Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: Results from a twelve-month randomized, double-blind, placebo-controlled trial
Anti–tumor necrosis factor α agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12-month double-blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor-prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months.
All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months.
Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C-reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX–treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between-group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05).
Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.
Rheumatoid arthritis (RA) is the most common, potentially treatable cause of disability in the western world (1). Evidence supports the early use of disease-modifying antirheumatic drugs (DMARDs) in RA; however, the optimal treatment strategy is uncertain (2). Ideally, effective therapy would produce rapid and sustained suppression of inflammatory disease, resulting in preserved function and prevention of joint damage, without risk of long-term toxicity. A hypothesis in RA research is that early in the disease process, a “window of opportunity” exists, where therapeutic intervention has a disproportionate impact on outcome (3–5). Proof of this concept for an anti–tumor necrosis factor α (anti-TNFα) agent would require maintenance of response after cessation of treatment.
The development of biologic agents, in particular, those that target TNFα, has heralded a new era in the management of chronic inflammatory diseases. Data from studies of patients with longstanding RA show that these agents are effective in improving clinical, functional, and radiographic outcomes and have demonstrated the ability to arrest radiographic progression (6). There is only 1 published randomized study of an anti-TNFα agent in early RA, the Early Rheumatoid Arthritis Study (ERAS), a direct comparison of etanercept with methotrexate (MTX) (7). The study demonstrated rapid control of disease activity with etanercept, with a convergence between groups by the 12-month time point. At 12 months, there was a significant difference in Sharp erosion scores, but not the total scores or joint space narrowing values, in favor of the 25-mg etanercept group. With 12 months of further followup in an open-label extension, significant benefits in the total Sharp and erosion scores, the American College of Rheumatology 20% improvement criteria (ACR20), and functional improvement were demonstrated (8). Importantly, the benefits were seen in the second year after rapid and sustained suppression of disease activity in the first year, suggesting an important role of rapid suppression of inflammatory disease as well as of continued etanercept therapy.
Anti-TNFα agents have been successfully used in a number of other inflammatory conditions, including Crohn's disease (9), ankylosing spondylitis (10), and psoriasis and psoriatic arthritis (11). In Crohn's disease, intermittent short courses or single infusions can be sufficient to suppress disease activity for long periods (12). However, in RA, which is characterized by a chronic progressive course, sustained therapy is required, and when therapy with anti-TNFα is withdrawn, the only published evidence suggests that disease activity rapidly returns (within 12 weeks) (13). These data come from the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study, where patients were selected for disease that was resistant to MTX therapy, with a mean disease duration of 11 years. The results are therefore not unexpected, given the prior failure of the maintenance component of their therapy.
If it is accepted that the greatest potential for therapeutic intervention in RA is at the time of first presentation, then use of the most effective therapy at this time seems the most logical approach. However, treatment with anti-TNFα agents in all RA patients for their lifetimes would not be economically viable in most healthcare systems. An alternative approach is required. Using an analogy from oncology, there could be 2 therapeutic phases: remission induction and maintenance.
Magnetic resonance imaging (MRI) is being increasingly used as an outcome measure in RA clinical trials. Longitudinal studies have confirmed the direct relationship between inflammatory disease (MRI-detected synovitis) and subsequent damage (MRI-detected erosions) (14, 15). Erosions on MRI have also been demonstrated to correspond to and precede detectable radiographic erosions by a median of 2 years (16). MRI has numerous advantages over plain radiography, including 3-dimensional image acquisition, ability to image soft tissues and bone simultaneously, and ability to assess inflammatory bone lesions. Most importantly, its greater sensitivity allows the use of smaller numbers of patients in clinical studies.
This randomized, double-blind, placebo-controlled trial of infliximab and MTX in patients with early, poor-prognosis, previously untreated RA was undertaken to assess the impact of infliximab on MRI evidence of synovitis and bone lesions over 12 months and on clinical outcome 12 months after stopping infliximab. The study tested the hypothesis that a remission-induction approach would produce an optimal response both in the short term (MRI outcomes) and in the medium term (clinical outcomes at 2 years). As a proof-of-concept study, it was statistically powered for synovitis, the primary inflammatory lesion in RA, using the most sensitive measure of change (MRI quantification) as its primary end point.
PATIENTS AND METHODS
Patients were eligible to take part in the study if they had the following features: a diagnosis of RA that met the ACR classification criteria (17), <12 months of symptoms, no previous treatment with DMARDs or oral corticosteroids, metacarpophalangeal (MCP) joint involvement (the primary imaging end point), stable dosage of nonsteroidal antiinflammatory drugs for 2 weeks prior to screening, and poor prognosis according to the Persistent Inflammatory Symmetrical Arthritis (PISA) scoring system (3). The PISA scoring system awards 1 point each for rheumatoid factor (RF) positivity, possession of the shared epitope (HLA–DR1/DR4/DR10), a C-reactive protein (CRP) level >20 mg/liter, female sex, and a Health Assessment Questionnaire (HAQ) raw score >4, as well as 2 points for a HAQ raw score >11. A score of ≥3 indicates a poor prognosis (3). The HAQ is a validated self-report questionnaire that assesses functional status (18).
Patients were excluded if they had any of the following: any current inflammatory condition with signs or symptoms that might confound the diagnosis (e.g., connective tissue disorders); previous use of anti-TNFα agents, cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents; or a known allergy to murine proteins. Patients were also excluded if they had any contraindication for infliximab therapy, including a history of lymphoproliferative disease or any known malignancy over the previous 5 years or evidence of previous tuberculosis infection on chest radiograph.
After protocol approval by the Local Research and Ethics Committee, patients were recruited for the study between March 1, 2000 and March 30, 2001. The study was conducted in accordance with the Declaration of Helsinki per the latest amendment.
Eligible patients were randomized to receive a standard dosage of infliximab (3 mg/kg of body weight) or placebo. On the day of the first infusion (baseline), patients underwent a complete disease activity assessment and imaging. Infusions were given at baseline, 2 weeks, and 6 weeks, and then at 8-week intervals through to 46 weeks. First infusions were administered over 2 hours and subsequent infusions over 1 hour. All patients began MTX (7.5 mg once each week) and folic acid (5 mg twice each week) at baseline, with escalation of the MTX dosage according to a standardized step-up protocol; all patients were receiving 15 mg/week by week 14 of study. Further increments up to 25 mg were titrated against evidence of active clinical disease, aiming for remission. No other DMARDs were allowed until after the visit at week 54.
The first 54 weeks of the study were carried out in a double-blind manner and thereafter in an observational manner. Persistent nonresponders were treated with step-up combination therapy according to clinic protocol in an open-label manner. This involved the addition of sulfasalazine then hydroxychloroquine therapy according to the disease activity. Additional therapy was determined by an experienced rheumatologist (MAQ) based on findings of the clinical assessment but without knowledge of the patient's HAQ score, metrologic findings, etc. No corticosteroids were permitted during the first 14 weeks of study. Thereafter, parenteral (intraarticular or intramuscular) corticosteroids were permitted as clinically required, to a maximum dose of 120 mg of methylprednisolone in each 3-month study period.
The primary end point of the study was comparison of MRI-measured synovitis at week 14 between groups. Secondary outcome measures included MRI-measured synovitis, bone edema, and erosion scores at 4 weeks and 54 weeks, conventional radiographs scored according to the van der Heijde modification of the total Sharp score (19), and clinical disease activity measures, including ACR remission and responder rates (20%, 50%, and 70%) (20), Disease Activity Score in 28 joints (DAS28) (21), and functional assessments according to the HAQ scores at 54 weeks. Quality of life was measured at 0, 14, and 54 weeks using the RA Quality of Life (RAQoL) questionnaire, a validated quality-of-life measure in RA (22). Patients were observed for a further 50 weeks after the final assessment of the randomized phase, with clinical data (ACR response and DAS28, HAQ, and RAQoL scores) collected at 78 and 104 weeks and conventional radiographs at 104 weeks.
MRI scans of the second through fifth MCP joints of the dominant hand were performed using a commercially available 1.5T Gyroscan ACS NT whole-body MRI system (Philips Medical Systems, Best, The Netherlands) with image acquisition. With the patient lying prone and the arm extended, a Philips linear circular 11-cm surface coil was placed on the dorsum of the hand. Five sequences were performed as previously described (14). Images were scored for synovitis, bone edema (inflammatory changes, which represents the earliest bone lesion on MRI), and erosions according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) definitions by 2 experienced readers (PGC and PJO) who were blinded to the identity of the patient as well as the clinical findings (14).
Plain radiographs of the hands and feet were obtained at baseline, 54 weeks, and 104 weeks. Radiographs were scored blindly using the van der Heijde modification of the Sharp method (19).
Patients were assigned to a treatment group using an adaptive stratified randomization technique, with RF positivity as the stratum. The sample size in this pilot study was estimated at 10 patients per treatment arm based on previous work in our department using MRI outcome measures (14). Baseline variables were analyzed using Student's t-test (parametric) or Wilcoxon's rank sum test (nonparametric) as appropriate. MRI outcomes were analyzed using Wilcoxon's 2-sample rank sum test (equivalent to the Mann-Whitney U test). Other variables were analyzed using parametric (2-sample t-test) and nonparametric tests as appropriate. The CRP area under the curve was calculated using the trapezium rule for each subject and then analyzed using Wilcoxon's 2-sample rank sum test. This method of analysis was chosen because assessment of time-integrated CRP levels was thought to be superior to comparison of levels at individual time points.
The baseline characteristics of the 2 treatment groups are presented in Table 1. There were no significant differences in baseline characteristics between the groups. One patient developed cutaneous vasculitis after only 1 infusion of the study drug (infliximab) and was withdrawn from the study, but was included in the intent-to-treat analysis.
Table 1. Baseline demographics of the treatment groups*
Infliximab plus MTX (n = 10)
Placebo plus MTX (n = 10)
MTX = methotrexate; RF = rheumatoid factor; CRP = C-reactive protein; HAQ = Health Assessment Questionnaire; IQR = interquartile range.
Age, mean ± SD years
51.3 ± 9.5
53.1 ± 13.7
Symptom duration, mean ± SD months
7.4 ± 4.6
6 ± 3.7
RF positive, %
CRP, mean ± SD mg/liter
47 ± 27.9
37 ± 38.8
HAQ score, median (IQR)
The study achieved its primary end point (a significant reduction in synovitis compared with baseline), with a reduction in the median total synovitis score from 5.5 to 3.4 in the infliximab plus MTX group compared with a reduction from 6.2 to 5.9 for the placebo plus MTX group at 14 weeks (P < 0.05). This difference was maintained, with a significant difference in the synovitis scores, at 54 weeks (median total synovitis score 3.8 in those taking infliximab plus MTX versus 6.6 in those taking placebo plus MTX; P < 0.05), despite convergence of the clinical parameters (see below). Bone edema scores were significantly improved at 4, 14, and 54 weeks in favor of infliximab treatment (P < 0.05). At 54 weeks, there were no new MRI erosions in the group treated with infliximab plus MTX. There were significantly fewer new erosions at 24 weeks (P = 0.0125) in those taking infliximab plus MTX than in those taking placebo plus MTX (Figure 1).
Despite a trend toward less damage in the infliximab plus MTX–treated patients over time, there were no significant between-group differences in the total Sharp scores from baseline to 24 months (mean change in the total Sharp scores 10 versus 12 for the infliximab plus MTX and placebo plus MTX groups, respectively).
ACR response and remission rates.
Patients treated with infliximab plus MTX demonstrated a significantly greater response at 14 weeks, as measured by the ACR20 (60% versus 20% in the placebo group), ACR50 (60% versus 0%), and ACR70 (60% versus 0%) criteria (P < 0.05). At 54 weeks, the responder rates begin to converge, with ACR20 responses of 80% in the infliximab plus MTX group and 60% in the placebo plus MTX group, ACR50 responses of 80% and 40%, respectively, and ACR70 responses of 70% and 30%, respectively. But, the ACR50 and ACR70 responses remained statistically significant (P < 0.05). There were no statistically significant differences in ACR responses at 104 weeks: 70% versus 50% for an ACR20 response, 70% versus 50% for an ACR50 response, and 50% versus 50% for an ACR70 response in the infliximab plus MTX and the placebo plus MTX groups, respectively.
Remission rates were greater in those taking infliximab plus MTX, with 7 patients meeting the ACR response criteria at some time up to week 104, as compared with 2 patients in the group taking placebo plus MTX. The median time in remission for the infliximab plus MTX group was 26 weeks, as compared with 0 weeks in the placebo plus MTX group (P < 0.05).
Patients treated with infliximab plus MTX demonstrated a significant reduction in the DAS28 score at 14, 54, and 104 weeks (P < 0.005). At 54 weeks, the median DAS28 score reflected mild disease (2.84), and at 2 years, the median activity was below remission levels (DAS28 score 2.52). Patients treated with placebo plus MTX demonstrated a significant reduction in the DAS28 score compared with baseline at 54 and 104 weeks (P < 0.05). There was a significant difference between groups at 14 weeks (P < 0.05), but at 54 and 104 weeks, there was no significant difference between groups, with convergence of disease activity over time (Figure 2).
An analysis of the CRP area under the curve utilizing 11 separate time points showed a significant reduction in favor of infliximab plus MTX therapy (P < 0.05) up to 54 weeks (Figure 3). After a single infusion of study drug, the mean CRP level normalized in the infliximab plus MTX–treated group. There was no significant change in the CRP level in either group between week 54 and week 104 (after cessation of infliximab and placebo).
Physical function and quality of life.
A significant functional benefit (measured by the HAQ) was demonstrated between groups at 14, 54, and 104 weeks, favoring infliximab plus MTX treatment (P < 0.05). In contrast, despite a trend toward improvements in physical function scores in the placebo plus MTX group, no significant changes from baseline were demonstrated (Figure 4). Data on quality of life reflected similar benefits. The infliximab plus MTX–treated patients experienced significantly greater improvements in RAQoL scores compared with the placebo plus MTX–treated patients at 14, 54, and 104 weeks (P < 0.05) (Figure 4).
DMARD and corticosteroid use.
The patients taking placebo plus MTX received more MTX than did those taking infliximab plus MTX (mean 19 mg versus 15 mg at 54 weeks and 19 mg versus 17 mg at 104 weeks). Three patients randomized to the placebo arm received 2 additional DMARDs in the second year of the study (sulfasalazine and hydroxychloroquine), and 1 patient randomized to the infliximab arm received additional sulfasalazine. Also, 1 patient randomized to the placebo arm who was treated with triple therapy continued to experience active disease and was given anakinra. Patients randomized to the placebo arm received greater amounts of corticosteroid. The mean total parenteral dose of methylprednisolone administered to patients randomized to the placebo arm was 341 mg over the study period, as compared with 146 mg in those randomized to the infliximab arm, with 275 mg versus 110 mg in the first year and 84 mg versus 36 mg in the second year, respectively.
Following the last infusion of study drug at 46 weeks, patients were observed for a further 58 weeks. The results above compare the 2 groups through to 104 weeks. Figures 5, 6, and 7 present data for individual patients in the infliximab plus MTX group for the CRP levels, DAS28 scores, and HAQ scores, respectively. One patient had a deterioration in the CRP level, and 2 patients had a deterioration in the DAS28 scores; however, no patient had a functional deterioration as measured by the HAQ after withdrawal of infliximab treatment. Therefore, looking at the DAS28 scores in the second year, of the 10 patients that received infliximab, 7 maintained responses, 2 had increases after infliximab withdrawal (at least 32 weeks after the last infusion), and 1 failed to respond at any point.
One patient developed cutaneous vasculitis after a single infusion of study drug (infliximab) and was withdrawn from the study. One patient randomized to the infliximab arm developed abnormal liver function test results (increased alanine aminotransferase levels), which limited the dosage escalation of MTX above 12.5 mg. One patient developed an infusion reaction on a single occasion; this resolved without therapeutic intervention after stopping the infusion for 30 minutes and recommencing at half the standard rate. No further infusion reactions were experienced by this patient.
This placebo-controlled pilot study evaluated a remission-induction approach using a TNFα inhibitor in addition to escalating MTX doses in patients with early, poor-prognosis RA who were treated at presentation. The study used MRI to assess short-term inflammatory and damage outcomes in a randomized design for 12 months, with further clinical observations to 24 months. The active infliximab arm demonstrated rapid normalization of the systemic acute-phase response (CRP), with corresponding suppression of inflammatory joint disease (joint counts, and MRI synovitis and bone edema at 14 weeks) and resultant prevention of damage (MRI erosions at 54 weeks). The rapid disease control was paralleled by a rapid (<14 weeks), sustained (104 weeks), and significant improvement in function and quality of life scores. The data suggest that rapid control of inflammation confers functional, quality of life, and MRI damage benefits, findings consistent with published data that correlate time-integrated inflammation with radiographic damage (15, 23–26) and functional impairment (27, 28). This is the first study to demonstrate a rapid improvement in quality of life, reflecting the magnitude and rate of disease suppression in our patients.
During the second 12 months of this study, we observed the patients after withdrawal of their randomized therapy. During this phase of the study, clinical disease activity measures (CRP, DAS28, ACR improvements) all converged, with no significant differences in these parameters at the 24-month assessment. However, despite the improvements in disease activity in the placebo plus MTX group over time, the slower control of disease activity failed to have a significant impact on the subjective outcomes of function and quality of life, with both parameters significantly better in the patients receiving infliximab plus MTX at 24 months. This appears to emphasize the importance not only of adequate disease suppression over time, but also of rapid disease suppression for optimal improvement in these outcomes. Rapid control of disease activity may prevent patients entering the “sick role” and may avoid the socioeconomic disadvantages associated with chronic illness, which extend beyond the antiinflammatory nature of the therapy.
Presenting averages when dealing with small numbers in studies can be misleading. Individual data on CRP levels, DAS28, and HAQ scores in patients receiving infliximab plus MTX are illustrated in Figures 5, 6, and 7. Two patients demonstrated an increase in the DAS28 score after infliximab withdrawal, in the latter half of the second year of followup. One failed to demonstrate an ACR response from baseline and was classified as a nonresponder despite the DAS28 score, and the other had an increase in DAS28 score at 2 years, which was accounted for by an increase in joint counts, but the CRP level and global, HAQ, and RAQoL scores were not increased, and no additional therapy was deemed necessary by the assessing physician. Previous data in patients with established disease suggest that withdrawal of infliximab results in a rapid flare of disease and a requirement for additional therapy, yet this is not supported by our data in early, poor-prognosis RA (13).
It must be pointed out that the study failed to show a significant difference in radiographic outcome at 2 years, despite a trend in favor of the infliximab plus MTX–treated patients. The study was not powered to show differences in conventional radiographs over the study period, and the frequency of radiographic change was low, giving a very small power to show a difference. The point of this study was that by using MRI, which has greater sensitivity for bone erosions than conventional radiography, a smaller number of patients could be studied with adequate statistical power.
It is acknowledged that the therapeutic approach of intervention prior to irreversible damage and disability is optimal and improves outcome (2). Previous studies have shown symptomatic and structural benefit from the early use of aggressive combination therapy (29, 30). These pilot data resulted in an average DAS28 score within the remission range (median 2.52) and benefits in function and quality of life at 24 months without the use of large doses of corticosteroids and their inherent long-term toxicity risk. Moreover, the benefits were largely sustained (see above) 12 months after the intervention was ceased.
An explanation for this may be that for agents such as infliximab, the speed and magnitude of response is greater than was previously achievable with corticosteroids and conventional DMARDs. Using an oncology analogy, infliximab may simply debulk the disease (remission induction) sufficiently for the conventional DMARDs to provide continued disease suppression at low levels (maintenance therapy). Alternatively, the early use of anti-TNFα agents in general and infliximab in particular may have a specific effect on the processes that sustain inflammation. Of particular note in this respect is the potential ability of this drug to bind to membrane-bound TNFα and potentially induce cell death by apoptosis and other mechanisms (31). Such an effect could have a profound impact on the disease over the long term, especially if combined with continued disease suppression with MTX.
Whatever the process, these data provide further evidence for the “window of opportunity” hypothesis in RA. The implications of this study could be considerable, but these data must be interpreted within the limits of the pilot study design. The results in the second year were unexpected, since previously reported studies in patients with established disease had shown rapid return of RA upon withdrawal of TNFα (13). The second-year data were also collected in an observational manner and, so, provide weaker evidence than the data obtained from randomized trials. The small numbers of patients studied also increase the possibility of the results occurring by chance. Therefore, the study acts principally as a hypothesis-generating study, requiring large-scale randomized trials to further validate this therapeutic approach.
Despite the design limitations of the study, however, for patients with RA, these results are comparable to the best reported (and were achieved in patients selected for poor prognosis). If larger studies confirm these data, this protocol may provide a possible solution to the economic issues of early therapy with biologics. In many countries, anti-TNFα therapy is only recommended for patients with recalcitrant RA. The reluctance to recommend it for first-line use in early RA is principally economic, since the cost of life-long treatment of such a prevalent disease would be beyond any realistic budget. The approach presented may offer the potential for the drug to be used for a limited (affordable) period, at a time when it has the greatest opportunity to make a difference. Large-scale studies are under way to confirm these findings.