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Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety

  • Alberto Alonso-Ruiz1Email author,
  • Jose Ignacio Pijoan2,
  • Eukene Ansuategui3,
  • Arantxa Urkaregi4,
  • Marcelo Calabozo1 and
  • Antonio Quintana5
BMC Musculoskeletal Disorders20089:52

DOI: 10.1186/1471-2474-9-52

Received: 05 May 2007

Accepted: 17 April 2008

Published: 17 April 2008

Abstract

Background

To analyse available evidence on the efficacy and safety of anti-TNFα drugs (infliximab, etanercept and adalimumab) for treating rheumatoid arthritis (RA).

Methods

We searched systematically for randomised controlled clinical trials on treatment of RA with anti-TNFα drugs, followed by a systematic review with metaanalysis. Trials were searched from MEDLINE, EMBASE and Cochrane Library databases. The American College of Rheumatology (ACR) efficacy response criteria were used. Safety parameters provided by the trials were also assessed. Positive and undesired effects were estimated using combined relative risks (RR), number needed to treat (NNT) and number needed to harm (NNH). Heterogeneity was evaluated by Cochrane's Q and I2 statistics.

Results

Thirteen trials (7087 patients) met the inclusion criteria. The combined RR to achieve a therapeutic response to treatment with recommended doses of any anti-TNFα drug was 1.81 (95% CI 1.43–2.29) with a NNT of 5 (5–6) for ACR20. NNT for ACR50 [5 (5–6)] and ACR70 [7 (7–9)] were similar. Overall therapeutic effects were also similar regardless of the specific anti-TNFα drug used and when higher than recommended doses were administered. However, lower than recommended doses elicited low ACR70 responses (NNT 15). Comparison of anti-TNFα drugs plus methotrexate (MTX) with MTX alone in patients with insufficient prior responses to MTX showed NNT values of 3 for ACR20, 4 for ACR50 and 8 for ACR70. Comparison of anti-TNFα drugs with placebo showed a similar pattern. Comparisons of anti-TNFα drugs plus MTX with MTX alone in patients with no previous resistance to MTX showed somewhat lower effects. Etanercept and adalimumab administered as monotherapy showed effects similar to those of MTX. Side effects were more common among patients receiving anti-TNFα drugs than controls (overall combined NNH 27). Patients receiving infliximab were more likely to drop out because of side effects (NNH 24) and to suffer severe side effects (NNH 31), infections (NNH 10) and infusion reactions (NNH 9). Patients receiving adalimumab were also more likely to drop out because of side effects (NNH 47) and to suffer injection site reactions (NNH 22). Patients receiving etanercept were less likely to drop out because of side effects (NNH for control versus etanercept 26) but more likely to experience injection site reactions (NNH 5).

Conclusion

Anti-TNFα drugs are effective in RA patients, with apparently similar results irrespective of the drug administered. Doses other than those recommended are also beneficial. The main factor influencing therapeutic efficacy is the prior response to DMARD treatment. The effect of treatment with etanercept or adalimumab does not differ from that obtained with MTX. The published safety profile for etanercept is superior but the fact that no patients are treated with higher than recommended doses requires explanation.

Background

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease of the joints, which often causes joint destruction, deformity and functional impairment [1]. Early administration of disease-modifying antirheumatic drugs (DMARDs) is crucial and the use of nonsteroidal anti-inflammatory drugs and glucocorticoids remains a fundamental aspect of medical management of RA. The discovery that the macrophage-derived proinflammatory cytokine tumour necrosis factor alpha (TNFα) plays a central role in the pathogenesis of RA [2] led to the introduction of anti-TNFα drugs, a new biological DMARD class. Evidence showing that anti-TNFα drugs are very effective in RA has led to a substantial change in the treatment of this disease [3]. Three such drugs have been commercialized since 1999: infliximab, etanercept and adalimumab. Despite this relative short history, a considerable amount of information has already been accumulated [46]. However, many questions about this new class of drugs still remain unanswered: are all available anti-TNFα drugs equally effective; does their efficacy depend upon their being administered together with methotrexate (MTX); does efficacy depend on dose; are they more effective than MTX; are all anti-TNFα drugs equally safe; what is the efficacy/safety profile? To date, no direct "head-to-head" comparative studies of the different anti-TNFα drugs have been published. An alternative approach to answering the foregoing questions is to perform a systematic review with metaanalysis of relevant research. A metaanalysis with emphasis on the risk of cancer and infections has been reported [7]. Also, a study using an indirect comparative approach to the relative efficacies of the three anti-TNFα drugs in the treatment of RA showed no differences among them [8].

In this paper, we conduct a systematic review of randomised controlled clinical trials of anti-TNFα drugs in RA followed by a metaanalysis of the efficacy and safety of different doses of infliximab, etanercept and adalimumab.

Methods

Study selection criteria

We carried out a search of all randomised controlled clinical trials of anti-TNFα drugs (infliximab, etanercept or adalimumab) for treating patients with RA. Patients had to satisfy the American College of Rheumatology (ACR) criteria [9] for diagnosis and to have active disease. Trial duration had to be at least 6 months with efficacy measured by ACR response [10]. Clinical trials were excluded if they either used administration routes other than recommended or included no treatment arm with recommended doses. Only information published in the trial reports was assessed.

Efficacy parameters

We used the ACR responses ACR20, ACR50 and ACR70 (improvements of at least 20, 50 and 70%, respectively, on a series of predetermined measures) as efficacy parameters [10].

Safety parameters

The following safety parameters reported in the selected trials were analyzed: number of patients suffering any adverse event, withdrawals due to adverse events, serious adverse events, infections, serious infections, infusion reactions, injection-site reactions, malignancies and overall mortality.

Search strategy

Trials were searched in scientific journals and congress conference proceedings. Information from the MEDLINE, EMBASE and Cochrane Library databases up to October 2006 was checked using a high-sensitivity strategy. The descriptors used were rheumatoid arthritis, infliximab, etanercept, adalimumab, randomised controlled trial and meta-analysis. The computerised search was completed with a manual search of reference lists from the articles retrieved and from rheumatological journal articles published in 2006 (technical details are available from the authors). There was no language restriction.

Data extraction

Two investigators (AA-R and MC) independently examined each eligible study and extracted data. Trials with information only in abstract format were excluded. Data were extracted using an ad hoc form with key items for each trial: study design, patients' characteristics (sex, age and duration of disease evolution), patient inclusion criteria, drugs and doses used, treatment duration and ACR response and safety parameters. Special attention was paid to both inclusion criteria and clinical features of patients included in each trial, as they were deemed central aspects for assessing heterogeneity. The quality of each individual study was assessed and scored using the Jadad scale [11].

Statistical analysis

For each single trial the relative risk (RR) of attaining an ACR response was obtained as a measure of the effect. Overall efficacy estimates (combined relative risk) for each anti-TNFα drug (as monotherapy or in association with MTX or another DMARD) compared to a control (placebo, MTX or another DMARD) were attained using the ACR20, ACR50, and ACR70 criteria as the main outcome variables. We used DerSimonian-Laird's method to estimate a random-effects model. Heterogeneity was evaluated using Cochrane's Q and I2 statistics and explored via subgroup analysis. The I2 statistic is calculated from Q and can be interpreted as the percentage variability in study results attributable to between-study differences [12]. The number of patients needed for experimental treatment versus control (NNT) to obtain an additional positive ACR response was also estimated [13].

We also used the RR to estimate the risk of adverse effects; and we estimated the number needed to harm (NNH), defined as the number of patients receiving active treatment that would harm one patient compared to controls [1315].

Publication bias was assessed graphically using a funnel plot [16] and statistically evaluated by the regression symmetry test described by Egger et al. [17] and the adjusted rank correlation test proposed by Begg and Mazumdar [18]. We used the specific software Comprehensive Metaanalysis Version 2.0 for analysis and presentation of main results.

Results

Search results

Of the 46 publications located [1965], only 15 met the selection criteria and were consequently included in the metaanalysis [1933]. The remaining 31 were excluded for several reasons [3464] (Figure 1). The Maini trial [21] was included in the Lipsky et al. trial [19] and the van der Heijde et al. [28] and Klareskog et al. [27] trials were the same (TEMPO trial). We analyzed the entire set of 7087 patients recruited for the 13 trials selected: four using infliximab [19, 20, 22, 23] (2581 patients), four etanercept [2426, 28] (1637 patients) and five adalimumab [2933] (2869 patients). The methodological quality of the studies was moderate to high (3–5) except Bathon's trial [24], which had a lower Jadad score of 2 because it neither mentioned nor explained whether treatment allocation was based on a random procedure (Table 1).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig1_HTML.jpg
Figure 1

Flow chart of the selection process for inclusion of Randomised Controlled Trials (RCT) in the overview.

Table 1

Summary of trials included in the metaanalysis

Trial (reference) Comparisons Jadad's scale (J)

Groups and N of patients

Mean age (years)

Mean disease duration (years)

N of swollen joints

N of tender joints

CRP (mg/dl)

HAQ

Mean N of previous DMARDs

Previous response to MTX

Lipsky et al. (19) Infliximab+MTX vs. MTX J [5]

3 mg/Kg 8 wk *

86

54

10

22

32

3.9

1.8

3.8

Insufficient

 

3 mg/Kg 4 wk

86

52

9

21

31

3.5

1.7

2.6

 
 

10 mg/Kg 8 wk

87

54

11

23

32

3.3

1.7

2.5

 
 

10 mg/Kg 4 wk

81

52

12

24

34

4.2

1.7

2.5

 
 

MTX

88

51

11

21

31

4.0

1.7

2.5

 
 

total

428

        

St. Clair et al. (20) Infliximab+MTX vs. MTX J [3]

3 mg/Kg 8 wk *

373

51

0,8

21

32

2.9

1,5

71%

Not previously MTX

 

6 mg/Kg 8 wk

378

50

0,9

22

33

3.0

1,5

68%

 
 

MTX

298

50

0,9

22

34

2.6

1,5

65%

 
 

total

1049

      

DMARDs naive

 

Quinn et al. (22) Infliximab+MTX vs. MTX J [3]

3 mg/Kg 8 wk *

10

51

0,6

NA

NA

4.7

1,3

Not previously DMARDs

Not previously MTX

 

MTX

10

53

0,5

  

3.7

1.3

  
 

total

20

        

Westhovens et al. (23) Infliximab+MTX vs. MTX J [4]

3 mg/Kg 8 wk *

360

53

7.8

15

22

1.6

1.5

NA

Insufficient

 

10 mg/Kg 8 wk *

361

52

6.3

15

22

1.6

1.5

  
 

MTX

363

52

8.4

15

22

1.2

1.5

  
 

total

1084

        

Moreland et al. (24) Etanercept vs. placebo J [5]

25 mg twice weekly *

78

 

11

25

33

4.7

1.6

3.3

Insufficient

 

10 mg twice weekly

76

53

13

25

34

5.3

1.7

3.4

 
 

placebo

80

53

12

25

35

4.1

1.7

3.0

 
 

total

234

51

       

Weinblatt et al. (25) Etanercept+MTX vs. MTX J [3]

25 mg twice weekly *

59

 

13

20

28

2.2

1.5

2.7

Insufficient

 

MTX

30

 

13

17

28

2.6

1.5

2.8

 
 

total

89

48

       
   

53

       

Bathon et al. (26) Etanercept vs. MTX J [2]

25 mg twice weekly *

207

51

1

24

31

3.3

NA

0.5

Not previously MTX

 

10 mg twice weekly

208

50

0.9

24

31

4.4

 

0.5

 
 

MTX

217

49

1

24

30

3.7

 

0.6

 
 

total

632

        

van der Heijde et al. (28) (TEMPO) Etanercept+MTX vs. MTX vs. Etanercept J [4]

25 mg twice weekly +MTX *

231

 

7

22

34

2.9

NA

2.3

 
 

25 mg twice weekly *

223

 

6

23

35

2.2

 

2.3

 
 

MTX

228

52

7

22

33

3.5

 

2.3

 
 

total

682

53

       
   

53

       

Weinblatt et al. (29) (ARMADA) Adalimumab+MT X vs. MTX J [3]

40 mg/2 wk *

67

57

12

17

28

2.1

1.5

2.9

Insufficient

 

20 mg/2 wk

69

53

13

17

28

2.8

1.5

3.0

 
 

80 mg/2 wk

73

55

12

17

30

2.8

1.5

3.1

 
 

MTX

62

56

11

16

28

3.1

1.6

3.0

 
 

total

271

        

van de Putte et al. (30) Adalimumab vs. Placebo J [5]

40 mg/2 wk *

113

52

10

20

33

5.2

1.8

3.8

Insufficient

 

20 mg/2 wk

106

53

9

19

33

5.2

1.8

3.7

 
 

20 mg/wk

112

54

11

19

35

4.7

1.8

3.6

 
 

40 mg/wk

103

51

11

19

33

4.9

1.8

3.8

 
 

Placebo

110

53

11

19

35

5.7

1.8

3.6

 
 

total

544

        

Furst et al. (31) (STAR) Adalimumab+ DMARD vs. DMARD J [3]

40 mg/2 wk *

318

 

9

20

27

1.5

1.3

57–60%

Insufficient

 

DMARD

318

 

11

21

27

1.5

1.4

2 or plus

 
 

total

636

55

       
   

55

       

Keystone et al. (32) Adalimumab+MT X vs. MTX J [3]

40 mg/2 wk *

207

56

11

19

27

1.8

1.4

2.4

Insufficient

 

20 mg/wk

212

57

11

19

27

1.4

1.4

2.4

 
 

MTX

200

56

10

19

28

1.8

1.4

2.4

 
 

total

619

        

Breedveld et al. (33) (PREMIER) Adalimumab+MT X vs. MTX vs. Adalimumab J [4]

40 mg/2 wk + MTX *

268

52

0,7

21

31

NA

1.5

NA

Not previously MTX

 

40 mg/2 wk

274

52

0,7

22

32

 

1.6

  
 

MTX

257

52

0,8

22

32

 

1.5

  
 

total

799

        

*groups receiving doses currently recommended

NA: not available

CRP: C-reactive protein

HAQ: health assessment questionnaire

Trial characteristics

Table 1 shows the major characteristic of the 13 trials included in the review. Information on efficacy at 6, 12 and 24 months and the previously-described safety parameters were analyzed.

There are four infliximab trials: Lipsky et al. [19], St. Clair et al. [20], Quinn et al. [22] and Westhovens et al. [23]. Lipsky et al. [19] used a randomised double blind 12-month trial (with information at 6 and 12 months). Four hundred and twenty-eight patients insufficiently responsive to MTX were included. Patients were randomized to 5 arms, four with infliximab plus MTX and a control arm with MTX alone. The purpose of this study was to demonstrate that infliximab was capable of inhibiting the progression of structural joint damage. It was a continuation of the Maini et al. trial [21]. The St. Clair et al. trial [20] compared infliximab plus MTX with MTX alone. The 1049 patients included in this trial had a recent onset of RA (disease duration in the range 3 months to 3 years). They had not previously received MTX, and MTX was administered following a rapid dose-increasing schedule during the trial (7.5 mg/wk at week 0, increasing by 2.5 mg per week to 15 mg/wk at week 5 and 20 mg/wk at week 8). The trial lasted 12 months. The Quinn et al. [22] trial was a small study comparing infliximab plus MTX with MTX alone in recent-onset RA patients. Westhovens et al. [23] conducted a 12-month trial but the double blind efficacy data were analyzed at week 22.

Four trials testing etanercept were analysed. Moreland et al. [24] compared etanercept in monotherapy with a placebo. Weinblatt et al. [25] compared etanercept plus MTX with MTX alone. In the Bathon et al. trial [26], etanercept in monotherapy was compared with MTX. Finally, the TEMPO trial (Trial of Etanercept and Methotrexate with radiographic Patient Outcomes) [28] compared etanercept in monotherapy with both MTX and a combination of etanercept plus MTX. Moreland et al. included 234 patients [24] in a 6 month-trial comparing the response to etanercept with placebo. Patients had previously shown an inadequate response to at least 1 DMARD (80% to MTX). They had received an average of three DMARDs and were therefore defined as refractory to standard treatments. Weinblatt et al. [25] included 89 patients with inadequate responses to MTX. The duration of the trial was 6 months. Bathon et al. [26] recruited 632 patients with recent RA onset (less than 3 years' duration). Patients ought not to have been treated with MTX previously. The trial lasted 1 year (with information at 6 and 12 months) and MTX was administered in a rapid dose-increasing schedule (initial dose 7.5 mg/wk, increased to 15 mg/wk at week 4 and 20 mg/wk at week 8). The TEMPO trial [28] included 682 patients with RA and insufficient DMARD responses. Around 40% had previously received MTX (but patients previously treated with MTX had neither discontinued it owing to toxicity nor been treated with MTX within 6 months of enrolment). The trial lasted 2 years. MTX was administered in a rapid dose-increasing schedule to 20 mg/wk in 8 weeks. The main goal of this study was to demonstrate that etanercept was capable of inhibiting the progression of structural joint damage.

There were five adalimumab trials. The ARMADA trial (The Anti-tumour necrosis factor Research study programme of the Monoclonal Antibody adalimumab in rheumatoiD Arthritis) [29] compared the efficacy of 6 months' treatment with adalimumab plus MTX with MTX alone in 271 patients with insufficient responses to MTX and at least one other DMARD. The van de Putte et al. trial [30] compared the efficacy of adalimumab with a placebo after 6 months treatment. All 544 patients included had inadequate responses to MTX and 3 other DMARDs. The basic purpose of the STAR trial (Safety Trial of Adalimumab in Rheumatoid arthritis) [31] was to study adalimumab safety. It recruited 636 patients with inadequate responses to any DMARD who were subsequently randomised either to continue with their current DMARD alone or to use a combination of the DMARD with adalimumab for 6 months. The Keystone et al. [32] trial had a similar design to ARMADA with a 12-month duration (information at 6 and 12 months), comparing adalimumab plus MTX with MTX alone in 619 patients. The basic purpose of this study was to demonstrate that adalimumab could inhibit the progression of structural joint damage. The PREMIER trial [33] compared the efficacies of adalimumab, adalimumab plus MTX and MTX alone in 799 patients at 24 months without previous treatment with MTX.

For each selected trial we extracted data on major features of the study design and characteristics of the patients included (Table 1). Weekly doses of MTX administered to the patients during the trials averaged 16 mg, except for the St. Clair et al. [20], TEMPO [28]. Bathon et al. [26] and PREMIER trials [33], in which MTX was administered in a rapid dose-increasing schedule to 20 mg/wk. The clinical profile of RA also varied across trials. Patients had a long history of RA (around 10 years) in most trials but a shorter evolution time in four of them: under 3 years in the St. Clair et al. [20], Bathon et al. [26] and Quinn et al. [22] and PREMIER [33] trials and around 6 years in the TEMPO [28] study. Therapeutic use of MTX prior to enrolment in the trial was also considered, because failure of or inadequate response to prior MTX administration entails a low response rate in the control group.

Metaanalysis results

Efficacy of anti-TNFα drugs. Global analysis

We studied the efficacies of the anti-TNFα drugs in the 13 trials included [1933] (Table 2). Global comparison of the ACR20 efficacy of any dose of any anti-TNFα drug with any control treatment showed a combined effect of 1.81 (95% CI 1.43–2.29) with an NNT of 6 (5–7). The combined effects were 1.89 (1.30–2.75) for adalimumab trials, 1.71 (1.11–2.63) for etanercept trials and 1.82 (1.19–2.77) for infliximab trials. Further analyses using ACR50 and ACR70 efficacies showed very similar results (Figure 2).
Table 2

Efficacy of anti-TNFα drugs on ACR20, ACR50 and ACR70 responses

Trial (reference) Comparisons Duration of trial in months

Groups

N of patients

6 month ACR20

6 month ACR50

6 month ACR70

12 month ACR20

12 month ACR50

12 month ACR70

24 month ACR20

24 month ACR50

24 month ACR70

Lipsky et al. (19) Infliximab+MTX vs. MTX 12 months

3 mg/Kg 8 wk +MTX*

86

 

22/86

7/86

36/86

18/86

9/86

   
 

3 mg/Kg 4 wk +MTX

86

43/86

25/86

9/86

41/86

29/86

31/86

   
 

10 mg/Kg 8 wk +MTX

87

43/86

27/87

15/87

51/87

34/87

22/87

   
 

10 mg/Kg 4 wk +MTX

81

45/87

21/81

9/81

48/81

31/81

15/81

   
 

Total Infliximab

340

47/81

95/340

40/340

176/340

112/340

77/340

   
 

MTX

88

178/340

4/88

0/88

15/88

7/88

2/88

   
 

Total

428

18/88

        

St. Clair et al. (20) Infliximab+MTX vs. MTX 12 months

3 mg/Kg 8 wk +MTX*

373

 

NA

NA

231/373

171/373

123/373

   
 

6 mg/Kg 8 wk +MTX

378

   

249/378

189/378

140/378

   
 

Total Infliximab

751

NA

  

480/751

360/751

263/751

   
 

MTX

298

   

161/298

95/298

62/298

   
 

Total

1049

         

Quinn et al. (22) Infliximab+MTX vs. MTX 12 months

3 mg/Kg 8 wk +MTX*

10

   

8/10

8/10

7/10

   
 

MTX

10

NA

NA

NA

6/10

4/10

3/10

   
 

Total

20

         

Westhovens et al. (23) Infliximab+MTX vs. MTX 6 months

3 mg/Kg 8 wk +MTX*

360

 

110/360

48/360

      
 

10 mg/Kg 8 wk +MTX

361

199/360

119/361

54/341

      
 

Total Infliximab

721

205/361

229/721

102/721

      
 

MTX

363

404/721

33/363

16/363

      
 

Total

1084

87/363

        

oreland et al. (24) Etanercept vs. placebo 6 months

25 mg 2 twice weekly *

78

 

31/78

11/78

      
 

10 mg 2 twice weekly

76

46/78

18/76

7/76

      
 

Total Etanercept

154

37/76

49/154

18/154

      
 

Placebo

80

83/154

4/80

1/80

      
 

Total

234

9/80

        

Weinblatt et al. (25) Etanercept+MTX vs. MTX 6 months

25 mg 2 +MTX *

59

42/59

23/59

9/59

      
 

MTX

30

8/30

1/30

0/30

      
 

Total

89

         

Bathon et al. (26) ** Etanercept vs. MTX 12 months

25 mg 2 twice weekly *

207

147/207

NA

NA

149/207

101/207

52/207

   
 

10 mg 2 twice weekly

208

NA

NA

NA

NA

NA

NA

   
 

Total Etanercept

415

56/217

NA

NA

141/217

93/217

47/217

   
 

MTX

217

         
 

Total

632

         

van der Heijde et al. (28) (TEMPO) Etanercept+MTX vs. etanercept vs MTX 24 months

25 mg 2 twice weekly +MTX *

231

NA

NA

NA

196/231

159/231

99/231

199/231

164/231

113/231

 

25 mg 2 twice weekly*

223

   

169/223

107/223

54/223

167/223

120/223

60/223

 

Total Etanercept

454

   

365/454

266/454

153/454

386/454

284/454

173/454

 

MTX

228

   

171/228

98/228

43/228

162/228

96/228

4/228

 

Total

682

         

Weinblatt et al. (29) ARMADA) dalimumab+MTX vs. MTX 6 months

40 mg/2 s+MTX*

67

45/67

37/67

18/67

      
 

20 mg/2 s+MTX

69

33/69

22/69

7/69

      
 

80 mg/2 s+MTX

73

48/73

31/73

14/73

      
 

Total Adalimumab

209

126/209

90/209

39/209

      
 

MTX

62

9/62

5/62

3/62

      
 

Total

271

         

van de Putte et al. (30) Adalimumab vs. Placebo 6 months

40 mg/2 wk *

113

 

25/113

14/113

      
 

20 mg/2 wk

106

52/113

20/106

9/106

      
 

20 mg/wk

112

38/106

23/112

11/112

      
 

40 mg/wk

103

44/112

36/103

19/103

      
 

Total Adalimumab

434

55/103

104/434

53/434

      
 

Placebo

110

189/434

9/110

2/110

      
 

Total

544

21/110

        

Furst et al. (31) (STAR) Adalimumab+DAMAR D vs. DAMARD 6 months

40 mg/2 wk *

318

 

93/318

47/318

      
 

DMARD

318

169/318

35/318

10/318

      
 

Total

636

111/318

        

Keystone et al. (32) Adalimumab+MTX vs. MTX 12 months

40 mg/2 wk +MTX*

207

131/207

80/207

43/207

122/207

86/207

48/207

   
 

20 mg/wk +MTX

212

129/212

87/212

36/212

116/212

80/212

44/212

   
 

Total Adalimumab

419

260/419

167/419

79/419

238/419

166/419

92/419

   
 

MTX

200

59/200

19/200

5/200

48/200

19/200

9/200

   
 

Total

619

         

Breedveld et al. (33) (PREMIER) Adalimumab+MTX vs. adalimumab vs MTX 24 months

40 mg/2 wk+MTX*

268

NA

NA

NA

196/268

166/268

123/268

185/268

158/268

126/268

 

40 mg/2 wk *

274

   

148/274

112/274

71/274

134/274

101/274

77/274

 

Total Adalimumab

542

   

344/542

278/542

194/542

319/542

259/542

203/542

 

MTX

257

   

162/257

118/257

72/257

144/257

111/257

72/257

* groups receiving doses currently recommended

NA: not available

https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig2_HTML.jpg
Figure 2

Efficacy of all doses of anti-TNFα drugs on ACR20, ACR50 and ACR70 responses. Effect refers to the risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Analysis of this set of 13 trials provided evidence of relevant and statistically significant heterogeneity (Q = 157.7; p < 0.001; I2 92%). Although the limited number of trials reduced the discriminatory power of the funnel plot, it suggested a certain degree of asymmetry (Figure 3), which was statistically confirmed by both the Begg and Mazumdar adjusted rank correlation test (p = 0.033) and Egger's regression asymmetry test (p = 0.001).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig3_HTML.jpg
Figure 3

Funnel plot of selected studies. The x-axis shows effect estimates (RR) on a logarithmic scale (any effect estimate greater than zero therefore indicates better results for experimental treatment) while the y-axis measures the precision of each study (as the inverse of the standard error of the effect estimate measured on a logarithmic scale).

Bearing all these aspects in mind, we focused on the analysis of subgroups that appeared more homogeneous on both clinical and trial design grounds: previous exposure and response to DMARDs, mainly MTX, dose of anti-TNFα drug administered and control treatment selected (active or placebo, single or combined). The effects (RR) obtained with different doses of anti-TNFα appear in Table 3. The distinct NNTs and the analysis of heterogeneity appear in Table 4. Evidently the specific subgroups of trials characterised by these features are much less heterogeneous on analysis.
Table 3

Effects (RR and NNT (95% CI)) obtained with different doses of anti-TNFα drugs

  

All doses of anti-TNFα drugs vs. control 4618 vs. 2261*

Recommended doses of anti-TNFα drugs vs. control 2874 vs. 2260**

High-doses drugs vs. control 1169 vs. 921*** of anti-TNFα

Low-doses of anti-TNFα drugs vs. control 251 vs. 252****

Anti-TNFα

ACR

RR (CI 95%)

NNT

RR (CI 95%)

NNT

RR (CI 95%)

NNT

RR (CI 95%)

NNT

Adalimumab

ACR20

1.9 (1.3–2.8)

6 (5–7)

2.0 (1.3–2.9)

5 (4–6)

3.5 (1.6–7.3)

3 (2–4)

2.4 (1.4–4.1)

5 (4–8)

 

ACR50

2.7 (1.6–4.4)

6 (5–7)

2.8 (1.6–4.7)

5 (5–6)

4.7 (1.9–12.0)

4 (3–5)

2.9 (1.6–5.1)

7 (5–13)

 

ACR70

3.3 (1.8–6.3)

9 (7–11)

3.5 (1.9–6.7)

7 (6–8)

6.1 (1.8–20.8)

7 (5–11)

3.0 (1.1–7.9)

17 (9–77)

Etanercept

ACR20

1.7 (1.1–2.6)

7(5–10)

1.7 (1.1–2.7)

6 (5–8)

There are no trials with high doses of Etanercept

4.3 (1.9–10.1)

3 (2–5)

 

ACR50

2.1 (1.1–3.9)

6 (5–9)

2.2 (1.1–4.3)

6 (4–7)

  

4.7 (1.7–13.4)

6 (4–13)

 

ACR70

2.0 (0.9–4.4)

NS

2.1 (0.9–4.5)

NS

  

7.4 (0.9–58.5)

NS

Infliximab

ACR20

1.8 (1.2–2.8)

5 (4–6)

1.7 (1.1–2.6)

5 (4–6)

2.0 (1.2–3.6)

5 (4–5)

There are no trials with low doses of Infliximab

 

ACR50

2.6 (1.5–4.7)

5 (5–6)

2.2 (1.2–4.1)

6 (5–7)

2.8 (1.5–5.5)

5 (4–6)

  
 

ACR70

2.9 (1.4–5.8)

8 (6–10)

2.4 (1.2–5.0)

9 (7–13)

3.3 (1.5–7.2)

7 (6–7)

  

Overall

ACR20

1.8 (1.4–2.3)

6 (5–7)

1.8 (1.4–2.3)

5 (5–6)

2.5 (1.5–4.2)

4 (5–4)

2.9 (1.7–5.1)

4 (3–6)

 

ACR50

2.5 (1.8–3.4)

6 (5–6)

2.4 (1.7–3.4)

5 (5–6)

3.4 (2.0–5.8)

5 (4–5)

3.2 (2.0–5.3)

6 (5–10)

 

ACR70

2.8 (1.9–4.2)

8 (7–9)

2.7 (1.8–4.1)

7 (7–9)

3.9 (2.0–7.6)

7 (6–8)

3.5 (1.4–8.6)

15 (10–38)

NNT: number of patients needed to be treated

RR (95%CI): relative risk (95% confidence limits)

NS: non-significant results

*4618 patients being treated with anti-TNFα (except 208 patients Bathon's trial being treated with 10 mg of etanercept twice a week) vs 2261 patients of the control groups

**2874 patients with recommended doses of anti-TNFα drugs (Infliximab 3 mg/Kg/8 week; etanercept 25 mg twice a week; adalimumab 40 mg every 2 weeks) vs 2260 patients of the control groups

***1169 patients with high-doses of anti-TNFα drugs (infliximab 3 mg/Kg 4 week, 6 mg/Kg 8 week, 10 mg/Kg 8 week and 10 mg/Kg 4 week; adalimumab 40 mg/week, 80 mg/2 week) vs 921 patients of the control groups

****251 patients with low-doses of anti-TNFα drugs (etanercept 10 mg twice weekly; adalimumab 20 mg/2 week) vs 252 patients of the control groups

Table 4

Efficacy and heterogeneity

Comparisons (Anti-TNFα vs. control)***

ACR response

Anti-TNFα Events/Total

Control Events/Total

RR (CI 95%)

NNT

Q

I2%

All doses of anti-TNFα drugs vs. control (4618 vs. 2261)

ACR20

2709/4618

941/2261

1.8 (1.4–2.3)

6 (5–7)

157.7*

92

 

ACR50

1879/4618

519/2261

2.5 (1.8–3.4)

6 (5–6)

109.8*

89

 

ACR70

1106/4618

 

2.8 (1.9–4.1)

8 (7–9)

52.4*

77

Recommended doses of anti-TNFα drugs vs. control (2874 vs. 2260)

ACR20

1808/2874

949/2261

1.8 (1.4–2.3)

5 (5–6)

149.5*

92

 

ACR50

1247/2874

519/2261

2.4 (1.7–3.4)

5 (5–6)

102.9*

88

 

ACR70

733/2874

270/2261

2.7 (1.8–4.1)

7 (7–9)

49.2*

76

High-doses of anti-TNFα drugs vs. control (1169 vs. 921)

ACR20

697/1169

293/921

2.5 (1.5–4.2)

4 (4–5)

57.2*

93

 

ACR50

469/1169

149/921

3.4 (2.0–5.8)

5 (4–5)

30.5*

87

 

ACR70

295/1169

85/921

3.9 (2.0–7.6)

7 (6–8)

16.6*

76

Low-doses of anti-TNFα drugs vs. control (251 vs. 252)

ACR20

108/251

39/252

2.9 (1.7–5.1)

4 (3–6)

4.9

59

 

ACR50

60/251

18/252

3.2 (2.0–5.3)

6 (5–10)

1.5

0

 

ACR70

23/251

6/252

3.5 (1.4–8.6)

15 (10–38)

1.2

0

Anti-TNFα drugs vs. control in patients with No insufficient response to MTX (1964 vs. 1010)

ACR20

1346/1964

641/1010

1.1 (0.9–1.3)

NS

2.4

9

 

ACR50

1013/1964

408/1010

1.3 (1.1–1.5)

9 (7–13)

8.8

55

 

ACR70

669/1964

227/1010

1.5 (1.3–1.7)

12 (9–19)

7.0

43

Anti-TNFα drugs vs. control in patients with insufficient response to MTX (2654 vs. 1251)

ACR20

1427/2654

308/1251

2.3 (2.0–2.7)

4 (3–5)

28.2*

75

 

ACR50

866/2654

113/1251

3.6 (2.9–4.4)

5 (4–5)

7.2

3

 

ACR70

437/2654

43/1251

4.4 (3.2–6.0)

7 (6–8)

4.2

0

Anti-TNFα drugs at recommended doses plus MTX vs. MTX alone in patients with insufficient response to MTX (779 vs. 743)

ACR20

444/779

167/743

2.6 (2.1–3.3)

3 (3–4)

4.3

7

 

ACR50

274/779

65/743

4.1 (2.6–6.6)

4 (4–5)

4.6

13

 

ACR70

132/779

30/743

4.1 (2.4–7.1)

8 (7–11)

2.5

0

Anti-TNFα drugs versus placebo at recommended doses (191 vs. 190)

ACR20

98/191

30/190

3.4 (1.6–7.3)

3 (3–4)

3.8*

74

 

ACR50

56/191

13/190

4.4 (1.5–12.5)

5 (4–7)

2.9

66

 

ACR70

25/191

3/190

8.1 (2.5–26.4)

9 (7–16)

0.1

0

Anti-TNFα drugs at recommended doses plus MTX versus MTX alone in patients with no previous resistance to MTX (882 vs. 793)

ACR20

631/882

500/793

1.2 (1.1–1.2)

10 (7–16)

0.4

0

 

ACR50

504/882

315/793

1.6 (1.4–1.7)

6 (5–8)

1.1

0

 

ACR70

352/882

180/793

1.8 (1.5–2.1)

6 (5–8)

3.9

23

Anti-TNFα drugs versus MTX at recommended doses (704 vs. 702)

ACR20

466/704

474/702

1.0 (0.9–1.1)

NS

6.9*

71

 

ACR50

320/704

309/702

1.0 (0.9–1.2)

NS

3.6

45

 

ACR70

177/704

162/702

1.1 (0.9–1.3)

NS

2.2

11

RR (95%CI): relative risk (95% confidence limits)

NNT: number of patients needed to be treated

Q: Cochrane's Q

I2: percentage of variability in study results attributable to between-study differences

* statistical heterogeneity

NS: non-significant results

*** number of patients being treated with anti-TNFα versus number of patients in the control groups

Efficacy of anti-TNFα drugs depending on prior exposure and response to MTX

The efficacy results (Figure 4) show that this factor leads to rather different estimates and should be taken into account. When the effect of an anti-TNFα drug is assessed in patients who have received no previous MTX treatment, the relative ACR20 effect is small and only marginally statistically significant: 1.10 (0.96–1.26). On the other hand, when the anti-TNFα drug effect is analysed in patients with previously insufficient responses to MTX, the relative effect is substantially larger (2.32 [1.99–2.72]) and both clinically relevant and statistically significant [NNT of 4 (3–5)]. Similar results are seen with the ACR50 and ACR70 responses, though here the effect in patients naïve to MTX is statistically significant compared to control arms.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig4_HTML.jpg
Figure 4

Efficacy of anti-TNFα drugs depending on an insufficient response to MTX prior to trial commencement. Effect refers to risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'Upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Analysis of the effect of different doses of anti-TNFα drugs

We analysed the efficacy of anti-TNFα drug administration in three separate groups: currently recommended doses (infliximab 3 mg/Kg/8 week; etanercept 25 mg twice a week; adalimumab 40 mg every 2 weeks); high doses (infliximab 3 mg/Kg/4 week, 6 mg/Kg/8 week, 10 mg/Kg/8 week and 10 mg/Kg/4 week; adalimumab 40 mg/week, 80 mg/2 week); and low doses (etanercept 10 mg 10 mg twice weekly; adalimumab 20 mg/2 week). No patient receiving infliximab was prescribed lower than recommended doses, and no patient treated with etanercept received higher than recommended doses. The group given adalimumab 20 mg/week was not included as this dose schedule can be considered neither above nor below the currently recommended regime. The combined and individual effects of the adalimumab, etanercept and infliximab trials at any dose or in subgroups based on the dose level are shown in Table 3. A statistically significantly beneficial effect is apparent with recommended, higher or lower doses in all the comparisons made, except for the ACR70 response to etanercept. Accordingly, the NNTs are very similar for all anti-TNFα drugs.

Analysis of the effect of anti-TNFα drugs at recommended doses

Five trials [19, 23, 25, 29, 32] compared the effects of anti-TNFα drugs plus MTX with MTX alone in patients with insufficient responses to MTX. A beneficial combined effect in the ACR20 response is shown: RR 2.60 (2.05–3.31) with an NNT of 4 (3–4). Analyses using the ACR50 and ACR70 responses showed very similar results (Figure 5). There was no evidence of statistical heterogeneity among the different drug classes (Table 4).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig5_HTML.jpg
Figure 5

Efficacy of anti-TNFα drugs at recommended doses in combination with MTX compared with MTX alone in patients with insufficient responses to MTX. Effect refers to risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'Upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Only two trials [24, 30] assessed the effect of anti-TNFα drugs versus placebo, showing a combined positive effect on the ACR20 response with an RR of 3.42 (1.60–7.30) and an NNT of 3 (3–4). Although there was a statistically significant heterogeneity of effects according to which drug had been used (Q = 3.8; p = 0.049; I2 = 74) with etanercept apparently more effective than adalimumab (Figure 6), it should be emphasized that there was no direct head to head comparison among them. There was no statistical evidence of heterogeneity in either the ACR50 or the ACR70 response, but the estimates of the effect varied widely between the two drugs, with a pattern similar to that obtained with the ACR20 outcome and based on a rather small number of patients.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig6_HTML.jpg
Figure 6

Efficacy of anti-TNFα drugs versus placebo at recommended doses. Effect refers to risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'Upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Four trials [20, 22, 28, 33] compared the effect of anti-TNFα drug plus MTX with MTX alone in patients with no previous resistance to MTX. This analysis showed a small but significant combined effect on the ACR20 response of 1.15 (1.07–1.22) with an NNT of 10 (7–16) (Figure 7). The ACR50 showed a combined effect of 1.56 (1.41–1.72) whereas that effect was 1.77 (1.52–2.05) for ACR70. No statistically significant heterogeneity was present for any of these outcomes.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig7_HTML.jpg
Figure 7

Efficacy of anti-TNFα drugs plus MTX compared to MTX alone in patients with no previous resistance to MTX (at the recommended doses). Effect refers to risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'Upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Three trials compared efficacies of anti-TNFα drugs with MTX alone as control [26, 28, 33]. The ACR20 combined effect showed no significant difference among the arms, with RR = 1.00 (0.92–1.08). Results were similar for the ACR50 and ACR70 responses (Figure 8). The heterogeneity was marginally significant for ACR20 and significant for ACR50 (Table 4).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig8_HTML.jpg
Figure 8

Efficacy of anti-TNFα drugs compared to MTX at recommended doses. Effect refers to risk of obtaining the corresponding response with anti-TNFα drug relative to control treatment. 'Lower' and 'Upper' represent the 95% confidence interval limits for the efficacy estimate. Random-effect models.

Safety analysis

An overview of the adverse events reported in the selected trials is displayed in Table 5. The number of withdrawals due to adverse events according to treatment arm was reported in all trials. Information on the incidence of serious infections, malignancies and mortality is also provided, specifying whether patients were in the experimental or control arms, but information about the specific treatment group of the patient was sometimes lacking. Other important safety information (overall number of adverse events, severe adverse events, total number of infections, infusion reactions and injection-site reactions) was provided much less consistently.
Table 5

Number of patients who presented adverse effects in trials with anti TNFα drugs

Trial (reference) Anti-TNFα drug

Groups

N of patients

Withdrawn adverse event

Total adverse events

Serious adverse events

Infections

Serious infections

Infusion reactions

Injection- site reactions

Malignancies

Mortality

Lipsky et al. (19) Infliximab

3 mg/Kg 8

86

5

_

_

_

_

  

_

_

 

wk +MTX

86

9

_

_

_

_

  

_

_

 

3 mg/Kg 4

87

4

_

_

_

_

  

_

_

 

wk +MTX

81

8

_

_

_

_

  

_

_

 

10 mg/Kg 8

340

26

323

58

244

22

  

5

5

 

wk +MTX

88

7

83

18

53

7

NA

 

0

3

 

10 mg/Kg 4

          
 

wk +MTX

          
 

Total

          
 

Infliximab

          
 

MTX

          

St. Clair et al. (20) Infliximab

3 mg/Kg 8

373

34

 

_

_

21

_

 

0

1

 

wk +MTX

378

35

 

_

_

19

_

 

4

1

 

6 mg/Kg 8

751

69

 

103

414

40

135

 

4

2

 

wk +MTX

298

9

NA

32

141

6

20

 

0

2

 

Total

          
 

Infliximab

          
 

MTX

          

Quinn et al. (22) Infliximab

3 mg/Kg 8

10

1

 

1

 

0

1

 

0

0

 

wk +MTX

10

0

NA

0

NA

0

0

 

0

0

 

MTX

          

Westhovens et al. (23) Infliximab

3 mg/Kg 8

360

18

_

_

 

6

  

2

0

 

wk +MTX

361

20

_

_

 

18

  

2

2

 

10 mg/Kg 8

721

38

512

55

 

24

  

4

2

 

wk +MTX

363

8

239

27

NA

6

NA

 

1

1

 

Total

          
 

Infliximab

          
 

MTX

          

Moreland et al. (24) Etanercept

25 mg twice

78

2

   

0

 

_

0

0

 

weekly

76

5

   

0

 

_

0

0

 

10 mg twice

154

7

   

0

 

71

0

0

 

weekly

80

3

NA

NA

NA

0

 

10

0

0

 

Total

          
 

Etanercept

          
 

Placebo

          

Weinblatt et al. (25) Etanercept

25 mg twice

59

2

  

30

0

 

23

0

0

 

weekly

30

1

NA

NA

19

0

 

2

0

0

 

+MTX MTX

          

Bathon et al. (26) Etanercept

25 mg twice

207

11

     

_

3

1

 

weekly

208

12

     

_

2

1

 

10 mg twice

415

23

     

140

5

2

 

weekly

217

24

NA

NA

NA

NA

 

16

2

0

 

Total

          
 

Etanercept

          
 

MTX

          

van der Heijde et al. (28) (TEMPO) Etanercept

25 mg twice

231

37

_

_

_

23

  

5

1

 

weekly

223

34

_

_

_

24

  

5

1

 

+MTX

454

71

379

64

285

47

 

69

10

2

 

25 mg twice

228

47

185

37

147

25

 

4

2

1

 

weekly

          
 

Total

          
 

Etanercept

          
 

MTX

          

Weinblatt et al. (29) (ARMADA) Adalimumab

40 mg/2 wk

67

0

   

_

 

_

_

_

 

+MTX

69

4

   

_

 

_

_

_

 

20 mg/2 wk

73

1

   

_

 

_

_

_

 

+MTX

209

5

   

2

 

32

1

0

 

80 mg/2 wk

62

2

NA

NA

NA

0

 

2

0

0

 

+MTX

          
 

Total

          
 

Adalimumab

          
 

MTX

          

van de Putte et al. (30) Adalimumab

40 mg/2 wk

113

7

_

_

 

_

 

_

_

1

 

20 mg/2 wk

106

4

_

_

 

_

 

_

_

0

 

20 mg/wk

112

3

_

_

 

_

 

_

_

0

 

40 mg/wk

103

3

       

0

 

Total

434

17

429

53

 

10

 

46

4

3

 

Adalimumab

110

2

105

16

NA

0

 

1

1

1

 

Placebo

          

Furst et al. (31) (STAR) Adalimumab

40 mg/2 wk

318

9

275

17

166

4

 

62

1

1

 

DMARD

318

8

275

22

157

6

 

37

0

1

Keystone y cols. (32) Adalimumab

40 mg/2 wk

207

26

_

_

_

11

 

_

_

2

 

+MTX*

212

16

_

_

_

5

 

_

_

1

 

20 mg/wk

419

42

391

97

269

16

 

101

4

3

 

+MTX

200

13

181

37

111

1

 

48

0

0

 

Total

          
 

Adalimumab

          
 

MTX

          

Breedveld et al. (33) (PREMIER) Adalimumab

40 mg/2 wk

268

32

_

  

9

  

2

1

 

+MTX*

274

26

_

  

3

  

4

4

 

40 mg/2 wk

542

58

524

  

12

  

6

5

 

Total

257

19

245

NA

NA

7

 

NA

4

1

 

Adalimumab

          
 

MTX

          

NA: not available

* Overall data provided although specific data per arm not provided

Regarding withdrawals due to adverse events, we found no significant overall difference between the experimental and control groups, with a pooled RR of 1.25 (0.65–2.39) (Figure 9). Results differed depending on the specific anti-TNFα given: patients in the etanercept arms were less likely to withdraw from adverse events than their control counterparts, but the opposite was the case for adalimumab and infliximab, all those comparisons reaching statistical significance. There was statistically significant heterogeneity among the drugs (Q = 29.3; p = 0.003; I2 59) but not within the groups given each specific drug. The results were the same when only groups receiving recommended doses of anti-TNFα drugs were studied. Higher than recommended doses of infliximab led to a higher withdrawal rates. There were no significant differences in withdrawal rates between lower than recommended dose and control arms.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2474-9-52/MediaObjects/12891_2007_Article_458_Fig9_HTML.jpg
Figure 9

Adverse event withdrawn in patients with all doses of anti-TNFα drugs.

There were more adverse events in patients allocated to anti-TNFα drugs (RR 1.02 (1.00–1.04)) (p = 0.021) (Table 6). Patients receiving infliximab showed a higher frequency of serious adverse events (p = 0.048) and infections (p = 0.004), but the combined estimates for all three anti-TNFα drugs and safety outcomes were not significant.
Table 6

Adverse events in patients being treated with anti-TNFα drugs versus control

ADVERSE EVENTS (anti TNFα vs. control) (references)

Anti-TNFα

Anti-TNFα Adverse events/total

Controls Adverse events/total

RR (95%CI)

NNH(95%CI)

Q

I2 %

Withdrawn adverse event

Adalimumab

131/1922

44/947

1.4(1.0–2.0)

47(26–251)

1.2

0

(4826 vs. 2261)

Etanercept

103/1082

75/555

0.7(0.5–0.9)

-26(-143 a -14)

2.4

0

** (19,20,22,23,24,25,26,28,29,30,31,32,33)

Infliximab

134/1822

24/759

2.0(1.3–3.1)

24(17–41)

4.9

0

 

Total

368/4826

143/2261

1.3(0.7–2.4)

NS

29.3*

59

Total adverse events (3228 vs. 1564) (19,23,28,30,31,32,33)

Adalimumab

1619/1713

806/885

1.1(0.9–1.1)

NS

1.9

0

(3228 vs. 1564)

Etanercept

379/454

185/228

1.0(0.9–1.1)

NS

0

0

(19,23,28,30,31,32,33)

Infliximab

835/1061

322/45

1.0(0.9–1.0)

NS

1.6

39

 

Total

2833/3228

1313/1564

1.0(1.0–1.5)

27(17–59)

2.9

0

Serious adverse events

Adalimumab

167/1171

75/628

1.0(0.7–1.4)

NS

2.6

25

(3235 vs. 1615)

Etanercept

64/454

37/228

0.9(0.5–1.6)

NS

0

0

(19,20,22,23,28,30,31,32)

Infliximab

217/1610

77/759

1.4(1.0–2.0)

31(17–167)

6.2

52

 

Total

448/3235

189/1615

1.1(0.8–1.6)

NS

14.3*

51

Infections

Adalimumab

435/737

268/518

1.1(0.9–1.2)

NS

0.7

0

(2341 vs. 1162)

Etanercept

315/513

166/258

1.0(0.9–1.0)

NS

0.9

0

(19,20,25,28,31,32,33)

Infliximab

658/1091

194/386

1.2(1.1–1.3)

10(7–24)

0.03

0

 

Total

1408/2341

628/1162

1.9(0.9–1.2)

NS

8.6

41

Serious infections

Adalimumab

44/1922

14/947

1.2(0.6–2.8)

NS

5.8

31

(4188 vs.1937)

Etanercept

47/454

25/28

0.9(0.4–2.3)

NS

0

0

(19,20,22,23,24,25,28,29,30,31,32,33)

Infliximab

90/1812

19/726

1.8(0.9–3.4)

NS

2.7

26

 

Total

181/4188

58/1937

1.4(0.8–2.2)

NS

11.8

32

Infusión reactions

(761 vs. 308)

(20,22)

Infliximab

136/761

20/308

2.7(1.7–4.2)

9(7–14)

0.005

0

Injection-site reactions

Adalimumab

241/1380

88/690

1.7(1.0–3.0)

22(13–67)

12.6*

72

(2454 vs. 1245)

Etanercept

303/1074

32/555

5.1(2.9–8.8)

5(4–6)

2.3

0

(24,25,26,28,29,30,31,32)

Total

544/2454

120/1245

3.0(1.0–8.6)

8(7–10)

51.8*

86

Malignancies

Adalimumab

16/1922

5/947

1.1(0.4–2.7)

NS

1.6

0

(4826 vs. 2261)

Etanercept

15/1082

4/555

1.9(0.6–5.7)

NS

0.3

0

(19,20,22,23,24,25,26,28,29,30,31,32,33)

Infliximab

13/1822

1/759

2.6(0.6–11.6)

NS

1.1

0

 

Total

44/4826

10/2261

1.5(0.8–3.0)

NS

3.3

0

Mortality

Adalimumab

10/1922

3/947

1.3(0.4–4.7)

NS

2.0

0

(4826 vs. 2261)

Etanercept

4/1082

1/555

1.5(0.2–9.5)

NS

0.2

0

(19,20,22,23,24,25,26,28,29,30,31,32,33)

Infliximab

9/1822

5/759

0.5(0.2–1.4)

NS

0.4

0

 

Total

23/4826

9/2261

0.8(0.3–2.1)

NS

4.4

0

RR (95%CI): relative risk (95% confidence limits)

NNH: number needed to harm

Q: Cochrane's Q

I2: percentage of variability in study results attributable to between-study differences

* statistical heterogeneity

NS: non-significant results

** this figure include 208 patients of the Bathon trial not included in efficacy studies as efficacy date were not reported

Information on severe infections, malignancies and deaths was provided in all trials except for severe infections in the Bathon trial. No significant combined increases in risk were seen for any of these results.

We also inquired whether higher than recommended doses are associated with higher incidences of adverse events. The reported data were incomplete, however, as the Lipsky et al. trial [19] did not assign the 22 severe infections detected to each corresponding infliximab dose arm. The risk of severe infection when receiving high doses of infliximab [20, 23] was significantly increased (p = 0.006) with an NNH of 40 (26–91), but the risk of developing malignancies was not increased (p = 0.116). Nor did the two trials [29, 30] administering high doses of adalimumab report the dose received by patients experiencing severe infections.

Discussion

This study approached a problem of major clinical and socio-economic importance: the efficacy and safety of anti-TNFα drugs in the treatment of rheumatoid arthritis (RA). We have considered these drugs both individually and as a specific therapeutic group. We have evaluated their efficacy as monotherapy and in combination with MTX. In addition, the efficacies of different doses and the safety of these drugs were explored.

Our search of the literature on the efficacy of anti-TNFα drugs in RA identified thirteen clinical trials fulfilling the required criteria for inclusion in the systematic review and metaanalysis. All thirteen were randomised-controlled trials with a minimal follow-up time of 6 months and used comparable standardised parameters of efficacy. Although the general quality of the trials was high, some difficulties became apparent during the review. The number of trials fulfilling the required criteria was small. Furthermore, there were several sources of clinically relevant heterogeneity: different control treatments were used, populations were not homogeneous, follow-up times differed among trials and the doses administered varied widely (Table 1). Also, the funnel plot asymmetry might indicate publication bias or other types of problems.

In our study, combined analysis of the results from all trials using the recommended doses led us to conclude that anti-TNFα drugs (considered as a therapeutic group) show an effect significantly superior to that of control treatments. However, the heterogeneity was very high, calling for subgroups and more homogeneous comparisons. We only evaluated those trials for which relevant homogeneous comparisons were possible, and a substantial reduction in heterogeneity was apparent when we focused on these groups (Table 4). Comparison of the three anti-TNFα drug plus MTX with MTX alone in patients with insufficient responses to MTX showed no significant heterogeneity of effects, yet despite the absence of head to head comparisons we found no evidence whatsoever that the relative effects of individual drugs are different. Etanercept seemed superior to adalimumab when both drugs were compared to placebo. However, the response observed in the control group of the adalimumab study was substantially higher than that of the etanercept reference group, which casts doubts on the actual comparability of the results and makes it difficult to draw definitive conclusions until the drugs have been compared directly in well designed, head to head randomised trials. Anti-TNFα drug plus MTX had a greater effect than MTX alone in patients with no previous resistance to MTX, but the magnitude of this effect was markedly lower than that obtained in patients with previously inadequate responses to MTX. Trials that assessed this specific efficacy issue recruited patients with short-lasting, less severe disease showing high responses to both experimental and control treatments, thus explaining the lower relative and absolute efficacy estimates (Table 4). In fact, the effects achieved with etanercept and adalimumab in these patients were equivalent to those obtained using MTX for the first time.

When the potential influence on efficacy of doses administered was evaluated, both higher and lower doses than are currently recommended seemed to elicit similar effects, except for the effect of lower doses on ACR70. However, comparisons in this last case are based on a small number of patients.

In the light of these findings it seems sensible to advise that current treatment of moderate and severe RA should be started with MTX. Anti-TNFα drugs should be restricted to patients who do not respond sufficiently to DMARD combinations until experimental evidence demonstrates that the new biological drugs have greater efficacy in earlier stages of RA. It might also be potentially useful to start the indicated treatment with a low dose and then increase it as a function of the magnitude of the response. An alternative option might be to start with the current recommended doses and try to decrease them after a significant stable effect is reached, in order to minimise adverse effects. This issue encompasses important clinical and economic implications probably meriting further research.

For a correct interpretation of our results, the fact that our analyses were based on the ACR response should be taken into account. In recent years, another multidimensional index, the DAS index, has been increasingly used [65]. However, it was not used in any of the trials included in the current review. ACR20, 50 and 70 responses are well-known validated response criteria and they were available in all these anti-TNFα studies, enabling us to conduct a combined analysis and statistical evaluation of the results. Another important subject in the evaluation of the response of RA to anti-TNFα drugs is the quantification of radiological damage (inhibition of progression of structural joint damage). The modified Sharp score was analysed in six trials providing 12-month results and showing the ability of infliximab, etanercept and adalimumab to inhibit the progression of structural joint damage in RA [19, 20, 26, 28, 32, 33]. Nevertheless, several factors deterred us from using this score as an outcome variable: since it is not normally distributed, the way this index was summarised and displayed in the identified trials did not permit statistical pooling of the results. Moreover the clinical implications of this radiological finding are not yet well understood.

Safety issues are also of central concern. Although we focused solely on published results from well-designed randomised controlled trials, our review shows that patients receiving anti-TNFα drugs are more prone to experience adverse events. Although some of the relative safety estimates are statistically significant, their magnitude is rather small and their clinical relevance should be also addressed. Patients on infliximab and adalimumab withdrew from the trial because of adverse events more frequently than patients on etanercept. Treatment with infliximab is associated with higher frequencies of serious adverse events and infections. If high doses are administered, there is also an increased likelihood of severe infections. All in all, the safety/efficacy relationship as estimated by the NNH/NNT ratio appears to be favourable.

Two metaanalysis have been performed previously [66, 67] focusing the problem, although none has been published. Both showed a greater efficacy of etanercept against infliximab. A comprehensive technical report addressing these issues, including an economic evaluation, has recently been published by Chen et al. [68]. Although the deadline for inclusion of studies was February 2005, that article pooled information from 29 studies as its inclusion criteria were much broader: it included studies of shorter duration [46, 43, 4648, 44], studies using other than the recommended routes of administration [49, 51, 52], studies in which no arm received recommended doses [62] and a trial in which efficacy was not measured using ACR criteria [58]. It also included unpublished studies. Despite this less restrictive approach, the Chen et al. paper likewise confirms the efficacy of all three marketed anti-TNFα drugs at recommended doses, especially when administered to patients with previous resistance to MTX.

A metaanalysis recently published by Bongartz et al. [7] focused on safety matters regarding infliximab and adalimumab. The risk of malignancies and infections was increased when higher doses were administered. There have been some controversies surrounding its conclusions, involving the accuracy of clinical trials with short follow-up as a means of detecting severe adverse events [69]. With respect to severe infections, our metaanalysis, although it detected a higher frequency in the anti-TNFα arms, showed no significant difference. We pooled safety data from the three available treatments whereas Bongartz et al. [7] only analysed infliximab and adalimumab using a fixed effects pooling method. If we restrict our analysis to infliximab and adalimumab and use a fixed effects model, we also find a significantly higher frequency of severe infections (p = 0.047) with an NNH of 61 (41–126). Therefore, it is likely that the use of both drugs, especially in higher than recommended doses, may increase the risk of severe infections. This risk has not so far been shown for etanercept, but as far as we are aware no study with higher than recommended doses has been published. Our results regarding the incidence of malignancies do not agree with those of Bongartz et al. [7], but they also include malignancies developed at a later stage when the trials are no longer underway.

Recently, two systematic reviews with meta-analysis have been published addressing the role of anti-TNFα drugs as added to MTX vs. MTX alone [70, 71]. Both articles select a very limited number of trials, and share an important design limitation, namely, they compare clinical trials that recruit both MTX-naïve patients and MTX-resistant patients, which, from our standpoint leads to their results facing validity problems.

There are limitations to our study that are also shared by other published metaanalyses [7, 68] and deserve further comment. The number of published studies is scarce, there is significant heterogeneity in some relevant aspects (patient clinical profiles, comparisons undertaken and lengths of follow-up) and information on safety parameters varies widely among trials. We have attempted to deal with these limitations in the original research by designing and applying rather stringent selection criteria so that our results are based on solid coherent evidence. This reinforcement of internal validity might have been at the expense of some loss of generalizability, yet the quality of information excluded is at least controversial. We have provided these pooled NNTs as a kind of effect estimate for average risk patients. In an attempt to minimise the presence of factors known to influence risks and therefore NNTs, we have selected rather homogeneous studies in terms of minimum follow-up, diagnostic criteria and have further made subgroup analyses accounting for several important clinical characteristics. We have performed an extensive and detailed analysis of available efficacy and safety data.

Conclusion

It may be concluded that the three marketed anti-TNFα drugs are more effective than the corresponding control treatments (MTX or placebo) in RA patients, with an NNT of 5 for ACR20 and ACR50 and of 7 for ACR70 at currently recommended doses (Table 3). High heterogeneity among trials is apparent in key design aspects and is reflected in the results of the combined analysis of all trials, calling for more in-depth assessment of more homogeneous subgroups. When this task is addressed, patients with previously inadequate responses to MTX show similar positive responses when any of the anti-TNFα drugs are added to their treatment regimes. However, when anti-TNFα drug plus MTX is compared with MTX alone in patients with no previous resistance to MTX, the relative efficacy of the combined regime is much lower. Etanercept and adalimumab are superior to the placebo but their effect in monotherapy is similar to that obtained with MTX. Therefore, we advise against starting treatment with anti-TNFα drugs until a lack of adequate response to MTX is clearly documented. Increasing doses lead to no increase in efficacy (Table 3). Analysis of the effect of low anti-TNFα doses suggests that patients treated with etanercept or adalimumab might obtain clinically substantial benefits with doses lower than those currently recommended if indicated on the basis of safety or other grounds.

Overall, patients on anti-TNFα drugs experience adverse events more frequently and those using infliximab and adalimumab have higher withdrawal rates. Infliximab use is associated with a higher likelihood of severe adverse events including severe infections. Interestingly, though, patients using etanercept seem to do so with lower frequency, although this finding might be due to the limitation of the range of doses used to those recommended by the manufacturer. We found no significant difference in the development of malignancies during the follow-up times in the studies. The safety/efficacy relationship is favourable, especially if recommended doses are used. The safety profile of etanercept might be apparently superior because the other drugs were tested over a wider range of doses, including higher than recommended ones.

Although more research is warranted, especially well-powered head to head randomised comparisons of anti-TNFα drugs, our study helps to clarify some frequently encountered questions in the clinical care of RA patients.

Declarations

Authors’ Affiliations

(1)
Rheumatology service (Cruces Hospital)
(2)
Clinical epidemiology section (Cruces Hospital)
(3)
Health library (Donostia Hospital)
(4)
Department of applied mathematics, statistics and operational research, faculty of science and technology (University of the Basque Country)
(5)
Department of pharmacology, faculty of medicine and odontology (University of the Basque Country)

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