How aggressive should initial therapy for rheumatoid arthritis be?

T. Pincus and T. Sokka

Vanderbilt University Medical Center, Nashville, TN, 37232–4500, USA

Correspondence to: T. Sokka. E-mail: tuulikki.sokka{at}vanderbilt.edu

SIR, The report of Matteson et al. [1] concerning their experience with 111 rheumatoid arthritis (RA) patients who were treated primarily with hydroxychloroquine continues a long line of careful clinical investigation by the authors. We were surprised, however, by their characterization of patients with a mean value of 25 swollen joints, 23 tender joints and HAQ disability score of 1.1 as having ‘mild’ RA, most of whom could be treated with hydroxychloroquine for 2 yr. We would regard mean values after 2 yr of nine swollen joints, seven tender joints and HAQ disability scores of 0.4, along with an increase in the percentage of patients with erosions from 26 to 59%, as unacceptable at this time [2].

Severe long-term outcomes of RA including functional declines, work disability and increased mortality were recognized in the 1980s [3, 4]. Many reports recognize that patients whose inflammatory activity, measured as joint tenderness, swelling and erythrocyte sedimentation rate (ESR), was only partially improved over several years had progression of damage, measured as joint deformity and radiographic scores [5]. For example, in 100 patients over 5 yr, joint tenderness, swelling and ESR were partially improved while joint deformity and scores for radiographic damage indicated disease progression (Fig. 1) [6].



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FIG. 1. Changes in measures in 100 patients with rheumatoid arthritis over 5 yr determined by effect sizes. From Callahan et al. [6], with permission.

 
Statistical significance of improved measures of inflammatory activity does not necessarily indicate clinical significance of the observations [7]. Aggressive treatment strategies for early RA have been advocated, with a goal beyond statistical significance toward remission [2, 8–10]. We would have treated most of these patients with methotrexate and anticipated many fewer swollen and tender joints. Methotrexate is the disease-modifying anti-rheumatic drug (DMARD) that is significantly more likely to be continued at 5 yr because of greater efficacy and tolerability and fewer adverse events than any other DMARD [11, 12], including hydroxychloroquine. Methotrexate appears the ‘anchor drug’ of choice for most patients with early RA [13], including those with a level of severity described in the cohort of Matteson et al. [1].

At this time, evidence of improved long-term outcomes in RA with aggressive treatment strategies is emerging, including radiographic damage [14], functional capacity [15], work disability [16] and survival [17, 18]. However, these reports remain unusual, and many patients continue to experience ‘side-effects’ of the disease [19].

We certainly admire the effort of Matteson et al. to collect rigorous data in standard clinical care, which we have advocated [20]. However, we suggest a reassessment of the hydroxychloroquine treatment strategy in these patients with early RA.

The authors have declared no conflicts of interest.

References

  1. Matteson EL, Weyand CM, Fulbright JW, Christianson TJH, McClelland RL, Goronzy JJ. How aggressive should initial therapy for rheumatoid arthritis be? Factors associated with response to ‘non-aggressive’ DMARD treatment and perspective from a 2-yr open label trial. Rheumatology 2004;43:619–25.[Abstract/Free Full Text]
  2. 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;15:591–6.[ISI][Medline]
  3. Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK. Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 1984;27:864–72.[ISI][Medline]
  4. Scott DL, Grindulis KA, Struthers GR, Coulton BL, Popert AJ, Bacon PA. Progression of radiological changes in rheumatoid arthritis. Ann Rheum Dis 1984;43:8–17.[Abstract]
  5. Pincus T, Sokka T. Partial control of Core Data Set measures and Disease Activity Score (DAS) measures of inflammation does not prevent long-term damage: evidence from longitudinal observations over 5–20 years. Clin Exp Rheumatol 2002;20: S42–S48.[ISI][Medline]
  6. Callahan LF, Pincus T, Huston JW III, Brooks RH, Nance EP Jr, Kaye JJ. Measures of activity and damage in rheumatoid arthritis: depiction of changes and prediction of mortality over five years. Arthritis Care Res 1997;10:381–94.[ISI][Medline]
  7. Pincus T, Stein CM. Why randomized controlled clinical trials do not depict accurately long-term outcomes in rheumatoid arthritis: Some explanations and suggestions for future studies. Clin Exp Rheumatol 1997;15:S27–S38.[ISI][Medline]
  8. Pincus T. Rheumatoid arthritis: A medical emergency? Scand J Rheumatol 1994;23(Suppl 100):21–30.
  9. Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis 1995;54:944–7.[ISI][Medline]
  10. Weinblatt ME. Rheumatoid arthritis: treat now, not later! [editorial]. Ann Intern Med 1996;124:773–4.[Free Full Text]
  11. Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting anti-rheumatic therapy in rheumatoid arthritis: A 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 1990;17:994–1002.[ISI][Medline]
  12. Pincus T, Marcum SB, Callahan LF. Long-term drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second-line drugs and prednisone. J Rheumatol 1992;19:1885–94.[ISI][Medline]
  13. Sokka T, Pincus T. Contemporary disease modifying antirheumatic drugs (DMARD) in patients with recent onset rheumatoid arthritis in a US private practice: methotrexate as the anchor drug in 90% and new DMARD in 30% of patients. J Rheumatol 2002;29:2521–4.[ISI][Medline]
  14. Pincus T, Ferraccioli G, Sokka T et al. Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review. Rheumatology 2002;41:1346–56.[Abstract/Free Full Text]
  15. 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.[CrossRef][ISI][Medline]
  16. Puolakka K, Kautiainen H, Mottonen T et al. Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis. A five-year randomized followup trial. Arthritis Rheum 2004;50:55–62.[CrossRef][ISI][Medline]
  17. 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.[CrossRef][ISI][Medline]
  18. 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.[CrossRef][ISI][Medline]
  19. Pincus T, Callahan LF. The ‘side effects’ of rheumatoid arthritis: Joint destruction, disability and early mortality. Br J Rheumatol 1993;32(Suppl 1):28–37.[Medline]
  20. Pincus T, Brooks RH, Callahan LF. A proposed standard protocol to evaluate rheumatoid arthritis (SPERA) that includes measures of inflammatory activity, joint damage, and longterm outcomes. J Rheumatol 1999;26:473–80.[ISI][Medline]
Accepted 28 July 2004





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