Drs. Smolen, Maini, Kalden, van der Heijde, Breedveld, and Furst have received consulting fees and/or honoraria (less than $10,000 per year) from Centocor. Drs. Han, Bala, and Maini own stock in Johnson and Johnson, of which Centocor is a subsidiary. In 2002, Drs. Maini and van der Heijde gave expert testimony at the FDA hearing on inhibition of structural damage, for which they received fees. The Kennedy Institute of Rheumatology has a patent and a research and licensing agreement from Centocor and receives royalties from the use of infliximab in rheumatoid arthritis; as a coinventor, Dr. Maini receives a percentage under the Kennedy Institute's formula for the division of royalties.
Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: A detailed subanalysis of data from the anti–tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study
Version of Record online: 7 APR 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 4, pages 1020–1030, April 2005
How to Cite
Smolen, J. S., Han, C., Bala, M., Maini, R. N., Kalden, J. R., van der Heijde, D., Breedveld, F. C., Furst, D. E., Lipsky, P. E. and ATTRACT Study Group (2005), Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: A detailed subanalysis of data from the anti–tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis & Rheumatism, 52: 1020–1030. doi: 10.1002/art.20982
- Issue online: 7 APR 2005
- Version of Record online: 7 APR 2005
- Manuscript Accepted: 10 SEP 2004
- Manuscript Received: 7 SEP 2003
- Centocor, Inc., Malvern, Pennsylvania
To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment.
Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti–Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial.
At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo–treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX–treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001).
Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.
Rheumatoid arthritis (RA) is associated with persistent inflammation of the synovial tissue as well as damage to articular structures, including cartilage and bone, and progressive disability. Early in RA, disability correlates with signs and symptoms of inflammation, whereas subsequently it correlates more closely with articular damage detected radiographically (1). Protection from disability, the long-term goal of RA therapy, therefore requires both control of inflammation and protection from radiographic damage.
Results of several earlier studies suggested a correlation between persistent inflammation and articular damage (2–5). Since inflammation is driven by proinflammatory cytokines (6), these clinical data as well as evidence from experimental models (7, 8) suggest that the action of proinflammatory cytokines, such as tumor necrosis factor (TNF), is intimately associated with joint destruction. In contrast, there is accumulating evidence from studies of experimental arthritis that inflammatory disease activity and destruction can be dissociated from one another (9–12). Bone erosion is clearly mediated by activated osteoclasts (10–13), and the pathways leading to differentiation and activation of osteoclasts are of pivotal importance for the occurrence of bone erosions (10, 12, 14). TNF activates the pathway leading to osteoclast activation, in a dose-dependent manner (15, 16). Interestingly, among rheumatic diseases, RA is associated with the highest levels of TNF production (17). Thus, high levels of TNF could account for the greatly and often rapidly destructive nature of the disease. Accordingly, reduction of the biologic consequences of TNF, as accomplished by the TNF blocking therapies (18), may reduce the pressure on osteoclast differentiation and thus joint destruction even in the absence of effects on synovial inflammation; experimental evidence for this has been obtained from studies of TNF-transgenic mice treated with anti-TNF agents (11).
TNF blockers affect signs and symptoms as well as radiographic progression of RA (19–21). In particular, infliximab, a recombinant IgG1κ human-murine chimeric monoclonal anti-TNF–specific antibody, in combination with methotrexate (MTX), has been shown to reduce signs and symptoms, to inhibit progression of structural damage, and to improve physical function in patients with moderate to severe RA whose disease remains active despite MTX therapy. The data in support of these conclusions were largely derived from the pivotal multicenter phase III clinical trial termed ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy) (19, 22). We have previously reported that radiographic progression was reduced not only in patients in the ATTRACT study who had a clinical response to infliximab plus MTX, but also in those who did not have a clinical response (19). However, the ATTRACT “nonresponders,” who were categorized as such by the American College of Rheumatology 20% response criteria (ACR20) (23) after 54 weeks of therapy, might have manifested some improvement in inflammation that could have accounted for their radiographic benefit, and the results of an analysis of another trial involving combination therapy in RA patients had suggested this possibility (24).
To further assess this issue, the ATTRACT data were analyzed in greater detail. We separated the patient groups into ACR20 responders and nonresponders and analyzed their clinical as well as radiographic features over time. More importantly, to determine whether infliximab therapy could have differing effects on destruction and on inflammation, we also performed further subanalyses applying more stringent criteria for lack of antiinflammatory effect than simply failure to achieve an ACR20 response or lesser degrees of improvement in inflammation. These analyses demonstrated that inhibition of radiographically evident articular damage in RA patients could be achieved by treatment with infliximab plus MTX, even when no changes in individual signs and symptoms or serologic measures of inflammation were observed.
PATIENTS AND METHODS
The eligibility criteria and design of the study have been described in detail elsewhere (19, 22). Men and women with active RA despite treatment with MTX in dosages of at least ≥12.5 mg/week participated in the study. Active RA was defined based on the presence of ≥6 swollen joints, ≥6 tender joints, and at least 2 of the following: morning stiffness of ≥45 minutes, an erythrocyte sedimentation rate (ESR) of ≥28 mm/hour, and a serum C-reactive protein (CRP) concentration of ≥2 mg/dl.
This investigation was a subanalysis of the previously reported ATTRACT study (19, 22). Patients in the ATTRACT study were randomly assigned to receive MTX at the same stable dosage they had been receiving on a weekly basis before study enrollment, in combination with infusions of placebo or of infliximab at 3 mg/kg or 10 mg/kg for up to 102 weeks. No other disease-modifying antirheumatic drugs were permitted, and therefore, patients who switched to other therapies during the study were regarded as nonresponders (lack of efficacy) across all treatment groups. All patients received intravenous infusions at the initiation of treatment (week 0) and at weeks 2 and 6. Two infliximab plus MTX groups (one receiving 3 mg/kg and the other receiving 10 mg/kg) received subsequent infusions every 4 weeks, whereas two other infliximab plus MTX groups (one receiving 3 mg/kg and the other receiving 10 mg/kg) received infliximab every 8 weeks and placebo infusions at the interim 4-week visits. The MTX-only group received placebo infusions every 4 weeks.
Patients were allowed to continue taking nonsteroidal antiinflammatory drugs and oral glucocorticoids (prednisone, ≤10 mg/day) at the same dosage they had been receiving at the time of study entry. The study protocol was approved by the institutional review committee at each participating center, and each patient gave written informed consent.
The prevention of structural damage in the hands and feet was measured by the change from baseline to week 54 in the modified Sharp/van der Heijde score (25). This total radiographic score can range from 0 to 440, with higher scores indicating more articular damage. The variable analyzed was the average of the total radiographic scores as assessed by 2 readers (who were blinded with regard to treatment data) at week 54 minus the average of the 2 baseline scores. Radiographs of both the hands and the feet obtained at baseline and at week 54 were included in these analyses. Complete sets of radiographs were available for 348 patients (81%). Positive changes from baseline indicate progression of structural damage in the joints.
Clinical response at week 54 was defined according to the ACR20 criteria. In these analyses, the numbers of tender and swollen joints were evaluated by an independent assessor who was blinded with regard to the patient's treatment assignment. Sixty-eight joints were assessed for tenderness and 66 joints for swelling. In the evaluation of ACR20 data, patients who discontinued treatment prior to week 54 were considered nonresponders, as were patients who had protocol-prohibited changes in medication and/or a joint surgical procedure.
Treatment group comparisons were made at week 54 for individual components of the ACR response criteria, fatigue, duration of morning stiffness, the ACR-N (26), and the 28-joint Disease Activity Score (DAS28) (27). The ACR-N, which assesses individual treatment response on a continuum, is defined as the smallest percentage of improvement from baseline in the numbers of tender and swollen joints and in the median percent improvement in scores for patient and physician global assessments, pain, disability, and CRP. In this analysis, the ACR-N was determined to be 0 if the patient withdrew from the study prior to completion or had a protocol violation, or if the ACR response worsened from baseline. In addition, we calculated the DAS28, which incorporates swollen and tender joint counts for 28 joints, ESR, and the patient's assessment of general health. DAS28 response was defined based on a combination of a significant change from baseline and the level of disease activity attained. Good DAS28 response was defined as a significant decrease in DAS28 (>1.2) and a low level of disease activity (≤3.2). Nonresponse was defined as a decrease of ≤0.6, or a decrease of 0.6–1.2 with a score of >5.1 on the DAS28. Any other scores were regarded as indicative of moderate responses (27, 28).
A further evaluation of ACR20 nonresponders at week 54 assessed the proportions of patients who had ≥20% improvement in tender and swollen joint counts along with ≥20% improvement in at least 2 of the other ACR20 components. Finally, analyses were performed to evaluate radiographic progression among patients with no improvement noted in the various measures of disease activity at week 54 and among patients without an ACR20 response at any visit from week 2 through week 54 (“no improvement” in this context indicates deterioration or no change in assessments). In an even more stringent evaluation, radiographic changes were assessed in patients with and those without infliximab therapy who had no change in the DAS28 (defined as DAS change of 0 ≤ 0.5) at both week 30 and week 54 (0.5 was chosen because even a moderate response requires, among other changes, an improvement of at least 0.6 in the DAS, according to the European League Against Rheumatism ; moreover, limitation to 0.5 would not allow patients with significant deterioration, more likely to occur in the placebo group, to be included in this analysis).
Analyses of continuous variables were performed by comparing results among the treatment groups using analysis of variance on van der Waerden normal scores. For categorical response parameters, treatment group comparisons were made using the chi-square test. All statistical testing was 2-sided. P values less than or equal to 0.05 were considered significant. Analyses were conducted using the SAS statistical package (version 6.12).
Role of the funding company
The study sponsor, Centocor, Inc., worked with the trial investigators in developing the protocol and analyzing and interpreting the data, as well as in developing and submitting the manuscript.
Patient disposition and baseline characteristics.
Four hundred twenty-eight patients were enrolled in the ATTRACT trial. Patient disposition is summarized in Figure 1. Baseline characteristics of patients in the study population have been reported previously (19, 22). At baseline, demographic and disease characteristics in the clinical responders and nonresponders were similar between the MTX plus placebo–treated and the infliximab-treated groups, with the following exceptions: among nonresponders, infliximab-treated patients were, on average, older (55 years) than MTX plus placebo–treated patients (51 years) (P = 0.019); among nonresponders, MTX plus placebo–treated patients had a longer duration of morning stiffness (208 minutes) than infliximab-treated patients (190 minutes) (P = 0.032); and among responders, all infliximab-treated patients had, on average, a higher previous MTX dosage (16.6 mg/week) than MTX plus placebo–treated patients (14.7 mg/week) (Table 1).
|ACR20 responders at week 54 (n = 191)||ACR20 nonresponders at week 54 (n = 237)|
|MTX plus placebo–treated (n = 15)||All infliximab-treated (n = 176)||MTX plus placebo–treated (n = 73)||All infliximab-treated (n = 164)|
|Male, no. (%)||5 (33)||41 (23)||13 (18)||37 (23)|
|Female, no. (%)||10 (67)||135 (77)||60 (82)||127 (77)|
|Age, years||49.7 ± 8.6||50.6 ± 11.4||51.2 ± 12.7||55.2 ± 11.4|
|Disease duration, years||9.9 ± 9.1||9.5 ± 7.7||10.8 ± 8.2||11.2 ± 9.5|
|Tender joint count||32.5 ± 19.1||32.5 ± 15.5||30.4 ± 18.2||32.5 ± 16.5|
|Swollen joint count||21.2 ± 10.8||22.6 ± 11.7||21.5 ± 12.1||22.7 ± 12.5|
|Rheumatoid factor, units/ml||317.8 ± 410.9||336.4 ± 448.0||346.7 ± 443.5||309.7 ± 398.5|
|Duration of morning stiffness, minutes||156.0 ± 79.5||188.6 ± 282.7||207.9 ± 303.7||190.5 ± 274.2|
|Fatigue, VAS||6.6 ± 1.8||6.3 ± 2.2||6.1 ± 2.4||6.5 ± 2.0|
|HAQ score||1.6 ± 0.5||1.6 ± 0.6||1.7 ± 0.7||1.8 ± 0.6|
|Patient global assessment, VAS||6.3 ± 2.5||5.9 ± 2.2||5.9 ± 2.5||6.4 ± 2.3|
|Physician global assessment, VAS||6.4 ± 1.8||6.0 ± 1.8||6.2 ± 1.7||6.0 ± 1.8|
|CRP, mg/dl||4.6 ± 4.6||3.8 ± 3.8||3.9 ± 4.1||3.6 ± 3.8|
|ESR, mm/hour||54.2 ± 26.9||49.1 ± 23.8||48.2 ± 24.6||50.9 ± 23.9|
|DAS28||6.8 ± 1.0||6.7 ± 1.0||6.6 ± 1.1||6.7 ± 1.0|
|Modified Sharp/van der Heijde score||88.4 ± 83.2||69.6 ± 66.1||80.5 ± 76.6||76.7 ± 73.0|
|MTX dosage within previous 3 months, mg/week||14.7 ± 2.5||16.6 ± 4.0||17.0 ± 4.4||16.1 ± 3.7|
|No. of prior DMARDs||1.5 ± 1.2||2.2 ± 1.6||2.4 ± 1.6||2.4 ± 1.6|
Significant improvement in clinical variables in patients treated with infliximab plus MTX, compared with MTX plus placebo, among ACR20 nonresponders.
DAS improvement in ACR20 nonresponders.
Among all patients, those treated with infliximab plus MTX had higher DAS28 and ACR20 response rates (i.e., higher proportions of patients meeting response criteria) compared with those receiving MTX plus placebo. In general, DAS28 response rates were higher than ACR20 response rates (Figure 2A). Among ACR20 nonresponders at week 54, those receiving infliximab plus MTX exhibited significantly more improvement in the DAS28 at week 54 (P < 0.001) compared with nonresponders who received MTX alone (Table 2 and Figure 2B); however, the rates of DAS28 response among ACR20 nonresponders were ∼60–80% lower than among ACR20 responders (Figure 2B).
|MTX plus placebo–treated (n = 73)||Infliximab plus MTX–treated|
|3 mg/kg every 8 weeks (n = 50)||3 mg/kg every 4 weeks (n = 45)||10 mg/kg every 8 weeks (n = 36)||10 mg/kg every 4 weeks (n = 33)||All infliximab-treated (n = 164)|
|Tender joint count|
|Mean ± SD||−10.38 ± 61.76||−24.42 ± 55.79||−26.87 ± 49.35||−19.09 ± 61.95||−41.09 ± 34.93||−27.33 ± 51.97|
|IQR||−53.0, 10.0||−66.5, 2.5||−64.0, 0.0||−62.0, 11.0||−62.5, −12.5||−65.0, 0.00|
|Swollen joint count|
|Mean ± SD||−3.38 ± 61.97||−11.06 ± 69.16||−23.38 ± 60.42||−37.24 ± 45.07||−43.91 ± 38.74||−26.75 ± 57.61|
|IQR||−38.0, 13.0||−54.5, 15.0||−59.0, −13.0||−71.0, −5.0||−73.5, −17.5||−67.0, −2.0|
|Mean ± SD||−4.35 ± 32.41||−0.92 ± 47.91||−11.18 ± 30.09||−5.17 ± 57.05||−14.97 ± 40.40||−7.53 ± 44.49|
|IQR||−11.0, 10.0||−18.0, 12.0||−32.5, 0.0||−33.0, 4.00||−38.0, 0.0||−32.0, 6.0|
|Patient global assessment, VAS|
|Mean ± SD||30.08 ± 130.91||2.98 ± 62.12||4.78 ± 95.09||−7.97 ± 46.23||206.00 ± 1274.44||42.71 ± 579.53|
|IQR||16.0, 36.0||−47.0, 29.0||−31.0, 13.0||−46.0, 19.0||−50.0, 13.0||−46.0, 18.0|
|Physician global assessment, VAS|
|Mean ± SD||2.52 ± 79.33||−15.73 ± 58.68||−33.70 ± 40.95||−15.14 ± 54.90||−42.03 ± 39.27||−25.87 ± 50.58|
|IQR||−30.0, 23.0||−61.0, 13.5||−62.5, −3.0||−45.0, 3.0||−77.0, −15.0||−63.0, 0.0|
|Mean ± SD||3.25 ± 41.65||−1.29 ± 58.48||−5.87 ± 44.17||−5.07 ± 46.36||−23.29 ± 42.14||−7.90 ± 49.17|
|IQR||−23.8, 25.0||−24.6, 18.4||−30.3, 10.0||−45.3, 32.1||−49.3, 0.0||−34.3, 16.7|
|Mean ± SD||40.96 ± 157.64||6.41 ± 111.50||3.22 ± 174.24||−2.09 ± 242.14||−1.94 ± 203.62||1.99 ± 180.66|
|IQR||−34.0, 46.0||−62.0, 25.0||−77.0, 22.0||−86.0, −18.0||−78.0, −14.0||−78.0, 9.0|
|Mean ± SD||−8.46 ± 48.29||−21.54 ± 65.04||−35.28 ± 47.01||−34.02 ± 57.60||−17.30 ± 41.85||−27.69 ± 54.29|
|IQR||−46.4, 10.0||−58.9, −5.1||−66.7, −15.0||−67.6, −14.3||−50.1, 7.8||−59.1, −3.6|
|Mean ± SD||20.97 ± 104.13||12.9 ± 92.40||−4.24 ± 43.00||3.23 ± 53.54||−19.30 ± 40.60||−0.60 ± 63.95|
|IQR||−14.0, 33.0||−16.5, 15.0||28.0, 13.0||−26.0, 27.0||−52.0, 13.0||−30.0, 19.0|
|Duration of morning stiffness, minutes|
|Mean ± SD||−4.43 ± 109.64||26.92 ± 263.97||−27.68 ± 122.36||−46.91 ± 58.16||20.06 ± 411.19||−5.40 ± 246.40|
|IQR||−75.0, 25.0||−77.0, 0.0||−83.0, −25.0||−90.0, −20.0||−83.0, 0.0||−83.0, 0.0|
|Mean ± SD||−9.37 ± 16.81||−20.94 ± 20.99||−20.33 ± 20.26||−25.03 ± 20.43||−19.35 ± 18.26||−21.43 ± 20.03|
|IQR||−21.0, 0.0||−28.5, −10.5||−34.5, −7.0||−42.0, −8.0||−32.0, −5.0||−35.0, −7.0|
Significant improvement in individual components of the ACR response criteria among ACR20 nonresponders.
ACR20 nonresponders at week 54 who received infliximab plus MTX exhibited greater improvements in almost all ACR components evaluated, compared with ACR20 nonresponders at week 54 who received MTX plus placebo (Table 2). Differences between the treatment groups (all infliximab-treated versus MTX plus placebo–treated) in median percent change from baseline to week 54 were statistically significant for tender joint count (P = 0.014), swollen joint count (P < 0.001), duration of morning stiffness (P = 0.026), patient's and physician's global assessment of disease activity (P = 0.012 and P < 0.001, respectively), pain score (P = 0.038), CRP level (P < 0.001), ESR (P = 0.007), and fatigue score (P = 0.034) (Table 2). ACR20 nonresponders receiving infliximab plus MTX had only minor improvement in the Health Assessment Questionnaire (HAQ) score (29), which was not significantly different relative to the MTX plus placebo control group (Table 2). Actual median changes in swollen and tender joint counts were –6.0 and –8.0, respectively, among all infliximab plus MTX–treated ACR20 nonresponders, compared with –1.0 and –4.0, respectively, in the MTX plus placebo–treated ACR20 nonresponders. As already suggested from the analysis of the DAS28 response rates, these data indicate that among ACR20 nonresponders, infliximab plus MTX affected most disease activity variables to a greater extent than did MTX plus placebo, although the effect was much lower than among ACR20 responders treated with infliximab plus MTX.
In an additional analysis of ACR20 nonresponders at week 54, a significantly higher proportion of patients who received infliximab plus MTX had ≥20% improvement in tender and swollen joint counts, along with ≥20% improvement in at least 2 of the other ACR20 components, compared with patients who received MTX and placebo (12% and 3%, respectively; P = 0.021). Taken together, these data suggest that even among ACR nonresponders, infliximab plus MTX affects variables reflective of the inflammatory process to a greater extent than does MTX plus placebo.
Radiographic benefit of infliximab plus MTX treatment among ACR20 nonresponders as well as patients who had no evidence of any clinical improvement.
Retardation of radiographic progression among patients who had no ACR20 response throughout the treatment period.
As previously reported for the individual dosage groups, radiographic progression was inhibited in patients treated with infliximab plus MTX among those who had a clinical response at 54 weeks, as well as in those who did not have a clinical response (19). Comparisons of the mean (and likewise the median) changes from baseline in the modified Sharp/van der Heijde radiographic score at week 54 among ACR20 nonresponders showed less progression among patients receiving infliximab plus MTX than among patients receiving only MTX (P < 0.001) (Figure 3). Similar findings were observed among ACR20 responders (P = 0.0011). Interestingly, the numerical difference between the MTX plus placebo and infliximab treatment groups among the ACR 20 nonresponders was similar to that seen among the respective ACR20 responders.
Thus, the inhibition of radiographic changes was similar among the infliximab plus MTX–treated groups regardless of whether the patients were ACR20 responders or nonresponders. In fact, even when compared with ACR20 responders receiving MTX plus placebo (who had mean and median increases in modified Sharp/van der Heijde scores of 6.04 and 1.96, respectively), radiographic progression was significantly inhibited among ACR20 nonresponders receiving infliximab plus MTX (mean and median increases of 1.25 and 0.50, respectively) (P < 0.001). Since missing radiographs could have biased the results, it is worth noting that among patients who had missing radiographic data, 96% of those receiving MTX plus placebo and 76% of those receiving infliximab plus MTX were ACR nonresponders. Thus, there is no reason to conclude that patients receiving MTX plus placebo who had no radiographic data may have had less radiographic progression than the remaining patients in this group.
In a further analysis, we evaluated radiographic progression among patients with no ACR20 response at any visit from week 2 through week 54. As shown in Figure 4, patients who did not have a clinical response to infliximab plus MTX therapy at any time point still exhibited prevention of structural damage that was statistically greater than that observed in patients who received MTX alone (P = 0.002, all infliximab plus MTX– versus MTX plus placebo–treated patients).
Retardation of radiographic progression among patients who had no evidence of any clinical improvement.
Together, the above data indicated that infliximab inhibited radiographic progression among ACR20 nonresponders. Furthermore, the clinical data had revealed that infliximab plus MTX, when compared with MTX plus placebo, produced a modest yet significant improvement in variables reflective of inflammation, even among ACR20 nonresponders. Therefore, we undertook a more stringent analysis of radiographic changes in patients who had deterioration or lack of improvement in individual clinical and laboratory variables. Compared with patients receiving MTX plus placebo, significantly less radiographic progression was observed in infliximab plus MTX–treated patients who exhibited no improvement in tender joint count (P = 0.002), swollen joint count (P = 0.007), HAQ score (P < 0.001), patient global assessment (P < 0.001), physician global assessment (P < 0.001), CRP level (P < 0.001), fatigue (P < 0.001), duration of morning stiffness (P = 0.011), or ACR-N (P < 0.001) (Figure 5). Moreover, there was no evidence of a dose-response relationship across the infliximab plus MTX treatment groups. Generally, there were no apparent differences in baseline variables between the infliximab plus MTX and the MTX plus placebo groups, either in baseline modified Sharp/van der Heijde scores or in rheumatoid factor status (data not shown).
Pearson correlation coefficients examining the relationship between percent change in CRP level from baseline and radiographic progression revealed a highly significant association between these two parameters among patients treated with MTX plus placebo (R = −0.54, P < 0.0001), while no such relationship was seen among patients receiving infliximab plus MTX (R = −0.02, P = 0.75). These results confirm the above evidence that infliximab has an effect on progression of damage irrespective of (or beyond) its effects on the inflammatory response.
In a final, rigorous analysis of the relationship between disease activity and radiographic progression, we assessed patients who had no significant change in the DAS28, i.e., no significant decrease or increase, defined as a change in DAS of ≤0.5 at both week 30 and week 54. At baseline, there was no significant difference in clinical variables related to radiographic progression between the MTX plus placebo and infliximab plus MTX groups: mean ± SD radiographic scores were 70 ± 47 and 57 ± 73 (P = 0.98), respectively, DAS28 scores were 6.3 ± 0.8 and 6.6 ± 1.1, respectively (P = 0.16 [i.e., slightly higher among patients receiving infliximab]), and rheumatoid factor was present in 57% and 58% of patients in the 2 groups, respectively. Patients receiving MTX plus placebo (n = 7) had a mean ± SD increase in radiographic score of 9.1 ± 7.3, while in patients receiving infliximab plus MTX (n = 12) the change was only 1.2 ± 5.5, again revealing significant (P = 0.04) inhibition of radiographic progression with infliximab therapy. Hence, among patients who had no symptomatic benefit at all, infliximab plus MTX treatment resulted in a slower rate of radiographic progression than did MTX treatment alone, suggesting significant effects of infliximab on joint damage, even in the absence of effects on inflammatory disease activity. These results indicate that radiographic benefits are separable from clinical benefits in RA patients treated with infliximab plus MTX.
Since the development of the ACR20 response criteria (23), this tool has been used as the primary efficacy end point in major clinical trials conducted in patients with RA, segmenting trial populations into clinical responders and nonresponders to treatment. However, the ACR response primarily constitutes a measure of disease activity (23, 30), while RA is characterized by joint damage in addition to joint inflammation, or synovitis. Since, in RA, there is a progressive increase in the correlation between radiographic damage and disability, it is important to consider whether therapeutic agents may have a direct impact on progressive joint damage.
In the ATTRACT study, 428 patients with RA who had active disease despite MTX therapy were evaluated. By ACR20 criteria, clinical response had been achieved at 54 weeks in 52% of the patients treated with infliximab plus MTX, compared with 17% of patients who received MTX plus placebo (19). To assess the effects of therapy in patients who did not have an ACR20 response, we examined the clinical and radiographic benefits of infliximab plus MTX in patients who were ACR20 nonresponders throughout the entire treatment period and at the week-54 end point. Clinical benefit was measured using individual components of the ACR response criteria, as well as the continuous measure of DAS28, and radiographic benefit was assessed by changes in the modified Sharp/van der Heijde score. The previously reported observation (19) that ACR20 nonresponders (i.e., patients who did not fulfill the minimum requirements for evidence of reduced inflammation) who received infliximab plus MTX exhibited a highly significant inhibition of radiographic disease progression when compared with that in nonresponders who received MTX plus placebo was analyzed in detail in the present study.
Interestingly, joint progression in ACR20 nonresponders who received MTX plus placebo was not different from that in ACR20 responders receiving MTX plus placebo (identical dosage of MTX). In contrast, the slowing of radiographic progression in ACR20 nonresponders receiving infliximab was similar to that in the respective ACR20 responders. Thus, among infliximab-treated patients, inhibition of TNF to a degree that was insufficient to reduce the inflammatory response beyond the threshold level of the currently used response criteria still led to modification of pathways leading to joint destruction, and similarly so compared with the results in patients exhibiting important reduction of disease activity. This was observed for all infliximab dosage levels; in fact, infliximab at the lowest dosage interfered with radiographic progression to a similar extent as the highest dosage. In contrast, among patients who did not receive infliximab therapy, there was a high propensity toward joint destruction regardless of achievement of or failure to obtain a reduction of disease activity. In MTX plus placebo–treated patients there was, therefore, no association between improvement in signs and symptoms of inflammation and radiographic benefit.
Thus, even among patients with an ACR20 response who had been treated with MTX plus placebo, radiographic disease progression was significantly enhanced compared with that in ACR20 nonresponders receiving infliximab plus MTX. This is further supported by the finding that the well-known relationship between CRP level and radiologic damage (2–4) was lost among patients treated with infliximab plus MTX, while it was fully apparent among those receiving MTX plus placebo.
Clinical nonresponders (according to the ACR20) who received infliximab plus MTX actually exhibited a small degree of clinical response. Although this response was significantly greater compared with that in nonresponders who received MTX plus placebo and included improvement in tender and swollen joint counts as well as in acute-phase response, functional assessment by HAQ did not differ between the groups. This suggests that the small but significant reduction in disease activity observed among ACR20 nonresponders receiving infliximab plus MTX was not sufficient to affect arthritis-related disability. Nevertheless, there is compelling evidence that, in the long term, accumulating joint destruction is associated with a deterioration in the HAQ score (1, 5). Therefore, interference with joint destruction is a highly important means of preventing functional deterioration over time and long-term disability.
As evidenced by the higher reduction in individual measures of disease activity in infliximab plus MTX–treated patients compared with MTX plus placebo–treated patients, ACR20 nonresponsiveness does not imply a total lack of effect on inflammatory activity. As previously addressed in reports by Lipsky (31) and Boers (32), many elements of the ACR core set of response criteria, including tender joint count and patient assessment of pain, do not correlate well with radiographic damage but are included in the definition of improvement because they are thought to be important indicators of disease activity. Moreover, nonresponse is a continuum (33). Thus, it is not surprising that some patients can fail to meet the ACR20 criteria for clinical response yet have measurable clinical improvement and also inhibition of radiographic progression; this has also been shown in studies of other therapeutic agents (34). Moreover, since disease activity scores are instruments used to demonstrate efficacy or inefficacy of therapies, they are biased to make patients appear as nonresponders even if they had some degree of response.
Notably, however, when more stringent criteria than ACR20 nonresponsiveness, namely, deterioration or lack of improvement in individual or composite measures of disease activity, were applied, the effect of infliximab on joint destruction was maintained. Regardless of the variable analyzed, patients who received infliximab plus MTX who had no improvement in tender or swollen joint counts, HAQ score, global assessments, acute-phase response, or even the composite DAS28 had a significant inhibition of the progression of radiographic changes when compared with MTX plus placebo–treated patients. Moreover, the inhibition of radiographic progression in patients receiving infliximab plus MTX was similar among clinical nonresponders and responders. Thus, even in the absence of any clinically evident antiinflammatory effect or a reduction in CRP level, infliximab still interfered with the destructive process. These data do not imply that destruction is independent of inflammation; in fact, destruction in RA is usually significantly related to the degree of inflammation, represented by synovitis and acute-phase response (2–4). However, the results strongly suggest that TNF blockade can inhibit the progression of joint damage even in RA patients in whom signs, symptoms, and serologic measures of inflammation, driven by residual (albeit reduced) TNF production or by other proinflammatory cytokines, are not affected.
The data obtained in this analysis are closely consistent with recent evidence from studies of experimental arthritis, i.e., that inflammation, or synovitis, and destruction may constitute two interrelated yet separate components of the arthritic process. Whereas bone destruction is induced by the osteoclastogenic properties of proinflammatory cytokines (TNF as RANKL inducer) (14–16), it can be inhibited, in experimental models, by treatments that do not significantly affect the degree of synovitis or clinical manifestations (9–12, 35). Moreover, the degree of osteoclast activation by TNF is clearly dose dependent (16). Given the fact that other arthritides with less destructive potential than RA have significantly lower (albeit still increased) levels of TNF (17, 36), it may be suggested that exceeding a threshold level of TNF expression is necessary for activation of osteoclasts and subsequent joint destruction. Consequently, reduction of bioactive TNF levels below that threshold in RA patients would be anticipated to affect progressive bone damage, but may be insufficient to have an important influence on synovitis.
In accordance with this suggested mechanism leading to the effects reported here, TNF blockade in experimental arthritis has a much higher impact on joint destruction and cartilage degradation than on inflammation (8, 11). Similar conclusions have been drawn in the clinical setting when radiographs and clinical data were obtained in 28 patients in a prospective, multicenter, randomized, placebo-controlled trial of treatment with prednisolone at 7.5 mg/day for 2 years. Analyses suggested that synovitis, whether measured clinically or radiologically, is more closely related to diffuse cartilage loss than to erosion progression. In that trial, any link between synovitis and erosions was abolished by glucocorticoid therapy while the link between synovitis and cartilage loss was not, providing evidence of at least two different mechanisms for the observed radiologic features (37). We acknowledge that the relatively short 12-month treatment period could be a limitation to the analyses presented here. However, based on a review of 6 randomized controlled trials of 4 different RA therapies (34), 6 months appeared to be a sufficient amount of time to demonstrate a beneficial treatment effect in terms of radiographic progression.
The data obtained in the present study may be interpreted further to imply that currently used surrogate measures of inflammation, e.g., joint counts or acute-phase response, have limitations. In fact, when reviewing data from most recent clinical trials of TNF blocking agents, it appears that remissions are rare and individual variables reflect persistence of significant residual disease activity at the end point, even when such values have been reduced from baseline, while radiographic progression has been shown to be retarded by ∼90% (19, 20, 38). These observations suggest a quantitative dichotomy between inflammation and radiographic damage. This is consistent with our knowledge that many inflammatory arthritides other than RA are not or are only modestly destructive, despite elevated levels of TNF and other proinflammatory cytokines, albeit to a lesser degree than that found in RA (17, 36, 39). TNF blockers seem to be effective in controlling joint inflammation in such disorders, perhaps even better than they control rheumatoid synovitis. Thus, a low level of inflammatory activity in RA, whose detailed quantification and composition appear to escape our current clinical and ex vivo molecular measurement and determination capabilities, may be present without driving the process of destruction.
The results of the current analyses indicate that therapy with infliximab plus MTX affords articular protection not associated with clinically manifest improvement in inflammation. These findings not only suggest that there are multiple pathways leading to joint damage in RA, but also reveal that even in the absence of clinically discernible antiinflammatory effects, infliximab therapy may revert RA from a highly destructive to a minimally or even nondestructive form of arthritis. Thus, TNF blockade in combination with MTX appears to have both antiinflammatory effects with consequent antiosteoclast activity and an antiosteoclast effect even in the absence of significant antiinflammatory activity as measured by current assessment methods.
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