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Editorial
 
Improving Outcomes in Rheumatoid Arthritis: What Determines Decisions to Change Ineffective Therapy?
TUULIKKI SOKKA, MD, PhD;
Jyväskylä, Finland; Vanderbilt University, Nashville, Tennessee, USA; HEIDI MÄKINEN, MD, Jyväskylä Central Hospital, Jyväskylä, Finland. Address reprint requests to Dr. Sokka. E-mail: tuulikki_sokka@hotmail.com Treatment of rheumatoid arthritis (RA) has been transformed greatly over the past decades from a "reactive" strategy of using disease modifying antirheumatic drugs (DMARD) only when the diagnosis was certain and damage apparent, to an aggressive strategy of "preventive" use of DMARD to control inflammation as completely as possible to slow joint damage. The new strategy has been accompanied by new DMARD, most notably methotrexate, and considerable evidence indicates that most patients with RA have better clinical status today compared with earlier periods. Availability of new biological therapies adds to the rheumatologist's armamentarium, helping many patients toward a state of low disease activity or remission. Changes in the treatment of RA have been accompanied by increased awareness on the part of rheumatologists of a need for quantitative documentation of patient status in clinical settings. In 1983, Verna Wright pointed out that "clinicians may write 'doing well' in the notes of a patient who has become progressively crippled before their eyes"1. This situation is becoming rarer in contemporary care of people with RA. A major advantage in quantitative assessment of RA patient status is the Disease Activity Score (DAS), which was developed as a composite score for disease activity in RA2-4. The DAS is a pooled index that includes 4 measures: tender joint count, swollen joint count, erythrocyte sedimentation rate (ESR), and patient global assessment. "High" disease activity was defined as the DAS level when a new DMARD was begun or changed from another due to lack of efficacy, while "low" disease activity was defined as a DAS level at which a new DMARD was not started or a DMARD was left unchanged for at least for one year or was stopped because of remission5. The DAS, which appeared in 1985, classifies patient status according to levels of "high" and "low" disease activity, reflecting decision-making concerning treatments for RA at that time. In this issue of The Journal, Soubrier and colleagues6 present predictors of change of treatments for RA in the clinic supervised by Dr. Dougados. They report a lower cutoff value for "high disease activity" according to the DAS28 than has previously been reported. Reevaluation of values of well established measures such as the DAS appears welcome at this time. Lower levels reflect improvements in patient status compared to previous decades. An improved clinical status of RA patients at this time compared to previous decades has been documented concerning disease activity7,8, functional capacity8-11, radiographic scores8,12,13, and other clinical measures8, including lower mortality rates in patients who responded to methotrexate14,15. Further, indirect evidence of improved patient clinical status is provided by observations that only a minority of patients in routine rheumatology care meet inclusion criteria in clinical trials16. The French study6 adds indirect evidence of improved care at this time, indicating lower cutoff levels to modify a DMARD therapy of DAS28esr = 4.2 and DAS28crp = 3.6, compared to disease activity levels in the Nijmegen early RA cohort in 1985-945, which correspond to DAS28 ≥ 5.117. In an ideal world, disease activity as a biological phenomenon would be the most important, if not the only, determinant of decision-making concerning treatment of RA. Suppression of current disease activity would prevent future joint damage and development of functional losses. A focus on disease activity implies that clinically assessed high disease activity invariably leads to change in therapy. However, many patients seen in a regular rheumatology clinic already have developed joint damage and have problems with physical function. A decision to change RA therapy may therefore be affected also by these damage variables, in addition to currently high inflammatory activity. Development of new erosions likely increases probability of change in therapy for RA if radiographs are used in routine evaluation of patients. Good function in activities of daily living is important from the patient's perspective and is reflected in global health, which is included in the DAS formula. Assessment using the Health Assessment Questionnaire would have augmented the completeness of the excellent analyses of the French group6. From an international approach, many variables beyond DAS scores, including patient demographics and psychosocial variables, healthcare system variables, and society-associated variables, may influence a decision to change RA therapy. In the French clinic, lower age and shorter disease duration were associated with a higher likelihood of changing therapy6. Other patient related variables may include number and type of comorbidities, education level, and ethnic background. Local traditions may play an important role in rheumatology daily practice. In some advanced clinics in the US, methotrexate reached popularity in the early 1980s, 10–20 years before it became the drug of choice in early RA in Europe. Enormous variation was seen in DMARD "ever used" in a cross-sectional study of consecutive patients with RA from 9 Western European countries18. This variation likely reflects local traditions concerning the choice and availability of DMARD. Accordingly, local traditions may also affect decisions to change RA therapy. Nowadays, many more DMARD, including biologic agents, are available compared to when the DAS was developed and definitions of "mild," "moderate," and "high" disease activity were reported. These definitions reflect the availability of DMARD and the standard of care at that time, which differs across decades. Moreover, availability of DMARD and especially biologic agents differs across countries. Further, guidelines on the use of biologic agents differ between countries and may strongly influence changes in RA therapy. The French study provides an example of a clinic where biologic agents are available for those who are regarded to need them. A consensus statement and national guidelines for prescribing biologic agents recommend these agents for patients who have currently active disease and have received treatment with one or 2 DMARD, usually including methotrexate19. In some countries, guidelines additionally require a certain level of disease activity. Examples include the UK, where guidelines recommend restricting biologics to patients who have DAS28 ≥ 5.120, while in The Netherlands, the activity requirement to start a biologic agent is DAS28 ≥ 3.2. In Denmark, a patient is required to have 6 or more swollen joints. Databases that reflect clinical practice nationwide indicate that the median disease activity score ranged from 5.2 to 6.0 on DAS28 in patients who started a biologic agent in Denmark and Norway in the early years of this decade21. In conclusion, the Soubrier report indicates that disease activity drives changes in therapy for RA, and that lesser disease activity is tolerated compared to the past. The study raises several important questions concerning daily rheumatology practice worldwide: Does current practice regarding changes in therapy for RA reflect disease activity, as well as patient psychosocial, healthcare system, and society-related variables? What about traditions and national guidelines? What guidelines should exist for decisions to change RA therapy? These questions should be examined more widely to improve standard clinical practice in many countries. 1. Smith T. Questions on clinical trials [editorial]. BMJ 1983;287:569. [MEDLINE] 2. van der Heijde DMFM, van't Hof MA, van Riel PLCM, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990;49:916-20. [MEDLINE] 3. van der Heijde DMFM, van't Hof M, van Riel PLCM, van de Putte LBA. Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol 1993;20:579-81. [MEDLINE] 4. Prevoo MLL, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PLCM. 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;38:44-8. [MEDLINE] 5. van Gestel AM, Prevoo MLL, van't Hof MA, van Rijswijk MH, van de Putte LBA, van Riel PLCM. 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;39:34-40. [MEDLINE] 6. Soubrier M, Zerkak D, Gossec L, Ayral X, Roux C, Dougados M. Which variables best predict change in therapy in rheumatoid arthritis in daily clinical practice? J Rheumatol 2006;33:1243-6. 7. Bergstrom U, Book C, Lindroth Y, Marsal L, Saxne T, Jacobsson L. Lower disease activity and disability in Swedish patients with rheumatoid arthritis in 1995 compared with 1978. Scand J Rheumatol 1999;28:160-5. [MEDLINE] 8. Pincus T, Sokka T, Kautiainen H. Patients seen for standard rheumatoid arthritis care have significantly better articular, radiographic, laboratory, and functional status in 2000 than in 1985. Arthritis Rheum 2005;52:1009-19. [MEDLINE] 9. Sokka T, Möttönen T, Hannonen P. Disease-modifying anti-rheumatic drug use according to the 'sawtooth' treatment strategy improves the functional outcome in rheumatoid arthritis: Results of a long-term follow-up study with review of the literature. Rheumatology Oxford 2000;39:34-42. [MEDLINE] 10. Krishnan E, Fries JF. Reduction in long-term functional disability in rheumatoid arthritis from 1977 to 1998: a longitudinal study of 3035 patients. Am J Med 2003;115:371-6. [MEDLINE] 11. Heiberg T, Finset A, Uhlig T, Kvien TK. Seven year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:191-5. [MEDLINE] 12. Sokka TM, Kaarela K, Möttönen TT, Hannonen PJ. Conventional monotherapy compared to a "sawtooth" treatment strategy in the radiographic procession of rheumatoid arthritis over the first eight years. Clin Exp Rheumatol 1999;17:527-32. [MEDLINE] 13. Sokka T, Kautiainen H, Häkkinen K, Hannonen P. Radiographic progression is getting milder in patients with early rheumatoid arthritis. Results of 3 cohorts over 5 years. J Rheumatol 2004;31:1073-82. [MEDLINE] 14. Krause D, Schleusser B, Herborn G, Rau R. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000;43:14-21. [MEDLINE] 15. Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173-7. [MEDLINE] 16. Sokka T, Pincus T. Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. J Rheumatol 2003;30:1138-46. [MEDLINE] 17. van Gestel AM, Anderson JJ, van Riel PLCM, et al. ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. J Rheumatol 1999;26:705-11. [MEDLINE] 18. Sokka T, Hetland ML, Verstappen S, et al. Current use of biologics and other DMARDs in a sample of 1579 patients with rheumatoid arthritis receiving routine clinical care in 9 Western European countries [abstract]. Ann Rheum Dis 2006;65 Suppl:SAT0172. 19. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor alpha blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 2005;64 Suppl:iv2-14. 20. Deighton CM, George E, Kiely PD, Ledingham J, Luqmani RA, Scott DG. Updating the British Society for Rheumatology guidelines for anti-tumour necrosis factor therapy in adult rheumatoid arthritis (again). Rheumatology Oxford 2006; mar 9 E-pub ahead of print. 21. Hjardem E, Hetland ML, Ostergaard M, Krogh NS, Kvien TK. Prescription practice of biological drugs in rheumatoid arthritis during the first 3 years of post-marketing use in Denmark and Norway: criteria are becoming less stringent. Ann Rheum Dis 2005;64:1220-3. [MEDLINE]
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