SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Objective

To compare outcome at 6 months in unselected “real-world” patients with rheumatoid arthritis treated with etanercept or infliximab as either monotherapy, cotherapy with methotrexate (MTX), or cotherapy with another disease-modifying antirheumatic drug (DMARD).

Methods

A total of 2,711 subjects starting treatment with their first biologic agent (1,453 infliximab and 1,258 etanercept) were followed up for 6 months. Outcome was assessed using the European League Against Rheumatism (EULAR) response criteria. Ordinal regression was used to model the response in the MTX and other DMARD cotherapy groups relative to the monotherapy group separately for the 2 anti–tumor necrosis factor α agents, after adjusting for baseline differences.

Results

Etanercept-treated patients had an increased likelihood of achieving a higher EULAR response category with cotherapy with MTX (odds ratio [OR] 2.0, 95% confidence interval [95% CI] 1.5–2.7) and with another DMARD (OR 1.2, 95% CI 0.9–1.6) as compared with monotherapy. For infliximab-treated patients, the likelihoods were 1.4 (95% CI 0.9–2.0) for MTX and 1.3 (95% CI 0.8–2.1) for other DMARDs versus monotherapy. Cotherapy with MTX or another DMARD produced significantly higher rates of remission with etanercept (12% and 11%, respectively) as compared with etanercept monotherapy (5%). Infliximab-treated patients showed similar remission rates in the MTX and other DMARD cotherapy groups (8% and 5%, respectively) as in the monotherapy group (7%).

Conclusion

In this study of real-world patients, the use of MTX and, to a lesser extent, other DMARDs as cotherapy with etanercept was associated with a higher likelihood of response. Although the infliximab guidelines suggest that MTX be used as cotherapy, in clinical practice, both monotherapy and cotherapy with DMARDs other than MTX are used. These data suggest that either of the latter strategies may be useful in patients who are intolerant to MTX.

Randomized controlled trials (RCTs) of the anti–tumor necrosis factor α (anti-TNFα) therapies infliximab and etanercept in rheumatoid arthritis (RA) have shown these drugs to be superior to placebo and to methotrexate (MTX) monotherapy in patients with active disease despite MTX (1–3). Based on the results of RCTs, it is recommended that infliximab be prescribed in conjunction with MTX in order to reduce the development of human antichimeric antibodies (HACAs) and prolong the benefits of the drug (1, 4). However, there will be a subset of patients who require infliximab therapy but who are intolerant of MTX. The potential effects of a HACA response on therapeutic regimens of infliximab without MTX that continue longer than 14 weeks have not been analyzed. Although there has not been an RCT examining non-MTX disease-modifying antirheumatic drugs (DMARDs) in combination with infliximab, results of open-label studies suggest that the combination of infliximab with either leflunomide (5–7) or cyclosporin A (8) may be effective, with no increase in toxicity as compared with either agent alone. However, these studies are limited by their small size and lack of a comparison group, including either a placebo or MTX, the current standard of care.

Recent publications have suggested that the combination of etanercept with MTX is superior to etanercept alone. The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) study compared etanercept with MTX, starting each as new monotherapy or both as combination therapy, and found the combination to be superior to either drug alone (9). However, the majority of patients in clinical practice who will receive etanercept will have already received MTX yet have ongoing disease activity. Although etanercept has been shown to be effective in combination with MTX in patients with MTX-resistant disease (3), it is not known if the combination is adding any additional benefit compared with etanercept monotherapy. A recent observational study addressed this question and found a higher rate of remission at 6 months of therapy in patients receiving the combination of etanercept with MTX as compared with etanercept alone (10), although, again, this latter study may have been limited by small numbers of patients. Despite this potential advantage, as seen with infliximab, there are patients who will not be able to tolerate MTX therapy but in whom continuation of other non-MTX DMARDs at the time etanercept is initiated may be desirable. The relative efficacy and safety of these combinations remains unknown.

Carefully conducted large-scale observational studies have the potential to answer questions about the relative efficacy of different treatment regimens, particularly if information on potential confounding variables, including those that have an influence on disease outcome, is collected at baseline. These studies can also provide additional, complementary information to that gained from RCTs on the “real-world” effectiveness of new therapies. The aim of this study was to analyze the relative effectiveness of anti-TNFα monotherapy (infliximab or etanercept) as compared with the combination of anti-TNFα therapy plus either MTX or a non-MTX DMARD.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

This analysis is embedded within a prospective observational study, the British Society for Rheumatology Biologics Register (BSRBR) and, in essence, comprises 2 separate but similar studies: one within an etanercept-treated cohort and the other within an infliximab-treated cohort. In each case, 3 groups were compared based on concomitant DMARD use: MTX, non-MTX DMARDs, and no DMARDs. Response at 6 months was compared within the anti-TNFα cohorts and between the 3 treatment groups, adjusting for any baseline differences.

Patient selection.

The BSRBR was established in October 2001 to carefully monitor the long-term safety and efficacy of biologic therapy. This national registry collects data in a standardized format on all patients ages 16 years and older throughout the UK who are starting therapy with a biologic agent because of a rheumatic disease. Decisions to start or change DMARD and biologic therapies are solely at the discretion of the treating rheumatologist, and thus the registry attempts to capture data based on routine clinical practice. Ethical approval for the BSRBR was obtained from the Central Office for Research Ethics Committees of the UK National Health Service.

Baseline information.

Baseline information on all patients registered was obtained from the treating rheumatologist via a standard patient pro forma questionnaire. Information included demographics, disease characteristics, current disability (measured with the Health Assessment Questionnaire [HAQ] [11]), past and present antirheumatic therapies, and current comorbidities. In addition, a current Disease Activity Score in 28 joints (DAS28) (12) was determined at the time the patient was starting the biologic agent. To qualify for biologic therapy in the UK, the patient must have failed therapy with at least 2 standard DMARDs, including MTX, and have a DAS28 above 5.1, indicating a high level of disease activity (13).

Followup information.

All patients are followed up every 6 months, and a standardized questionnaire is completed. Information collected at followup includes changes in the biologic and nonbiologic antirheumatic therapy, reasons for such changes, details of any adverse events, and a current DAS28.

Statistical analysis.

The current analysis was limited to patients who fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 classification criteria for RA (14) and were starting either etanercept or infliximab as their first biologic drug, as either monotherapy or in combination with another single DMARD. Patients receiving etanercept or infliximab were analyzed separately. Patients were divided into 1 of 3 DMARD groups based on their concomitant DMARD therapy at the time they started anti-TNFα therapy: anti-TNFα monotherapy, anti-TNFα plus MTX cotherapy, and anti-TNFα plus another single DMARD cotherapy. Baseline demographic and disease characteristics were compared between the 3 subgroups within each anti-TNFα therapy group using the chi-square test for independent proportions in the case of discrete variables and analysis of variance in the case of continuous variables. Statistical significance was set at P < 0.05.

The primary end point, drug effectiveness at 6 months of therapy, was measured using the European League Against Rheumatism (EULAR) response criteria (15) (Figure 1). Patients were classified into 3 groups based on their 6-month DAS28 and their absolute change from baseline according to the EULAR criteria: no response, moderate response, or good response. A good responder must demonstrate improvement of at least 1.2 units and achieve an absolute DAS28 score of <3.2. A nonresponder will demonstrate an improvement of ≤0.6 and have a final DAS28 score of >5.1. Moderate responses fall between these data points. Remission (final DAS28 <2.6) was defined according to the EULAR criteria (16). Subjects who discontinued their primary biologic drug because of toxicity were considered nonresponders with respect to the primary end point, regardless of their 6-month DAS28.

thumbnail image

Figure 1. The primary end point, drug effectiveness at 6 months of therapy, was determined according to the European League Against Rheumatism (EULAR) response criteria. Patients were classified into the 3 groups according to the absolute change in the EULAR response as compared with baseline, as well as the Disease Activity Score in 28 joints (DAS28) at 6 months.

Download figure to PowerPoint

The EULAR response was assessed within each anti-TNFα therapy group, comparing the subgroup receiving MTX or another single DMARD with the anti-TNFα monotherapy subgroup. The EULAR response was compared between groups using an ordinal logistic regression model, adjusting for any baseline differences between the subgroups. The resulting odds ratio (OR) is a measure of the probability of being in a higher EULAR response category. Results are presented with corresponding 95% confidence intervals (95% CIs).

In addition, the mean improvement in the DAS28 between DMARD subgroups was compared using the unpaired t-test, comparing both the MTX and non-MTX subgroups with monotherapy and then comparing the MTX group with the non-MTX group. Finally, logistic regression was used to compare the rates of remission, as defined above, between the 3 subgroups. All analyses were conducted using Stata version 8.2 software (17).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients.

A total of 2,711 patients were included in this analysis (1,258 taking etanercept and 1,453 taking infliximab). Etanercept was administered as a twice-weekly subcutaneous injection of 25 mg. Infliximab was administered at weeks 0, 2, and 6 and every 8 weeks thereafter at a dose of 3 mg/kg of body weight. Details of the DMARD treatment subgroups are presented in Table 1. The majority of patients starting infliximab (83%) took it in combination with MTX. However, 8% were receiving another DMARD and 9% were receiving no concurrent DMARD therapy. The majority of patients receiving etanercept were not receiving concomitant DMARD therapy (61%), with approximately equal proportions receiving either MTX (20%) or another single DMARD (19%) at the time etanercept was started.

Table 1. DMARD treatment subgroups*
DMARDEtanercept therapy (n = 1,258)Infliximab therapy (n = 1,453)
  • *

    DMARD = disease-modifying antirheumatic drug; MTX = methotrexate.

Cotherapy  
 MTX, no. (%)250 (20)1,204 (83)
 Non-MTX DMARD, no. (%)245 (19)121 (8)
  Non-MTX DMARD taken, no.  
   Leflunomide10358
   Azathioprine3927
   Sulfasalazine4114
   Hydroxychloroquine205
   Cyclosporin A158
   Penicillamine151
   Gold108
   Minocycline20
Monotherapy  
 No concurrent DMARD, no. (%)763 (61)128 (9)

Baseline characteristics.

Overall, the mean ± SD age of the study patients was 57 ± 12 years, and 78% of the patients were women. The mean ± SD disease duration was 15 ± 9 years. One-half of the patients (51%) were receiving corticosteroids and 64% were receiving NSAIDs. Disease activity at baseline was high (mean ± SD DAS28 6.7 ± 1.0), as was disability (mean ± SD HAQ score 2.2 ± 0.5). There were no overall differences between patients treated with either of the 2 anti-TNFα therapies.

There were clinically minor differences between the various DMARD subgroups, although given the large size of the groups, many of these differences were statistically significant (Table 2). Compared with patients in the etanercept treatment group who were not receiving concurrent DMARD therapy, patients receiving either MTX or another single DMARD with etanercept were 3–4 years younger, had shorter disease duration, but had very similar baseline DAS28 and HAQ scores. In addition, fewer patients receiving concurrent DMARD therapy with etanercept were receiving corticosteroids, and a higher proportion was receiving NSAIDs. Similar results were found when patients receiving infliximab plus MTX were compared with patients receiving infliximab monotherapy. However, with the exception of a lower proportion of corticosteroid use and a higher proportion of NSAID use, there were no significant differences between patients receiving infliximab with another single DMARD compared with those receiving infliximab monotherapy.

Table 2. Baseline characteristics of the study patients, by treatment group*
 MonotherapyMTX cotherapyNon-MTX DMARD cotherapyP
  • *

    MTX = methotrexate; DMARD = disease-modifying antirheumatic drug; DAS28 = Disease Activity Score in 28 joints; HAQ = Health Assessment Questionnaire; NSAIDs = nonsteroidal antiinflammatory drugs.

Etanercept    
 No. of patients763250245 
 Age, mean ± SD years58 ± 1254 ± 1255 ± 12<0.001
 Female, no. (%)613 (80)189 (76)193 (79)0.27
 Disease duration, mean ± SD years16 ± 1013 ± 815 ± 90.005
 DAS28, mean ± SD6.8 ± 1.06.6 ± 0.96.6 ± 0.9<0.001
 Previous no. of DMARDs, mean ± SD5 ± 24 ± 25 ± 2<0.001
 HAQ score, mean ± SD2.2 ± 0.52.1 ± 0.52.1 ± 0.5<0.001
 Current corticosteroids, no. (%)408 (54)110 (44)124 (51)0.01
 NSAIDs, no. (%)461 (60)168 (68)170 (69)0.01
Infliximab    
 No. of patients1281,204121 
 Age, mean ± SD years59 ± 1255 ± 1258 ± 12<0.001
 Female, no. (%)101 (79)925 (77)90 (74)0.65
 Disease duration, mean ± SD years16 ± 1114 ± 914 ± 90.11
 DAS28, mean ± SD6.8 ± 1.16.7 ± 0.96.8 ± 1.10.50
 Previous no. of DMARDs, mean ± SD5 ± 24 ± 25 ± 2<0.001
 HAQ score, mean ± SD2.2 ± 0.52.1 ± 0.52.2 ± 0.60.03
 Current corticosteroids, no. (%)89 (69)577 (48)71 (59)<0.001
 NSAIDs, no. (%)68 (53)800 (66)73 (60)0.005

Drug survival at 6 months.

At the end of the first 6-month followup period, 20% of the etanercept patients and 21% of the infliximab patients had discontinued therapy for any reason (Table 3). The rate of discontinuation among patients receiving etanercept was similar for all 3 subgroups. A higher proportion of patients receiving infliximab monotherapy discontinued therapy before the first 6-month followup. With regard to the reasons for discontinuing treatment, there was no statistically significant difference between the 3 DMARD subgroups for either anti-TNFα therapy, although there was a trend toward a higher rate of discontinuation following an adverse event in both monotherapy groups. This difference was not explained by a higher rate of drug-related reactions (either injection site or infusion reactions) in either monotherapy group.

Table 3. Drug survival during the first 6 months of therapy, by treatment group*
 MonotherapyMTX cotherapyNon-MTX DMARD cotherapy
  • *

    MTX = methotrexate; DMARD = disease-modifying antirheumatic drug.

Etanercept   
 No. of patients763250245
 Continued therapy, no. (%)595 (78)210 (84)199 (81)
 Discontinued therapy, no. (%)168 (22)40 (16)46 (19)
  Reason for discontinuing, no. (%)   
   Inefficacy69 (9)21 (8)21 (9)
   Adverse event87 (11)17 (7)23 (9)
   Other12 (2)2 (1)2 (1)
Infliximab   
 No. of patients1281,204121
 Continued therapy, no. (%)90 (70)955 (79)94 (78)
 Discontinued therapy, no. (%)38 (30)249 (21)27 (22)
  Reason for discontinuing, no. (%)   
   Inefficacy14 (11)107 (9)11 (9)
   Adverse event21 (16)119 (10)15 (12)
   Other3 (2)23 (2)1 (1)

EULAR response to etanercept therapy.

The 6-month EULAR responses in patients receiving etanercept are presented in Table 4. There was a clear trend toward a higher response among patients receiving the combination of etanercept and MTX compared with either etanercept monotherapy or etanercept in combination with a non-MTX DMARD. This was also reflected in the greater mean improvement in DAS28 in the etanercept plus MTX subgroup. After adjustment for age, sex, baseline differences in disease duration, DAS28, HAQ scores, previous number of DMARDs taken, and corticosteroid and NSAID use, there was an increased odds of the etanercept plus MTX combination group achieving a higher response category compared with both etanercept monotherapy (OR 1.98 [95% CI 1.45–2.71]) and with cotherapy with a non-MTX DMARD (OR 1.66 [95% CI 1.14–2.42]). Although there was a trend toward a better response among patients receiving non-MTX DMARDs compared with etanercept monotherapy, this did not reach statistical significance (adjusted OR 1.20 [95% CI 0.89–1.61]). Small numbers of subjects precluded analysis between the individual non-MTX DMARDs.

Table 4. Response to etanercept therapy at 6 months, by treatment group*
 MonotherapyNon-MTX DMARD cotherapyMTX cotherapy
  • *

    Odds ratios (ORs) were unadjusted or were adjusted for age, sex, disease duration, baseline Disease Activity Score in 28 joints (DAS28), baseline Health Assessment Questionnaire score, previous number of disease-modifying antirheumatic drugs (DMARDs) taken, and nonsteroidal antiinflammatory drug and corticosteroid use. MTX = methotrexate; EULAR = European League Against Rheumatism; 95% CI = 95% confidence interval.

No. of patients763245250
DAS28, mean ± SD   
 Baseline6.8 ± 1.06.6 ± 0.96.6 ± 0.9
 6 months4.8 ± 1.44.6 ± 1.54.3 ± 1.5
EULAR response at 6 months, no. (%)   
 Good response90 (12)48 (20)62 (25)
 Moderate response397 (52)115 (47)132 (53)
 No response276 (36)82 (33)56 (22)
Odds of response   
 Cotherapy versus monotherapy   
  Unadjusted OR (95% CI)1.0 (reference)1.35 (1.02–1.80)2.19 (1.65–2.91)
  Adjusted OR (95% CI)1.0 (reference)1.20 (0.89–1.61)1.98 (1.45–2.71)
 MTX versus non-MTX DMARD   
  Unadjusted OR (95% CI)1.0 (reference)1.53 (1.09–2.15)
  Adjusted OR (95% CI)1.0 (reference)1.66 (1.14–2.42)
Remission, no. (%)36 (5)24 (10)31 (12)
Odds of remission   
 Cotherapy versus monotherapy   
  Unadjusted OR (95% CI)1.0 (reference)2.22 (1.29–3.79)2.86 (1.73–4.74)
  Adjusted OR (95% CI)1.0 (reference)1.54 (0.84–2.85)2.24 (1.24–4.06)
 MTX versus non-MTX DMARD   
  Unadjusted OR (95% CI)1.0 (reference)1.29 (0.73–2.27)
  Adjusted OR (95% CI)1.0 (reference)1.32 (0.68–2.58)

There was also a higher rate of remission among patients receiving etanercept with MTX (12%) compared with either the etanercept monotherapy group (5%) or the non-MTX DMARD group (10%). After adjusting for baseline differences, patients receiving etanercept with MTX were still twice as likely to achieve remission compared with patients receiving etanercept alone (OR 2.24 [95% CI 1.24–4.06]).

EULAR response to infliximab therapy.

Patients receiving infliximab with MTX experienced a greater improvement in the mean DAS28 score compared with patients receiving infliximab monotherapy or cotherapy with a non-MTX DMARD (Table 5), although this difference was small and did not reach statistical significance. There was also a higher rate of nonresponse, as defined using the EULAR criteria, among patients receiving infliximab monotherapy (47%) as compared with those receiving either MTX cotherapy (34%) or cotherapy with a non-MTX DMARD (40%). However, there was no difference in the proportion of patients who achieved a good response.

Table 5. Response to infliximab therapy at 6 months, by treatment group*
 MonotherapyNon-MTX DMARD cotherapyMTX cotherapy
  • *

    Odds ratios (ORs) were unadjusted or were adjusted for age, sex, disease duration, baseline Disease Activity Score in 28 joints (DAS28), baseline Health Assessment Questionnaire score, previous number of disease-modifying antirheumatic drugs (DMARDs) taken, and nonsteroidal antiinflammatory drug and corticosteroid use. MTX = methotrexate; EULAR = European League Against Rheumatism; 95% CI = 95% confidence interval.

No. of patients1281211,204
DAS28, mean ± SD   
 Baseline6.8 ± 1.16.8 ± 1.16.7 ± 0.9
 6 months5.0 ± 1.64.9 ± 1.64.6 ± 1.6
EULAR response at 6 months, no. (%)   
 Good response19 (15)17 (14)202 (17)
 Moderate response49 (38)56 (46)592 (49)
 No response60 (47)48 (40)410 (34)
Odds of response   
 Cotherapy versus monotherapy   
  Unadjusted OR (95% CI)1.0 (reference)1.27 (0.79–2.04)1.59 (1.12–2.27)
  Adjusted OR (95% CI)1.0 (reference)1.26 (0.75–2.13)1.35 (0.92–2.00)
 MTX versus non-MTX DMARD   
  Unadjusted OR (95% CI)1.0 (reference)1.24 (0.88–1.77)
  Adjusted OR (95% CI)1.0 (reference)1.04 (0.71–1.53)
Remission, no. (%)9 (7)5 (4)98 (8)
Odds of remission   
 Cotherapy versus monotherapy   
  Unadjusted OR (95% CI)1.0 (reference)0.70 (0.24–2.03)1.18 (0.58–2.40)
  Adjusted OR (95% CI)1.0 (reference)0.68 (0.20–2.33)0.86 (0.37–2.00)
 MTX versus non-MTX DMARD   
  Unadjusted OR (95% CI)1.0 (reference)1.68 (0.72–3.92)
  Adjusted OR (95% CI)1.0 (reference)1.28 (0.53–3.10)

After adjusting for baseline differences between the groups, there was a trend toward a better EULAR response in both the MTX (OR 1.35 [95% CI 0.92–2.00]) and the non-MTX DMARD (OR 1.26 [95% CI 0.75–2.13]) subgroups as compared with the infliximab monotherapy subgroup, although again, neither comparison reached statistical significance. Similarly, there was no difference between the odds of achieving a higher EULAR response in the MTX cotherapy group compared with the non-MTX DMARD cotherapy group (OR 1.04 [95% CI 0.71–1.53]). After adjusting for baseline differences between the 3 groups, there was no difference in the rate of remission. Again, small numbers of study subjects precluded further analysis between the individual non-MTX DMARDs.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The results of this study support the benefit of the combined use of etanercept with MTX, which performed better than either etanercept alone or etanercept in combination with a non-MTX DMARD. Interestingly, the same was not as clear cut for infliximab with MTX cotherapy, and there are very limited data suggesting that concomitant therapy with either MTX or another DMARD is beneficial. Although there was a trend toward greater improvement among patients receiving MTX cotherapy compared with those receiving infliximab alone, the benefit was small and did not reach statistical significance. There was also no difference in the response rate between patients receiving cotherapy with MTX and those receiving an alternative DMARD.

The patients in this study were selected from a national prospective cohort study of biologic therapies for rheumatic diseases, and therefore, their outcomes reflect the experience of patients and rheumatologists as they occurred. They are not meant to replace data from RCTs, but rather, to complement such data. This observational study has also been able to address issues for which little to no clinical trial data exist, including the effects of combining anti-TNFα therapies with DMARDs other than MTX or of taking infliximab without concurrent MTX. The patients were typically those with longstanding, severe, and otherwise refractory disease, and hence, caution must be exercised in extrapolating the results to the use of these regimens in patients with earlier disease.

There are limitations to comparing treatment outcomes based on observational data, since the decision to treat patients is not random, but is highly dependent upon a number of variables, such as disease severity, patient choice and compliance, and comorbidities. However, we still found a significant difference between the combined use of etanercept plus MTX as compared with etanercept therapy alone after adjusting for any observed, albeit modest, differences. Yet, there may still be residual confounding by indication, which may have affected the response.

It is thus important to raise the question of whether there may have been other differences between the etanercept monotherapy and the MTX cotherapy groups that might have led to a better response in the latter group. This seems unlikely for a number of reasons. First, both of these groups had virtually identical disease activity (DAS28 scores) and cumulative damage (HAQ scores), which suggests that there was no prior likelihood of a better response in the MTX cotherapy group. Second, both groups had refractory RA, and even in the group that continued MTX cotherapy, their DAS28 scores indicated no evidence of any substantive, or even partial, response to suggest that they may have had a better outcome. Third, it is possible that there may have been other differences in therapy during the followup that resulted in a better response in the MTX group. Thus, if the MTX cotherapy group had also received more courses of intraarticular or pulsed steroids, then these differences might explain the better response. The interval data on such treatment changes are not sufficiently robust to address this possibility. However, it seems unlikely that these additional therapies would have been preferentially offered to the MTX cotherapy group.

Similarly, the decision to stop therapy because of inefficacy or an adverse event in this “real-world” study was at the discretion of the rheumatologist and was not subject to strict protocol. It is unlikely that there was any bias in the way such decisions were reached either between or within the 2 anti-TNFα treatment groups.

There is now mounting evidence of the beneficial effect of combination therapy with etanercept and MTX. In contrast to the current study, the TEMPO trial found greater efficacy with the combination of etanercept plus MTX when both were newly started at the same time, as compared with both drugs used individually (9). It is, however, unclear as to why adding MTX, when MTX therapy alone had failed, would produce a benefit. Both etanercept and MTX are effective therapies for RA. In this instance, the benefit may have been due to the combined but differing effects of these 2 drugs. Our study adds to the literature knowledge of the benefits of cotherapy with etanercept when added to previously started MTX in patients with ongoing active disease. In a Swedish cohort of only 97 patients receiving etanercept or etanercept plus MTX, a similar rate of remission in the combination group was found, and this rate of remission was significantly higher than that in the monotherapy group (10). However, although that study described a significantly better improvement in the DAS28 in patients receiving combination therapy, it did not identify any difference in the overall response rate as defined by the EULAR criteria. In our study, there was a significantly higher proportion of responders in the combination group (78%) than in the etanercept monotherapy group (64%). This benefit was maintained even after adjusting for baseline differences between the groups.

The mechanism of the benefit of etanercept when added to MTX therapy in patients with MTX-resistant disease is not clear. The baseline DAS28 scores among patients who were still receiving MTX at the time etanercept was started were slightly lower than those among patients who had discontinued the drug, suggesting that the former group may represent patients who were already partial responders to MTX. However, even after adjusting for these baseline differences patients receiving etanercept with MTX were twice as likely to be in a better EULAR response category than those receiving etanercept monotherapy. There is also the possibility that MTX may be acting as a response modifier for etanercept in this case. However, one difference between the groups, which cannot be adjusted for, is the fact the monotherapy group represents patients who had previously received MTX but discontinued the drug because of a lack of effect or because of toxicity. It is known that patients who respond to MTX have a better overall prognosis (18), and it is therefore possible that our patients taking MTX will have a better prognosis independently of the combination therapy. One interesting observation was that the remission rate was not different between the MTX versus other DMARD groups of etanercept-treated patients, which suggests that combined treatment with other DMARDs should be considered in patients who are intolerant to MTX.

Results of a previous clinical trial suggested that the combination of MTX and infliximab is superior to infliximab monotherapy (4), both for the reduction of immunogenicity and the prolongation of effects of the anti-TNFα therapy. However, that trial was small, and other larger trials have not explored this issue further. There was a clear trend toward better improvement among patients in our study who were receiving the combination of infliximab plus MTX, although this did not reach statistical significance. While small numbers in both the infliximab monotherapy and the non-MTX DMARD cotherapy subgroups will have affected the power of these comparisons with MTX, this study does provide some reassurance that for patients who cannot tolerate MTX, the substitution of another DMARD, or even monotherapy, may be appropriate. The infliximab dosage (3 mg/kg of body weight administered at baseline, weeks 2 and 6, and every 8 weeks thereafter) is the standard regimen used in the UK. It is possible that the widespread use of higher dosages, such as 5 mg/kg of body weight, might have produced different outcomes.

In theory, the approach outlined herein could be used not only to compare different cotreatments for each of the biologic agents, but also to compare the efficacy between the 2 biologic agents. In the UK, however, when biologic agents were first introduced, only infliximab was available. Given the financial constraints at the time these drugs first became available, it is possible that patients with the most severe disease and the most resistant to previous DMARDs were selected for therapy. In contrast, by the time etanercept was reintroduced in April 2003, it is possible that the threshold for their use as well as the disease severity had dropped. Thus, the concern is that although the disease indicators that were available to us suggested no important differences between the 2 drugs, we cannot completely allow for this difference in disease profile in this observational study. These considerations, however, would not affect the comparisons within groups.

In summary, the results from this large national registry of RA patients support the use of biologic agents as effective therapy in patients with resistant, active RA. Both infliximab and etanercept performed well. Combining etanercept with MTX offered a clear advantage to the patients enrolled in this study, with both a better overall response rate and a higher rate of remission. There may also be advantage to the combination of infliximab with other DMARD combinations, which may be as effective as combining the agent with MTX in situations in which MTX is contraindicated or not tolerated.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors acknowledge the enthusiastic collaboration of all consultant rheumatologists and their specialist nurses in the UK in providing the data used in this report. The substantial contribution of Andy Tracey, Katie McGrother, and Mark Lunt in database design and manipulation is acknowledged. We also acknowledge the support of Dr. Ian Griffiths (Chairman of the BSRBR Management Committee) and Professors Gabriel Panayi, David G. I. Scott, and David Isenberg (Presidents of the BSR during the period of data collection) for their active role in enabling the BSRBR to undertake its tasks, as well as Samantha Peters and Mervyn Hogg (BSR staff) for their considerable administrative support.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al, for the ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999; 354: 19329.
  • 2
    Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 47886.
  • 3
    Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 2539.
  • 4
    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: 155263.
  • 5
    Godinho F, Godfrin B, El Mahou S, Navaux F, Zabraniecki L, Cantagrel A. Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis. Clin Exp Rheumatol 2004; 22: 32830.
  • 6
    Hansen KE, Cush J, Singhal A, Cooley DA, Cohen S, Patel SR, et al. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 2004; 51: 22832.
  • 7
    Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study. Rheumatology (Oxford) 2002; 41: 6317.
  • 8
    Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari PV, Drosos AA. Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis. Ann Rheum Dis 2002; 61: 8225.
  • 9
    Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al, for the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) Study Investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 67581.
  • 10
    Van Vollenhoven RF, Ernestam S, Harju A, Bratt J, Klareskog L. Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious. Arthritis Res Ther 2003; 5: R34751.
  • 11
    Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol 1982; 9: 78993.
  • 12
    Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 448.
  • 13
    Ledingham J, Deighton C, on behalf of the British Society for Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology Guidelines for Prescribing TNFα Blockers in Adults with Rheumatoid Arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005; 44: 15763.
  • 14
    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.
  • 15
    Van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum 1996; 39: 3440.
  • 16
    Fransen J, Creemers MC, van Riel PL. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford) 2004; 43: 12525.
  • 17
    Stata statistical software: release 8.2. College Station (TX): Stata Corporation; 2004.
  • 18
    Krause D, Schleusser B, Herborn G, Rau R. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000; 43: 1421.