pincus T, Swearingen C, Wolfe F. Toward a multidimensional Health Assessment Questionnaire (MDHAQ): assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis Rheum 1999; 42:2220.
  74. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473.
  75. Vita AJ, Terry RB, Hubert HB, Fries JF. Aging, health risks, and cumulative disability. N Engl J Med 1998; 338:1035.
  76. Stucki G, Liang MH, Stucki S, et al. A self-administered rheumatoid arthritis disease activity index (RADAI) for epidemiologic research. Psychometric properties and correlation with parameters of disease activity. Arthritis Rheum 1995; 38:795.
  77. Mason JH, Anderson JJ, Meenan RF, et al. The rapid assessment of disease activity in rheumatology (radar) questionnaire. Validity and sensitivity to change of a patient self-report measure of joint count and clinical status. Arthritis Rheum 1992; 35:156.
  78. Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds. Arthritis Care Res (Hoboken) 2010; 62:181.
  79. Pincus T, Amara I, Segurado OG, et al. Relative efficiencies of physician/assessor global estimates and patient questionnaire measures are similar to or greater than joint counts to distinguish adalimumab from control treatments in rheumatoid arthritis clinical trials. J Rheumatol 2008; 35:201.
  80. Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One 2013; 8:e60635.
  81. Paulus HE, Egger MJ, Ward JR, Williams HJ. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic Diseases Group. Arthritis Rheum 1990; 33:477.
  82. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38:727.
  83. Felson DT, Anderson JJ, Lange ML, et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum 1998; 41:1564.
  84. Aletaha D, Funovits J, Smolen JS. The importance of reporting disease activity states in rheumatoid arthritis clinical trials. Arthritis Rheum 2008; 58:2622.
  85. van Gestel AM, Prevoo ML, van 't Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 1996; 39:34.
  86. van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 1998; 41:1845.
  87. Aletaha D, Martinez-Avila J, Kvien TK, Smolen JS. Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index. Ann Rheum Dis 2012; 71:1190.
  88. Thiele K, Huscher D, Bischoff S, et al. Performance of the 2011 ACR/EULAR preliminary remission criteria compared with DAS28 remission in unselected patients with rheumatoid arthritis. Ann Rheum Dis 2013; 72:1194.
  89. Zhang B, Combe B, Rincheval N, Felson DT. Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort. Arthritis Res Ther 2012; 14:R156.
  90. Sakellariou G, Scirè CA, Verstappen SM, et al. In patients with early rheumatoid arthritis, the new ACR/EULAR definition of remission identifies patients with persistent absence of functional disability and suppression of ultrasonographic synovitis. Ann Rheum Dis 2013; 72:245.
  91. Prevoo ML, van Gestel AM, van T Hof MA, et al. Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 1996; 35:1101.
  92. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981; 24:1308.
  93. Pincus T, Stein CM, Wolfe F. "No evidence of disease" in rheumatoid arthritis using methotrexate in combination with other drugs: a contemporary goal for rheumatology care? Clin Exp Rheumatol 1997; 15:591.