• Rheumatoid arthritis;
  • Antirheumatic agents;
  • Disease progression;
  • Structural joint damage


  1. Top of page
  2. Abstract
  7. Acknowledgements


Although early initiation of disease-modifying antirheumatic drugs (DMARDs) is effective in controlling short-term joint damage in individuals with rheumatoid arthritis (RA), the long-term benefit in disease progression is still controversial. We examined the long-term benefit of early DMARD initiation on radiographic progression in early RA.


We identified published and unpublished clinical trials and observational studies from 1966 to September 2004 examining the association between delay to treatment initiation and progressive radiographic joint damage. We included studies of persons with RA disease duration <2 years and DMARD therapy of similar efficacy during followup. The differences in annual rates of radiographic progression between early and delayed therapy were pooled as standardized mean differences (SMDs).


A total of 12 studies met the inclusion criteria. The pooled estimate of effects from these studies demonstrated a significant reduction of radiographic progression in patients treated early (−0.19 SMD, 95% confidence interval [95% CI] −0.34, −0.04), which corresponded to a −33% reduction (95% CI −50, −16) in long-term progression rates compared with patients treated later. Patients with more aggressive disease seemed to benefit most from early DMARD initiation (P = 0.04).


These results support the existence of a critical period to initiate antirheumatic therapy, a therapeutic window of opportunity early in the course of RA associated with sustained benefit in radiographic progression for up to 5 years. Prompt initiation of antirheumatic therapy in persons with RA may alter the long-term course of the disease.


  1. Top of page
  2. Abstract
  7. Acknowledgements

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes progressive joint destruction and disability and is currently without cure. It is the most common systemic rheumatic disease, affecting ∼1% of the population (1). Radiographic joint damage correlates strongly with long-term functional decline in patients with RA, and therefore preventing progressive joint damage has become a key treatment objective (2, 3). Until recently, the recommended therapeutic strategy was to start with nonsteroidal antiinflammatory drugs (NSAIDs) or low-dose glucocorticoids, and progressively introduce more potent antirheumatic therapies only if the NSAIDs and glucocorticoids were insufficient to control the disease (pyramid approach). In the last 15 years, treatment goals have evolved from a concept of symptom control to a concept of disease control (4). This has resulted in a more aggressive therapeutic approach with earlier introduction of disease-modifying antirheumatic drugs (DMARDs) (5), which have been proven to reduce structural joint damage.

The rationale for a prompt initiation of DMARDs in patients with RA is based on the idea that there is a critical period, a therapeutic window of opportunity, during early stages of the disease when treatment is more effective than later in the course of the disease. This concept covers a short-term effect with better disease activity responses and a long-term effect that would modify the disease permanently to a milder course. Randomized controlled trials (RCTs) have established the short-term efficacy of various DMARD combinations and anti–tumor necrosis factor (anti-TNF) therapies in RA (6–8), and earlier DMARD therapy is more effective than later therapy (9, 10). Although the short-term effects of early DMARD therapy on joint damage are established (11–15), the long-term benefits are controversial (16–18), with some trials demonstrating a persistent effect (19, 20) and others demonstrating no effect during a 5-year followup (21–23). To evaluate the long-term benefit of early DMARD therapy, we conducted a systematic review of the literature to test the hypothesis that early DMARD therapy reduces long-term radiographic progression in patients with RA.


  1. Top of page
  2. Abstract
  7. Acknowledgements

Search strategy.

With the help of a medical librarian, we identified all studies in any language on DMARD therapy and radiographic progression in early RA by a systematic search of the literature and electronic databases, including MEDLINE (1966 to September 2004), EMBASE (1974 to September 2004), and the Cochrane controlled trial registry. We also reviewed abstracts from the American College of Rheumatology (ACR) and the European League Against Rheumatism from 2002 through 2004. Search terms were rheumatoid arthritis or arthritis, antirheumatic drug or DMARD, structural joint damage or radiology, and cohort or longitudinal or followup studies. We obtained additional studies from consultants and by scrutinizing bibliographies of articles.

Conceptualization of selection criteria.

Rates of joint damage can be influenced by individual disease characteristics (i.e., genetic factors, inflammatory activity), efficacy of DMARDs (24), and the time between disease onset and the initiation of DMARDs. These factors must be taken into account when examining the effect of delayed DMARDs on progressive joint damage. Ideally, the most rigorous test to address this issue would be a double-blinded RCT comparing immediate versus delayed initiation of the same DMARD regimen with long-term followup (18). In our review, only 1 RCT with this design involving 23 subjects could be identified (25). Other RCTs addressed the issue but compared different DMARD combinations and sequences (11–13), making it difficult to clarify the effect of delayed treatment versus the effect of a given drug.

In the absence of definitive RCTs, we examined the effect of a delayed DMARD initiation on radiographic damage progression in cohort studies, the next best study design to address this issue (16). Two types of cohort studies have been used by researchers: open followup studies of randomized trials and longitudinal observational studies of patients with early RA. We assumed that long-term effects on radiographic disease progression of early versus delayed treatment could only be studied rigorously when both groups received similar antirheumatic therapy. Therefore data from followup studies of RCTs were suitable only if patients were free to receive any DMARD after trial termination, which effectively tends to balance DMARD regimen between the 2 arms.

The operational definitions of delayed DMARD initiation for the 2 types of cohort studies are contrasted and defined in Figure 1. Study inclusion criteria were as follows: subjects with RA according to ACR (formerly the American Rheumatism Association) criteria (26); disease duration <2 years at enrollment (early RA); cohort studies that had data on the time delay between disease onset and DMARD initiation, and followup studies of at least 1 year after termination of RCTs; duration of 3–24 months between early DMARD group and delayed DMARD group; comparable efficacy of DMARD regimen in treatment arms over followup period; and documentation of radiographic outcome. Exclusion criteria included duplicated data and DMARD regimen not comparable during followup.

thumbnail image

Figure 1. Representation of delayed disease-modifying antirheumatic drug (DMARD) initiation by study type. A, In cohort studies of patients with early rheumatoid arthritis, long-term radiographic progression is contrasted between subsets with early versus delayed initiation of DMARD therapy. B, In a randomized controlled trial (RCT), effective DMARD regimens are compared with placebo or a less effective DMARD regimen. At the end of the RCT period, blinding is removed and patients are free to receive any DMARD. In followup studies of these RCTs, delayed DMARD initiation is conceptualized as a relative delay to effective DMARD therapy in the comparator arm compared with the active treatment arm. Studies that did not receive comparable DMARDs during followup period were excluded so that long-term radiographic progression could be compared with respect to the initial therapeutic strategy. Shaded circle = DMARD initiation.

Download figure to PowerPoint


Outcome measures.

Radiographic outcome is considered the gold standard for assessing disease progression in RA (27). Different scoring systems are used to semiquantitatively assess radiographic damage (28). The average progression of radiographic damage is linear over time with large interindividual differences (29, 30). The rate of radiographic progression was estimated by the difference in radiographic scores during followup divided by the time interval, and is graphically represented by the slope of the line in Figure 1.

Relative efficacy of DMARDs.

The relative efficacy of a DMARD was based on arbitrary definitions used in previous studies (21, 24, 31–33): level I included hydroxychloroquine, oral gold, and penicillamine; level II included methotrexate, sulfasalazine, leflunomide, and parenteral gold; and level III included any combinations of level I and level II DMARDs. Anti-TNF agents were not classified because none of the included studies had used these therapies. The operational definition of comparable antirheumatic therapy was based on the relative efficacy of a DMARD regimen and the proportion of patients receiving a DMARD regimen during followup. Comparable DMARD regimen was then defined as differences <15% in the proportion of patients taking DMARDs of different levels of efficacy between both treatment groups. A difference of 15% was thought to be clinically meaningful and represented a statistically significant difference for average studies included in the analysis.

Estimated yearly progression rates at baseline.

We estimated yearly rates of radiographic progression at baseline by dividing the average radiographic damage scores at enrollment by the mean disease duration. This assumes damage scores of 0 at disease onset and an average linear progression (34). Estimated yearly progression rates at baseline appear to be the strongest predictor of future radiographic damage progression (35).

Qualitative evaluation of observational studies.

There are no generally accepted quality scoring criteria of observational studies (36). Therefore we used the following to evaluate how successful studies dealt with potential threats to validity: comparability of patients in both arms (2 = initial group allocation was randomized, 1 = similar characteristics in both treatment groups, 0 = not similar or not addressed), comparability of DMARD regimen in study arms (3 = identical DMARD regimen, 2 = results adjusted for differences in DMARD regimen, 1 = similar DMARD regimen [differences in the proportion of DMARDs at various levels of efficacy <15%], 0 = not similar), and radiographic joint damage data (1 = mean longitudinal radiographic progression [change scores or rates of progression], 0 = cross-sectional radiographic data). Scores for individual criteria were summed; the best possible score was 6.

Data extraction.

Two rheumatologists abstracted study data and evaluated quality independently. Disagreements were adjudicated by consensus with a third reviewer. Data included methodology of study, age, sex, sample size, number of completers, disease duration, DMARD regimen, time to DMARD, rheumatoid factor, and radiographic scoring method. When the data could not be culled from the article, we contacted the authors. When studies reported >2 cohorts or subgroups, we included only the 2 most similar cohorts with respect to DMARD regimen and disease characteristics.

Statistical analysis.

Rate of radiographic progression.

When studies reported mean change scores, the average difference in individual radiographic scores between baseline and the final assessment was divided by the mean duration of followup to obtain a yearly rate of radiographic progression. The standardized mean difference (SMD) allows comparison between studies that used different radiographic scoring systems (37). The SMD is calculated as the difference in mean rate of radiographic progression between intervention and comparator groups divided by the SD of the difference. It is a dimensionless measure that allows pooling and comparing of different studies and scoring systems. Confidence intervals of the SMDs were computed using Cohen's d and standard error (38). To relate the reduction in SMD units to a more familiar outcome, we transformed SMDs into percentage of reduction of radiographic progression rates. The difference in mean progression rates between the delayed treatment group and the early treatment group was divided by the progression rates in the delayed treatment group.

If a mean change score and its distribution were not available, rate of radiographic progression was computed by subtracting the baseline and final assessment and dividing this by mean duration of followup. We took a conservative approach to impute the SD of the change score by assuming unpaired data (39, 40). For 2 studies (22, 41), only nonparametric cross-sectional measures were available and radiographic progression was approximated by taking the difference of the medians with an SD estimated from the interquartile ranges (IQR; approximately equal to 1.35 SD) (40).


All analyses were performed with STATA, version 8 meta-analysis routines (StataCorp, College Station, TX). An α error of 0.05 was used. Random effects models, which do not assume a uniform treatment effect, were used (38) because heterogeneity was expected among observational studies (36). We tested for heterogeneity with the Mantel-Haenszel method. We graphed a funnel plot and used the test method developed by Begg and Mazumdar to assess the potential of publication bias (42).

Sensitivity analyses.

We assumed variability among studies a priori and performed separate sensitivity analyses for potential sources of heterogeneity to test the stability of our findings. Potential sources of heterogeneity included cohort versus open followup studies of RCTs, Larsen's versus Sharp's scoring method, study quality, yearly progression rates at baseline, disease duration at enrollment, and delay before DMARD initiation. Continuous variables were dichotomized at the median or the mean and significance testing was performed using meta-regression.


  1. Top of page
  2. Abstract
  7. Acknowledgements

Twelve studies, 6 followup studies and 6 cohort studies, with 1,133 patients were included (Table 1). The results of our literature search and the selection process are given in Figure 2. Of 362 candidate studies, 321 were excluded after reviewing the abstracts because they did not meet inclusion criteria (i.e., patients without early RA, no radiographic outcomes, incompatible study design). Twentynine additional studies were excluded after reviewing the articles, primarily because of noncomparable DMARD regimen during the followup period. Eleven investigators were contacted for additional information; of these, 10 responded and 8 provided additional data (see Acknowledgments). The kappa for inclusion and exclusion criteria fulfillment (κ = 0.92) and quality scores (κ = 0.81) showed good agreement.

Table 1. Characteristics of studies*
Author (reference)YearInitial DMARD interventionDelay in DMARD initiation, monthsFollowup period, years§No.Radiographic scoring methodMean age, yearsQuality score#Standardized differential rates of progression (95% CI)**
  • *

    DMARD = disease-modifying antirheumatic drug; 95% CI = 95% confidence interval; Level 1 = hydroxychloroquine, oral gold, or penicillamine; Level 2 = methotrexate, sulfasalazine, or parenteral gold; Level 3 = combination therapy.

  • For followup studies, this is the DMARD used during the randomized controlled trial; for cohort studies, this is the DMARD received by the early treatment group.

  • Difference in months in mean disease duration at DMARD initiation between the 2 treatment arms.

  • §

    Open followup period, after the randomized controlled trial had ended.

  • Total number of patients.

  • #

    Range from 0 to 6, higher scores indicate that studies dealt more effectively with potential threats to validity.

  • **

    Summary data presented as standardized mean differences with 95% CIs. A positive score indicates a protective effect.

  • ††

    Study started as a randomized controlled trial, but randomization was broken after 6 months; for this analysis it was considered a followup study.

  • ‡‡

    Studies were designed as randomized controlled trials, but the reported analyses did not use the randomized allocation and were therefore considered as cohort studies for the purpose of this analysis.

Followup studies         
 Van der Heijde (57)1990Level 2 vs. level 1112.249Sharp534−0.36 (−0.93, 0.21)
 Buckland-Wright (25)††1993Level 2 vs. placebo6123Microfocal radiographs564−0.11 (−0.94, 0.11)
 Egsmose (41)1995Level 1 vs. placebo8375Larsen573−0.30 (−0.76, 0.16)
 Landewe (19)2002Level 3 vs. level 2134.5148Sharp505−0.38 (−0.70, −0.05)
 Maillefert (22)2003Level 3 vs. level 2124146Sharp513−0.08 (−0.45, 0.29)
 Verstappen (21)2003Early level 1-2 vs. delayed level 1-2144189Sharp5740.15 (−0.20, 0.50)
Cohort studies         
 Luukkainen (58)1977Level 2: early vs. delayed95.678Larsen (count)442−0.27 (−1.09, 0.55)
 Bukhari (59)2003Level 1-2: early vs. delayed55136Larsen554−0.21 (−0.57, 0.15)
 Möttönen (60)‡‡2002Level 2-3: early vs. delayed122165Larsen4850.01 (−0.32, 0.34)
 Nell (43)2004Level 1-2: early vs. delayed9340Larsen543−1.17 (−1.84, −0.50)
 Marchesoni (61)‡‡2003Level 2-3: early vs. delayed12279Sharp493−0.07 (−0.53, 0.39)
 Sanmarti (62)2003Level 2: early vs. delayed6160Larsen523−0.15 (−0.66, 0.37)
thumbnail image

Figure 2. Flow of study selection process. * See Materials and Methods section for the inclusion criteria. RA = rheumatoid arthritis; DMARD = disease-modifying antirheumatic drug.

Download figure to PowerPoint

The summary measure for the followup studies was −0.18 SMD (95% confidence interval [95% CI] −0.39, 0.02) and the summary measure for the cohort studies was −0.21 SMD (95% CI −0.48, 0.06). Because there was no significant difference between these study designs (P = 0.89), we combined them in the analysis. The pooled estimate of effects demonstrated a significant reduction of long-term radiographic progression (−0.19 SMD, 95% CI −0.34, −0.04) (Figure 3) in patients with early RA who initiated DMARD therapy early compared with patients who initiated DMARD therapy later. This finding corresponds to a −33% reduction (95% CI −50%, −16%) in long-term radiographic progression rates in patients receiving early compared with delayed DMARD therapy. Patients in the delayed DMARD group started effective therapy an average of 9 months later than patients in the early DMARD group. The median followup was 3 years.

thumbnail image

Figure 3. Statistical evidence for a sustained effect of early treatment intervention on long-term joint damage. * Summary data presented as standardized mean differences (SMDs) and 95% confidence interval, † and as percentage of rate reduction compared with the delayed group. The size of the box is proportional to the size of the study.

Download figure to PowerPoint

No evidence for significant publication bias was apparent on a funnel plot or a specific test (Begg's test, P = 0.27). We also assessed the impact of our exclusion criteria by including all possible studies in the analysis and the summary measure was not significantly different (SMD −0.27; 95% CI −0.40, −0.14), suggesting that the results are not dependent on the studies selected.

Some heterogeneity was seen among the 12 studies (test for heterogeneity P = 0.16), but this was mainly due to 1 study (43). If this study was removed, heterogeneity would have disappeared (P = 0.75) and the summary measure would have been qualitatively unchanged (SMD −0.14; 95% CI −0.27, −0.01). We performed sensitivity analyses for possible sources of bias (Table 2) such as study characteristics, dissimilar risk factors of severe disease, or unequal exposure levels. Patients with more aggressive disease, as measured by higher estimated rates of radiographic progression at baseline, seemed to benefit most from early DMARD therapy (P = 0.04). Study characteristics and exposure levels did not significantly influence the rates of radiographic damage, but there was a tendency for studies with shorter disease duration at enrollment, with lower quality and using Larsen's scoring method, to report greater effect sizes. Other possible sources of heterogeneity such as efficacy of initial DMARD therapy (P = 0.82) or the proportion of female patients (P = 0.57) were not significant (data not shown).

Table 2. Selected sensitivity analyses for potential sources of bias*
Potential sources of biasSMD (95% CI)P
  • *

    SMD = standardized mean difference; 95% CI = 95% confidence interval; DMARD = disease-modifying antirheumatic drug.

  • A negative score indicates a reduction in the rate of progression compared with the delayed treatment group.

  • P value is comparing the difference between the average SMDs.

Differences in study characteristics  
 Study design 0.89
  Followup study−0.18 (−0.39, 0.02) 
  Cohort study−0.21 (−0.48, 0.06) 
 Radiographic scoring systems 0.73
  Larsen scores−0.26 (−0.52, −0.01) 
  Sharp scores−0.13 (−0.38, 0.11) 
 Study quality 0.36
  Quality score ≤3−0.29 (−0.56, −0.02)
  Quality score >3−0.14 (−0.33, 0.06) 
Differences in risk factors of severe disease  
 Estimated radiographic progression rates at   baseline (% maximum score/year) 0.04
  Low initial rates of progression (≤1.5%/year)−0.04 (−0.23, 0.16) 
  High initial rates of progression (>1.5%/year)−0.33 (−0.53, −0.13) 
 Positive rheumatoid factor (proportion) 0.93
  Low proportion (≤66%)−0.18 (−0.48, 0.12) 
  High proportion (>66%)−0.20 (−0.39, −0.01) 
Differences in exposure levels  
 Disease duration at enrollment 0.25
  ≤10 months−0.33 (−0.57, −0.08) 
  >10 months−0.14 (−0.34, 0.06) 
 Delay in DMARD initiation between treatment   arms 0.87
  ≤1 year−0.21 (−0.45, 0.03) 
  >1 year−0.18 (−0.41, 0.05) 


  1. Top of page
  2. Abstract
  7. Acknowledgements

The long-term rate of joint damage in early RA was reduced in patients who initiated DMARD therapy early compared with patients who initiated DMARD therapy later (−0.19 SMD; 95% CI −0.34, −0.04). An average delay of 9 months in starting DMARDs significantly increased radiographic progression subsequently. In patients with early RA, rates of radiographic progression average 4.3 Sharp score units/year (2). A reduction of 0.19 SMD represents a reduction of 1.4 Sharp units/year or a 33% decrease in radiographic progression rate and would prevent long-term functional disability (2, 44, 45), joint replacement surgery (29), and work disability (46). The effect size from early DMARD initiation was approximately half the effect size observed with methotrexate, which is considered standard therapy in RA (24). Of note, the effect of starting early DMARD therapy was observed several years after the intervention, regardless of subsequent treatment. Our conclusions are statistically robust, as demonstrated by multiple sensitivity analyses (Table 2). These data support the notion of a therapeutic window of opportunity early in the course of RA that results in a sustained benefit in radiographic progression.

To our knowledge, this is the first quantitative metaanalysis of the long-term effect of early DMARD therapy in patients with RA. Prompt DMARD initiation appears to be beneficial on other disease outcomes in patients with early RA. In cohort studies, indirect measures of disease, such as pain, functional disability, and work disability, are less severe in patients receiving early DMARD therapy (44, 47–50). Similarly, patients who receive early aggressive treatment are more likely to remain in remission (51) and have lower mortality rates (52) compared with patients who receive delayed DMARD therapy.

Why early introduction of DMARD therapy changes the long-term rate of structural damage is unknown. In an animal model of RA, anti-TNFα treatment demonstrated efficacy shortly after onset of the disease, but had little effect later in the course of the disease (53). It has been suggested that rheumatoid pannus is reversible in early disease but not later when it becomes self perpetuating (41). The results of the present meta-analysis support this hypothesis because the reduced progression was greater for shorter disease duration (SMD of −0.33 for disease duration <10 months versus SMD of −0.14 for longer disease duration).

There are potential limitations to this analysis related to the inherent quality of the data available. The period between disease onset and DMARD initiation was often ill defined and prone to error (54). However, similar definitions were used for all patients in a given study, so that the delay period was unlikely to be biased. Observational data are prone to confounding by indication, where patients who are more sick are likely to receive more aggressive therapy. However, this is unlikely to explain the observed effect, because patients treated earlier with DMARDs tend to have a more severe disease (47) and are more likely to have progressive structural damage than patients treated later. Therefore, confounding by indication would tend to underestimate the effect of early DMARD therapy. Another type of selection bias could result from completers-only analyses. Although attrition rates are always a concern, there is no evidence for systematic biases, which would imply differential dropout during followup. Confounding could also result from differences in DMARD regimen during followup (drug type, dose, duration). We have addressed this by excluding studies with noncomparable DMARD strategies during followup, but residual confounding is possible, in particular by glucocorticoid use. We defined comparable DMARD efficacy as being less than a 15% difference in the proportion of DMARDs in different efficacy levels. Another definition could have been used, but a sensitivity analysis showed similar results.

Patients with more aggressive disease, as measured by higher estimated rates of radiographic progression at baseline, seemed to benefit most from early DMARD initiation (P = 0.04). Neither different study designs (P = 0.89) nor disparate study quality (P = 0.36) contributed significantly to the study heterogeneity. One study had a significantly larger effect size then the overall summary measure (43). This smaller study was the only study to analyze DMARD initiation among patients with very early RA (≤3 months of disease duration), which could explain the larger effect size. To account for the heterogeneity among studies, we used a random effect model, which does not assume a uniform effect across all studies. Overall, these limitations underline the necessity of more research on this important clinical issue.

Radiographic end points in RA may not be normally distributed, and therefore the use of parametric statistics may not be appropriate. However, change scores of radiographic outcomes and yearly rates of radiographic progression are usually less skewed and have been used in meta-analysis (24, 55). Further imprecision could result from determining rates of radiographic progression from mean change scores instead of individual patient data. Two studies (22, 41) reported cross-sectional radiographic data only, but a sensitivity analysis of these studies compared with studies with longitudinal radiographic data demonstrated no significant difference (P = 0.84). Various scoring methods were used to measure structural joint damage. A sensitivity analysis of studies that used Larsen's scores versus Sharp's scores showed that both methods give qualitatively the same answer, even if the effect size in studies that used Larsen's scores tended to be nonsignificantly larger (P = 0.52).

In summary, a window of opportunity for initiating DMARD therapy appears to exist in early RA, which is associated with significantly improved long-term outcomes. Our results suggest that early DMARD therapy has a durable effect on the rate of radiographic progression of RA up to 5 years after DMARD initiation. To delay DMARD therapy for as little as 9 months after disease onset results in sustained radiographic deterioration, which underlines the importance of starting DMARD therapy as early as possible. Patients with more aggressive RA and early erosive disease seem to benefit most from prompt DMARD initiation. Delayed initiation of DMARDs may result from a variety of factors, from the organization and reimbursement of health services to patient and physician knowledge and preferences (56). Our study suggests that early referrals to a knowledgeable physician or a rheumatologist for definitive diagnosis, severity assessment, and early initiation of DMARD treatment could improve the long-term outcome of patients with RA. Physicians and patients should be aware of the importance of initiating DMARD therapy early in aggressive RA so the period between disease onset of RA and initiation of antirheumatic therapy is minimized.


  1. Top of page
  2. Abstract
  7. Acknowledgements

We thank Dr. Michael Stoto and L. B. Chibnik for methodologic advice, Dr. Michael Weinblatt for providing additional references, Dr. Soko Setoguchi for Japanese-English translations, and Drs. Raimon Sanmarti, Antonio Marchesoni, Valerie Nell, Suzan Verstappen, Paco Welsing, Jean-Francois Maillefert, Timo Möttönen, and Leroy Lard for data not contained in their publications, and Daniel Haake for assistance with the bibliographic search.


  1. Top of page
  2. Abstract
  7. Acknowledgements
  • 1
    Silman AJ. Rheumatoid arthritis. In: SilmanAJ, HochbergMC, editors. Epidemiology of the rheumatic diseases. Oxford: Oxford University Press; 2001. p. 3171.
  • 2
    Scott DL, Smith C, Kingsley G. Joint damage and disability in rheumatoid arthritis: an updated systematic review. Clin Exp Rheumatol 2003; 21(5 Suppl 31 ): S207.
  • 3
    American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002; 46: 32846.
  • 4
    Edmonds JP, Scott DL, Furst DE, Brooks P, Paulus HE. Antirheumatic drugs: a proposed new classification [editorial]. Arthritis Rheum 1993; 36: 3369.
  • 5
    Wilske KR, Healey LA. Remodeling the pyramid: a concept whose time has come. J Rheumatol 1989; 16: 5657.
  • 6
    Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis [published errata appear in N Engl J Med 2001;344:240 and N Engl J Med 2001;344:76]. N Engl J Med 2000; 343: 158693.
  • 7
    St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al, and the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004; 50: 343243.
  • 8
    Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, et al. Infliximab in active early rheumatoid arthritis. Ann Rheum Dis 2004; 63: 14955.
  • 9
    Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000; 43: 229.
  • 10
    Keystone EC, Haraoui B, Bykerk VP. Role of adalimumab in the treatment of early rheumatoid arthritis. Clin Exp Rheumatol 2003; 21(5 Suppl 31 ): S1989.
  • 11
    Van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with “second-line” antirheumatic drugs: a randomized, controlled trial. Ann Intern Med 1996; 124: 699707.
  • 12
    Van Jaarsveld CH, Jacobs JW, van der Veen MJ, Blaauw AA, Kruize AA, Hofman DM, et al. Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis 2000; 59: 46877.
  • 13
    Borg G, Allander E, Lund B, Berg E, Brodin U, Pettersson H, et al. Auranofin improves outcome in early rheumatoid arthritis: results from a 2-year, double blind placebo controlled study. J Rheumatol 1988; 15: 174754.
  • 14
    Quinn MA, Conaghan PG, Emery P. The therapeutic approach of early intervention for rheumatoid arthritis: what is the evidence? Rheumatology (Oxford) 2001; 40: 121120.
  • 15
    O'Dell JR. Treating rheumatoid arthritis early: a window of opportunity? [editorial]. Arthritis Rheum 2002; 46: 2835.
  • 16
    Boers M. Understanding the window of opportunity concept in early rheumatoid arthritis [editorial]. Arthritis Rheum 2003; 48: 17714.
  • 17
    Furst DE. Aggressive strategies for treating aggressive rheumatoid arthritis: has the case been proven? Lancet 2000; 356: 1834.
  • 18
    Landewe RB. The benefits of early treatment in rheumatoid arthritis: confounding by indication, and the issue of timing [editorial]. Arthritis Rheum 2003; 48: 15.
  • 19
    Landewe RB, Boers M, Verhoeven AC, Westhovens R, Mart AF, van de Laar MA, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002; 46: 34756.
  • 20
    Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum 2004; 50: 207281.
  • 21
    Verstappen SM, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, Borg EJ, et al, and the Utrecht Arthritis Cohort Study Group. Five-year followup of rheumatoid arthritis patients after early treatment with disease-modifying antirheumatic drugs versus treatment according to the pyramid approach in the first year. Arthritis Rheum 2003; 48: 1797807.
  • 22
    Maillefert JF, Combe B, Goupille P, Cantagrel A, Dougados M. Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study. Ann Rheum Dis 2003; 62: 7646.
  • 23
    Van Aken J, Lard LR, le Cessie S, Hazes JM, Breedveld FC, Huizinga TW. Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis. Ann Rheum Dis 2004; 63: 2749.
  • 24
    Jones G, Halbert J, Crotty M, Shanahan EM, Batterham M, Ahern M. The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials. Rheumatology (Oxford) 2003; 42: 613.
  • 25
    Buckland-Wright JC, Clarke GS, Chikanza IC, Grahame R. Quantitative microfocal radiography detects changes in erosion area in patients with early rheumatoid arthritis treated with myocrisine. J Rheumatol 1993; 20: 2437.
  • 26
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 27
    Van der Heijde DM. Radiographic imaging: the ‘gold standard’ for assessment of disease progression in rheumatoid arthritis. Rheumatology (Oxford) 2000; 39 Suppl 1: 916.
  • 28
    Van der Heijde DM. Plain X-rays in rheumatoid arthritis: overview of scoring methods, their reliability and applicability. Baillieres Clin Rheumatol 1996; 10: 43553.
  • 29
    Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis Rheum 1998; 41: 157182.
  • 30
    Hulsmans HM, Jacobs JW, van der Heijde DM, van Albada-Kuipers GA, Schenk Y, Bijlsma JW. The course of radiologic damage during the first six years of rheumatoid arthritis. Arthritis Rheum 2000; 43: 192740.
  • 31
    Albers JM, Paimela L, Kurki P, Eberhardt KB, Emery P, van 't Hof MA, et al. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Ann Rheum Dis 2001; 60: 4538.
  • 32
    Pincus T, Ferraccioli G, Sokka T, Larsen A, Rau R, Kushner I, 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 (Oxford) 2002; 41: 134656.
  • 33
    Sokka T, Kautiainen H, Hakkinen A, Hannonen P. Radiographic progression is getting milder in patients with early rheumatoid arthritis: results of 3 cohorts over 5 years. J Rheumatol 2004; 31: 107382.
  • 34
    Wick MC, Lindblad S, Weiss RJ, Klareskog L, van Vollenhoven RF. Estimated prediagnosis radiological progression: an important tool for studying the effects of early disease modifying antirheumatic drug treatment in rheumatoid arthritis. Ann Rheum Dis 2005; 64: 1347.
  • 35
    Strand V, Landewe R, van der Heijde D. Using estimated yearly progression rates to compare radiographic data across recent randomised controlled trials in rheumatoid arthritis. Ann Rheum Dis 2002; 61 Suppl 2: ii646.
  • 36
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al, and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283: 200812.
  • 37
    Lassere M. Pooled metaanalysis of radiographic progression: comparison of Sharp and Larsen methods. J Rheumatol 2000; 27: 26975; discussion 276.
  • 38
    EggerM, SmithGD, AltmanDG, editors. Systematic reviews in health care: meta-analysis in context. London: BMJ Books; 2003.
  • 39
    Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 1992; 45: 76973.
  • 40
    Deeks J, Higgins J, Altman D. Analysing and presenting results. In: AldersonP, GreenS, HigginsJ, editors. The Cochrane reviewers' handbook 4.2.2. Chichester, UK: John Wiley & Sons; 2004.
  • 41
    Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol 1995; 22: 220813.
  • 42
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088101.
  • 43
    Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004; 43: 90614.
  • 44
    Puolakka K, Kautiainen H, Mottonen T, Hannonen P, Korpela M, Julkunen H, et al, and the FIN-RACo Trial Group. 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: 5562.
  • 45
    Welsing PM, van Gestel AM, Swinkels HL, Kiemeney LA, van Riel PL. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum 2001; 44: 200917.
  • 46
    Wolfe F, Flowers N, Anderson J. Radiographic progression predicts substantial income loss and work disability in rheumatoid arthritis [abstract]. Arthritis Rheum 2000; 43 Suppl 9: S403.
  • 47
    Wiles NJ, Lunt M, Barrett EM, Bukhari M, Silman AJ, Symmons DP, et al. Reduced disability at five years with early treatment of inflammatory polyarthritis: results from a large observational cohort, using propensity models to adjust for disease severity. Arthritis Rheum 2001; 44: 103342.
  • 48
    Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M'Seffar A, et al. Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000; 27: 6239.
  • 49
    O'Dell JR, Paulsen G, Haire CE, Blakely K, Palmer W, Wees S, et al. Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial. Arthritis Rheum 1999; 42: 16915.
  • 50
    Munro R, Hampson R, McEntegart A, Thomson EA, Madhok R, Capell H. Improved functional outcome in patients with early rheumatoid arthritis treated with intramuscular gold: results of a five year prospective study. Ann Rheum Dis 1998; 57: 8893.
  • 51
    Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al, and the FIN-RACo trial group. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet 1999; 353: 156873.
  • 52
    Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25: 10727.
  • 53
    Joosten LA, Helsen MM, van de Loo FA, van den Berg WB. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNF α, anti-IL-1α/β, and IL-1Ra. Arthritis Rheum 1996; 39: 797809.
  • 54
    Amjadi-Begvand S, Khanna D, Park GS, Bulpitt KJ, Wong WK, Paulus HE. Dating the “window of therapeutic opportunity” in early rheumatoid arthritis: accuracy of patient recall of arthritis symptom onset. J Rheumatol 2004; 31: 168692.
  • 55
    Sharp JT. An overview of radiographic analysis of joint damage in rheumatoid arthritis and its use in metaanalysis. J Rheumatol 2000; 27: 25460.
  • 56
    Zonana-Nacach A, Campana-Parra A. The lag time between onset of symptoms, medical encounter, and initiation of disease-modifying antirheumatic drugs (DMARDS) in Mexican patients with early rheumatoid arthritis [abstract]. Arthritis Rheum 2004; 50 Suppl 9: S5512.
  • 57
    Van der Heijde DM, van Riel PL, Nuver-Zwart IH, van de Putte LB. Sulphasalazine versus hydroxychloroquine in rheumatoid arthritis: 3-year follow-up [letter]. Lancet 1990; 335: 539.
  • 58
    Luukkainen R, Kajander A, Isomaki H. Effect of gold on progression of erosions in rheumatoid arthritis: better results with early treatment. Scand J Rheumatol 1977; 6: 18992.
  • 59
    Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, et al. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum 2003; 48: 4653.
  • 60
    Mottonen T, Hannonen P, Korpela M, Nissila M, Kautiainen H, Ilonen J, et al. Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum 2002; 46: 8948.
  • 61
    Marchesoni A, Arreghini M, Battafarano N, Panni B, Tosi S. Factors associated with 2-year radiographic progression in patients with early rheumatoid arthritis [abstract]. Arthritis Rheum 2003; 48 Suppl 9: S541.
  • 62
    Sanmarti R, Gomez A, Ercilla G, Gratacos J, Larrosa M, Suris X, et al. Radiological progression in early rheumatoid arthritis after DMARDS: a one-year follow-up study in a clinical setting. Rheumatology (Oxford) 2003; 42: 10449.
  • 63
    Van Jchm VD. Favourable results of early second-phase antirheumatic drugs in rheumatoid arthritis. Ned Tijdschr Geneeskd 1997; 141: 7326.
  • 64
    Capell HA, Maiden N, Madhok R, Hampson R, Thomson EA. Intention-to-treat analysis of 200 patients with rheumatoid arthritis 12 years after random allocation to either sulfasalazine or penicillamine. J Rheumatol 1998; 25: 18806.
  • 65
    Rich E, Moreland LW, Alarcon GS. Paucity of radiographic progression in rheumatoid arthritis treated with methotrexate as the first disease modifying antirheumatic drug. J Rheumatol 1999; 26: 25961.
  • 66
    Nuki G, Bresnihan B, Bear MB, McCabe D, and European Group of Clinical Investigators. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 283846.
  • 67
    Capell HA, Lewis D, Carey J. A three year follow up of patients allocated to placebo, or oral or injectable gold therapy for rheumatoid arthritis. Ann Rheum Dis 1986; 45: 70511.
  • 68
    Hansen M, Podenphant J, Florescu A, Stoltenberg M, Borch A, Kluger E, et al. A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis: clinical benefits and skeletal side effects. Ann Rheum Dis 1999; 58: 7138.
  • 69
    Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, et al, and the Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Arthritis Rheum 2001; 44: 198492.
  • 70
    Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002; 46: 144350.
  • 71
    Allaart CF, Wieringa JW, Huizinga TW, Breedveld FC. Early treatment with DMARDs improves radiological outcome in patients with rheumatoid arthritis [abstract]. Ann Rheum Dis 2001; 60 Suppl 1: 163.
  • 72
    Sokka TM, Kaarela K, Mottonen TT, Hannonen PJ. Conventional monotherapy compared to a “sawtooth” treatment strategy in the radiographic progression of rheumatoid arthritis over the first eight years. Clin Exp Rheumatol 1999; 17: 52732.
  • 73
    Stenger AA, van Leeuwen MA, Houtman PM, Bruyn GA, Speerstra F, Barendsen BC, et al. Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol 1998; 37: 115763.
  • 74
    Van den Borne BE, Landewe RB, The HS, Breedveld FC, Dijkmans BA. Low dose cyclosporine in early rheumatoid arthritis: effective and safe after two years of therapy when compared with chloroquine. Scand J Rheumatol 1996; 25: 30716.
  • 75
    Calguneri M, Pay S, Caliskaner Z, Apras S, Kiraz S, Ertenli I, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: 699704.
  • 76
    Cannon GW, Emkey RD, Denes A, Cohen SA, Saway PA, Wolfe F, et al. Prospective 5-year followup of recombinant interferon-γ in rheumatoid arthritis. J Rheumatol 1993; 20: 186773.
  • 77
    Genovese MC, Martin RW, Fleischmann RM, Keystone EC, Bathon JM, Tsuji WH. Etanercept (ENBREL) in early erosive rheumatoid arthritis: clinical and radiographic data [abstract]. Arthritis Rheum 2003; 48 Suppl 9: S1223.
  • 78
    Peltomaa R, Paimela L, Helve T, Leirisalo-Repo M. Effect of treatment on the outcome of very early rheumatoid arthritis. Scand J Rheumatol 2001; 30: 1438.
  • 79
    Lard LR, Visser H, Speyer I, vander Horst-Bruinsma IE, Zwinderman AH, Breedveld FC, et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 2001; 111: 44651.
  • 80
    Minami M, Kaneda K. A long-term clinical analysis of the rheumatoid patients treated by a combination of GST and CCA. Ryumachi 1995; 35: 78091. In Japanese.
  • 81
    Ichikawa Y, Shinozawa T, Yoshida T, Kameda H, Suzuki Y, Kawai S, et al. Methotrexate and salazosulfapyridine in the long-term treatment of rheumatoid arthritis. Ryumachi 1995; 35: 66370. In Japanese.