RHEUMATOLOGY
Rheumatology 2012;51:v31–v37
doi:10.1093/rheumatology/kes116
Biologic monotherapy as initial treatment in
patients with early rheumatoid arthritis
Juan Gómez-Reino1
Abstract
Although biologic agents are most well established as part of combination regimens in patients with RA,
biologic monotherapy is common in clinical practice. To date, few double-blind, randomized clinical trials
have compared biologic monotherapy with MTX monotherapy. Five randomized double-blind trials evaluating the TNF antagonists etanercept (ERA and TEMPO), adalimumab (PREMIER) and golimumab
(GO-BEFORE) and the IL-6 receptor antagonist tocilizumab (AMBITION) were identified. We noted considerable variation in patient characteristics (i.e. disease duration and disease severity) in the five trials.
Studies involving monotherapy with TNF inhibitors found no clear clinical efficacy advantage over MTX
monotherapy. In the two trials that included a TNF inhibitor/MTX combination arm, combination therapy
was superior to monotherapy with either agent alone. In contrast, the AMBITION trial demonstrated that
tocilizumab monotherapy was superior to MTX in terms of clinical response, disease activity, remission
and functionality. Although results cannot be compared across clinical trials, tocilizumab was the only
biologic agent to demonstrate superiority to MTX as monotherapy in patients with RA with limited/no
exposure to MTX.
Key words: biologic monotherapy, rheumatoid arthritis, clinical efficacy.
Introduction
The importance of early therapeutic intervention to relieve
symptoms, prevent newly evolving joint erosions and joint
space narrowing and improve functional abilities and
quality of life in patients with active RA is well established
[1, 2]. The conventional DMARD MTX is the standard of
care for patients with RA. Although the efficacy of MTX in
reducing RA symptoms is recognized, it is often associated with increased toxicity and adverse events [1, 3].
Additionally, select patients with RA are intolerant to other
conventional DMARDs, and drug interactions exist that
preclude the use of DMARDs (including MTX) with certain
medications. These limitations highlight the need for additional therapies in patients with RA.
An increased understanding of the underlying disease
pathology has led to the development of various biologic
agents that have emerged as important therapeutic options for the treatment of RA [2, 4]. Biologic agents include
1
Division of Rheumatology, Department of Medicine, Hospital Clı́nico
Universitario, Universidad de Santiago, Santiago, Spain.
Submitted 2 December 2011; revised version accepted
29 March 2012.
Correspondence to: Juan Gómez-Reino, Division of Rheumatology,
Hospital Clı́nico Universitario, A Choupana s/n, 15706 Santiago, Spain.
E-mail: [email protected]
TNF antagonists (e.g. infliximab, etanercept, adalimumab,
certolizumab and golimumab), an IL-1 receptor antagonist
(anakinra), an anti-CD20 antibody (rituximab), a cytotoxic T
lymphocyte antigen-4 fusion protein (abatacept) and most
recently, an IL-6 receptor (IL-6R) antagonist (tocilizumab).
The efficacy of biologic agents in combination with MTX is
well established and that appears to be the most effective
regimen currently available for patients with early or established RA [2] who have failed to respond to traditional
DMARDs. However, biologic monotherapy also is commonly used in clinical practice. Indeed, a survey of RA
prescribing practices found that 28–30% of patients with
newly diagnosed RA received a biologic agent as monotherapy [5]. With the accumulation of efficacy data and a
favourable safety profile, we examined the role of biologic
agents as monotherapy in patients with RA. We reviewed
five clinical trials that examined biologic monotherapy as
initial treatment in patients with active RA who have not
been classified as inadequate responders or nonresponders to any conventional DMARD or have had limited or no prior exposure to MTX. PubMed searches were
done to identify clinical trials evaluating biologic monotherapy as initial treatment in patients with active RA who have
not been classified as inadequate responders or
non-responders to conventional disease-modifying
agents or have had limited or no prior exposure to MTX.
! The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
v32
GO-BEFORE [11]
AMBITION [9]
PREMIER [8]
TEMPO [7]
a
Taking CSs at baseline; bmean number of previous DMARDS; cvalues are for intent-to-treat population; dmean number of previous DMARDs/TNF inhibitors. ADA: adalimumab; ETAN:
etanercept; GOL: golimumab; NR: not reported; pts: patients; TCZ: tocilizumab.
4.4
3.3
3.7
3.2
2.6
3.0
4.1
4.0
3.9
3.0
3.1
2.6
2.6
2.4
NR
NR
NR
5.7
5.5
5.5
6.4
6.3
6.3
6.8
6.8
5.0
5.2
5.1
11.2
12.4
12.9
21.8
26.8
21.8
18.8
21.9
18.1
NR
NR
NR
NR
NR
24
24
24
23.0
22.6
22.1
21.8
22.1
21.1
19.1
19.2
14.9
15.2
15.9
NR
NR
NR
NR
NR
NR
NR
NR
NR
1.2d
1.1d
NR
NR
NR
NR
NR
NR
42
42
44
NR
NR
NR
33
33
NR
NR
NR
0.9
1.0
1.0
6.3
6.8
6.8
0.7
0.8
0.7
6.4
6.2
2.9
4.1
3.6
75
74
75
77
79
74
77
74
72
83
79
84
84
82
50
51
49
53.2
53.0
52.5
52.1
52.0
51.9
50.7
50.0
48.6
48.2
50.6
208
207
217
223
228
231
274
257
268
286c
284c
160
159
318
ETAN 10 mg
ETAN 25 mg
MTX
ETAN
MTX
ETAN/MTX
ADA
MTX
ADA/MTX
TCZ
MTX
MTX
GOL 100 mg
GOL 50 or 100 mg/MTX
ERA [6]
No. of pts
Regimen
Study
39
40
46
2.3b
2.3b
2.3b
33
32
33
1.2d
1.1d
52
59
54
42a
39a
41a
57
64
62
37a
35a
36a
48
47
68
64
68
31
31
30
35.0
33.1
34.2
31.8
32.3
30.7
31.8
31.1
27.3
27.3
28.3
DAS-28
TSS
Anti-TNF
Women, %
RA duration
(mean) years
Age (mean)
years
TABLE 1 Patient characteristics in monotherapy trials
In the 1-year, randomized, double-blind three-arm ERA
trial, patients with ERA [i.e. 43 years’ disease duration
(N = 632)] who were MTX naive were administered MTX
(maximum 20 mg weekly) or etanercept (10 or 25 mg
twice weekly; Table 1) [6–9]. Patients were required to
be at risk for rapidly progressive joint damage based on
a positive RF status, the presence of bone erosions,
tender joint count (TJC)/SJC, elevated acute-phase reactant levels (i.e. CRP, ESR) and morning stiffness. The primary clinical endpoint was the percentage improvement
in the numeric index of the ACR-N area under the curve
(AUC) at week 24, and the primary radiographic endpoint
was the change from baseline in total Sharp score (TSS) at
1 year. Regardless of the treatment group, 39–46% of
patients were previously on DMARD therapy and
23–25% were using a DMARD at the time of screening.
The mean number of prior DMARDs used by the patients
ranged from 0.5 to 0.6 [6].
Etanercept 25 mg was associated with a more rapid
rate of clinical improvement and less radiographic progression compared with MTX monotherapy during the initial months of treatment [6]. Patients in the etanercept
25-mg group had significantly higher ACR-N AUC values
compared with MTX at months 3, 6, 9 and 12 (Fig. 1) [6]. A
significantly greater proportion of patients receiving etanercept 25 mg showed ACR20, ACR50 and ACR70 improvement during the first 6 months of the study
compared with MTX; however, response rates were generally similar thereafter (Table 2) [6–10]. At 12 months,
ACR20 values for the etanercept 25-mg and MTX
groups (72 and 65%, respectively) were no longer significantly different. The etanercept 25-mg dose was significantly superior to the 10-mg dose as assessed by ACR20,
ACR50 and ACR70 responses and the ACR-N AUC at
12 months (P < 0.03 for all comparisons). Compared
with MTX, there also was a significant decrease in bone
erosion and joint space narrowing with etanercept.
MTX
Etanercept
CS
TNF antagonists
DMARD
Prior therapy, %
TJC
Five large clinical trials have assessed the efficacy of either
TNF antagonist monotherapy or tocilizumab monotherapy
in patients with RA who have limited or no prior exposure to
MTX [6–11]. Importantly, there were substantial differences
in patient characteristics in the various studies. For example, patients in the Early Rheumatoid Arthritis (ERA)
and PREMIER studies had short disease duration
(1 year) [6, 8], whereas those in the Trial of Etanercept
and MTX with Radiographic Patient Outcomes (TEMPO)
and the ACTEMRA vs MTX Double-Blind Investigative
Trial in Monotherapy (AMBITION) had a much longer disease duration (6–7 years) [7, 9]. Disease activity was lowest
in TEMPO [28-joint DAS (DAS-28) ranged from 5 to 6] [7]
and highest in AMBITION (DAS-28 = 6.8) [9], and mean
swollen joint count (SJC) ranged from 19 in AMBITION
[9] to 24 in ERA [6].
JC
Disease characteristics (mean)
Efficacy of biologic monotherapy in
clinical trials
CRP, mg/dl
Juan Gómez-Reino
www.rheumatology.oxfordjournals.org
Biologic monotherapy in RA
FIG. 1 Mean ACR-N responses by treatment in the ERA trial [6].
*P < 0.05 vs MTX; yP < 0.05 between etanercept groups. Reproduced from Bathon JM, Martin RW, Fleischmann RM et al.
A comparison of etanercept and MTX in patients with ERA. N Engl J Med 2000;343;1586–93. ! 2000. With permission
from Massachusetts Medical Society. All rights reserved.
TABLE 2 Efficacy findings of monotherapy trials at 1 yeara
ACR response, %
Study
ERA [6]
TEMPO [7, 9, 11]
PREMIER [8]
AMBITION [9]
GO-BEFORE [11]
Regimen/no.
of patients
ETAN 10 mg (n = 208)
ETAN 25 mg (n = 207)
MTX (n = 217)
ETAN (n = 223)
MTX (n = 228)
ETAN/MTX (n = 231)
ADA (n = 274)
MTX (n = 257)
ADA/MTX (n = 268)
TCZ (n = 286)
MTX (n = 284)
MTX (n = 160)
GOL100 mg (n = 159)
GOL50 or
100/MTX/MTX
(n = 318)
Disease activity
Radiographic
Health
ACR20
ACR50
ACR70
DAS-28b
Remission,
%c
TSSb
No
progression, %d
HAQb HAQ-DIb
60e
72
65
76
75
85
54
63
73
69.9
52.5
49.4
51.6
61.6
32e
49e
44e
48
43
69
41
46
62
44.1
33.5
29.4
32.7
38.4
15e
24e
21e
24
19
43
26
28
46
28.0
15.1
15.6
13.8
21.1
NR
NR
NR
NR
NR
NR
NR
NR
NR
3.31
2.05
NR
NR
NR
NR
NR
NR
16
13
35
23
21
43
33.6
12.1
28.1/11.3f
25.2/15.7f
38.1/22.3f
1.58e
1.00
1.59
0.52
2.80
0.54
3.0
5.7
1.3
NR
NR
NR
NR
NR
NR
NR
NR
68
57
80
51
37
64
NR
NR
NR
NR
NR
NR
NR
NR
0.7
0.6
1.0
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
0.8
0.8
1.1
0.7
0.5
NR
NR
NR
a
Shown are 24-week results for AMBITION and GO-BEFORE; bmean change from baseline; cDAS-28 4 2.6; dTSS 4 0.5;
estimated value from graph; fremission using CRP/ESR. ADA: adalimumab; ETAN: etanercept; HAQ-DI: HAQ Disability
Index; NR: not reported; TCZ: tocilizumab.
e
The percentage of patients with no increase in the erosion
score was higher (72% vs 60%; P = 0.007), and the mean
increase in erosion score at 12 months was lower (0.47 vs
1.03; P = 0.002), in the etanercept 25-mg group compared
with those receiving MTX. Although both drugs were generally well tolerated, treatment with etanercept 25 mg was
associated with fewer adverse events (P = 0.02) and fewer
infections (1.5 vs 1.9/patient-year; P = 0.006) than was
treatment with MTX. Nausea (17% vs 29%), rash
(12% vs 23%), alopecia (6% vs 12%) and mouth ulcers
www.rheumatology.oxfordjournals.org
(5% vs 14%) were less common in patients receiving
etanercept 25 mg compared with those receiving MTX,
whereas injection-site reactions were more frequent in
the etanercept 25-mg group than in the MTX group
(37% vs 7%). Overall, this study demonstrated that etanercept monotherapy more rapidly decreased symptoms
and joint damage in patients with ERA compared with
MTX. However, clinical response did not differ significantly
between those receiving the biologic agent and those
receiving the conventional DMARD at 12 months [6].
v33
Juan Gómez-Reino
TEMPO was a 52-week, double-blind, randomized
three-arm trial that also evaluated etanercept and MTX
monotherapies, but compared them with combination
etanercept and MTX in patients with active RA [7].
Eligible patients >18 years with disease duration of
6 months to 20 years were enrolled. Patients were
required to have had an incomplete response to
DMARDs other than MTX as assessed by the investigator.
Previous MTX users were enrolled only if they had no clinically important toxicity (or adverse effects) or lack of
response while on MTX (i.e. only patients deemed appropriate for MTX therapy were included). A total of 686 eligible patients with active RA were randomly assigned to
receive etanercept (25 mg twice weekly) or MTX (up to
20 mg every week) monotherapy or etanercept/MTX combination therapy (Table 1) [7]. The mean number of previous DMARDs used by patients was 2.3 in all three
treatment groups, and 42–44% of patients had received
prior MTX therapy. The primary endpoint was the ACR-N
AUC at week 24 of therapy [7].
Etanercept plus MTX combination therapy significantly
reduced disease activity, improved functional disability
and retarded radiographic progression compared with
either etanercept or MTX monotherapy; however, no significant difference between monotherapy regimens was
observed (Table 2) [7]. At 24 weeks, ACR-N AUC was significantly greater in the combination and etanercept monotherapy groups [18.3 percentage-years (95% CI 17.1, 19.6)
and 14.7 percentage-years (95% CI 13.5, 16.0), respectively] than in the MTX group [12.2 percentage-years (95%
CI 11.0, 13.4)]. At 1 year, significantly more patients receiving etanercept plus MTX combination therapy achieved
ACR20 response (85%) compared with those receiving
etanercept (76%; P = 0.0151) or MTX (75%; P = 0.0091)
alone. ACR50 and ACR70 responses also were consistently higher with the combination therapy regimen. For example, ACR50 response was achieved in 69, 48 and 43%,
respectively, of patients in the combination, etanercept
and MTX groups at 1 year (P < 0.0001 for combination vs
either monotherapy). Combination therapy also was associated with significantly greater reductions in DAS disease
activity compared with either monotherapy regimen.
One-year remission rates were 35, 16 and 13%, respectively, for the combination, etanercept and MTX groups.
Combination therapy also significantly improved functional
disability and retarded radiographic progression compared with either etanercept or MTX monotherapy, as evidenced by greater reductions in mean HAQ scores (1.0,
0.7 and 0.6, respectively; P < 0.0001 for combination vs
either monotherapy). Finally, the mean improvement in van
der Heijde-modified TSS was significantly greater in the
combination therapy group vs the etanercept and MTX
groups. Combination therapy was associated with a 0.54
reduction in TSS, whereas scores increased by 0.52 and
2.80, respectively, in the etanercept and MTX groups [7]. A
2-year follow-up of patients found that the benefits of combination therapy were sustained with significantly greater
effects on clinical response, disease activity, disability and
radiographic progression for combination therapy
v34
compared with either etanercept or MTX monotherapy
(Table 3) [10].
All regimens were generally well tolerated, with a similar
number of adverse events among treatment groups [7].
Injection-site reactions were significantly more common
in the combination and etanercept monotherapy arms
compared with the MTX group (10, 21 and 2%, respectively; P < 0.001 for both groups vs MTX). Nausea (24, 10
and 32%; P < 0.0001 for etanercept monotherapy vs MTX)
and vomiting (5, 3 and 11%; P < 0.05 for both groups vs
MTX) were less common in the etanercept groups [7].
Adalimumab
The efficacy and safety of adalimumab monotherapy were
evaluated in the PREMIER study, which compared adalimumab plus MTX vs either adalimumab or MTX monotherapy in patients with ERA [8]. PREMIER was a 2-year,
multicentre, randomized double-blind trial in 799 patients
with ERA (i.e. disease duration <3 years) with no prior
MTX exposure and prior treatment with no more than
two other DMARDs. Patients were randomly assigned to
one of the three regimens: adalimumab 40 mg s.c. every
other week plus MTX 20 mg/week, adalimumab 40 mg s.c.
every other week monotherapy or MTX 20 mg/week
monotherapy (Table 1) [8]. The co-primary endpoints
were ACR50 responses and the mean change from baseline in the modified TSS at year 1. The mean duration of
RA was <1 year and patients had active disease (mean
DAS-28, 6.3–6.4). Approximately one-third of patients had
received prior DMARDs and slightly more than one-third
were taking CSs at study onset [8].
Adalimumab plus MTX combination therapy was superior compared with either drug as monotherapy at both
1 and 2 years with respect to ACR responses, inhibition
of radiographic progression, improvement in HAQ scores
and clinical remission (Table 2) [8]. At 1 year, 62% of patients in the combination therapy group achieved ACR50
response compared with 41% and 46%, respectively, for
the adalimumab and MTX groups (P < 0.001 for combination therapy vs either monotherapy). ACR50 responses
continued to be significantly superior in the combination
group at year 2. Similar patterns were seen for ACR20,
ACR70 and ACR90 responses. ACR responses were not
significantly different between monotherapy groups
except that ACR20 at 1 year was significantly better in
the MTX group than in the adalimumab group. The combination therapy was associated with significantly less
radiographic progression over 2 years compared with
either monotherapy. Further, there was significantly less
radiographic progression in the adalimumab monotherapy
arm compared with the MTX monotherapy arm, as evidenced by lower mean increases in TSS at 6 months
(2.1 vs 3.5), 1 year (3.0 vs 5.7) and 2 years (5.5 vs 10.4;
P < 0.001 for all comparisons). Significantly more patients
receiving adalimumab plus MTX or adalimumab monotherapy had no radiographic progression (i.e. change in
van der Heijde-modified TSS 40.5 from baseline) compared with those receiving MTX monotherapy at 1 year
(64, 51 and 37%, respectively; P < 0.01 for both adalimumab groups vs MTX) or 2 years (61, 45 and 34%,
www.rheumatology.oxfordjournals.org
Biologic monotherapy in RA
TABLE 3 Disease characteristics after 2 years in the TEMPO trial: change from baseline in the ITT population [10]
Year
Year 1
TSS
Mean (95% CI)
Median (IQR)
Erosion score
Mean (95% CI)
Median (IQR)
Joint space narrowing score
Mean (95% CI)
Median (IQR)
Year 2
TSS
Mean (95% CI)
Median (IQR)
Erosion score
Mean (95% CI)
Median (IQR)
Joint space narrowing score
Mean (95% CI)
Median (IQR)
MTX (n = 206)
ETAN (n = 203)
ETAN/MTX (n = 213)
1.50 (0.42, 2.58)
0.00 (0.49 to 1.01)
0.33 (0.18, 0.84)a
0.00 (0.51 to 0.50)
0.80 (1.16, 0.44)b
0.00 (1.00 to 0.00)
0.99 (0.27, 1.71)
0.00 (0.45 to 0.73)
0.03 (0.32, 0.38)a
0.00 (0.51 to 0.00)
0.64 (0.93, 0.36)c
0.00 (1.00 to 0.00)
0.51 (0.09, 0.93)
0.00 (0.00 to 0.00)
0.30 (0.06, 0.54)
0.00 (0.00 to 0.00)
0.16 (0.31, 0.00)b
0.00 (0.00 to 0.00)
3.34 (1.18, 5.50)
0.00 (0.11 to 2.33)
1.10 (0.13, 2.07)a
0.00 (0.66 to 1.08)
0.56 (1.05, 0.06)b
0.00 (1.41 to 0.05)
2.12 (0.66, 3.57)
0.00 (0.37 to 1.46)
0.36 (0.25, 0.97)a
0.00 (0.66 to 0.50)
0.76 (1.13, 0.38)b
0.00 (1.07 to 0.00)
1.23 (0.39, 2.06)
0.00 (0.00 to 0.50)
0.74 (0.25, 1.23)
0.00 (0.00 to 0.00)
0.20 (0.03, 0.44)a
0.00 (0.00 to 0.00)
a
P < 0.05 vs MTX; bP < 0.05 vs MTX and vs ETAN; cP < 0.05 vs ETAN. ETAN: etanercept; ETAN/MTX: etanercept plus MTX;
IQR: interquartile range; ITT: intent-to-treat. Reproduced from van der Heijde D, Klareskog L, Rodriguez-Valverde V et al.
Comparison of etanercept and MTX, alone and combined, in the treatment of RA: two-year clinical and radiographic results
from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006;54;1070, with permission from John Wiley &
Sons, Inc.
respectively; P < 0.01 for both adalimumab groups vs
MTX). The clinical remission rate (i.e. DAS-28 <2.6) at 1
year was significantly higher in the combination therapy
group (43%) compared with the adalimumab and MTX
monotherapy groups (23 and 21%, respectively;
P < 0.001 for combination vs both monotherapy groups).
Similar results were observed at 2 years, with a significantly greater remission rate in the combination therapy
arm but no difference between the monotherapy arms (49,
25 and 27%, respectively; P < 0.001 for combination vs
both monotherapy arms) [8]. Patients completing the
2-year core trial were eligible to receive adalimumab
with or without MTX for a total of 10 years of treatment.
Results after 8 years of follow-up showed effective control
of joint progression with adalimumab, but longer-term
outcomes were superior in patients who initially received
combination therapy compared with those receiving adalimumab or MTX alone [12].
The adverse event profiles were comparable in all three
groups, with no significant differences in the overall adverse events, serious events or rates of infection except
that serious infections were significantly more common in
the combination therapy group than in the adalimumab
monotherapy group (2.9% vs 0.7%; P < 0.05) [8].
Overall, this study demonstrated that MTX plus adalimumab combination therapy was more effective than monotherapy in reducing symptoms associated with RA, but
that there was no clear advantage of adalimumab monotherapy compared with MTX monotherapy [8].
www.rheumatology.oxfordjournals.org
Golimumab
In a phase 3 trial, Golimumab Before Employing MTX as
the First-line Option in the Treatment of Rheumatoid
Arthritis of Early Onset (GO-BEFORE), 637 MTX-naive patients with RA were randomly assigned to receive placebo
plus MTX, golimumab 100 mg plus placebo, golimumab
50 mg plus MTX or golimumab 100 mg plus MTX [11].
The primary endpoint of the study was not met; analysis
of the ACR50 response at week 24 did not show a statistically significant difference between the golimumab plus
MTX groups combined compared with MTX plus placebo
(38 and 29%, respectively; P = 0.053) [11]. Following a
post hoc analysis that excluded three untreated patients,
a significant difference was noted between the combined
treatment groups and MTX alone. Other efficacy parameters, including DAS-28 response and remission rates,
also showed greater improvements with combined treatment than with placebo plus MTX. Golimumab monotherapy also reduced signs and symptoms, but was similar in
efficacy to MTX alone [11].
IL-6R inhibitor
The AMBITION study was designed to evaluate the efficacy and safety of IL-6R inhibition through tocilizumab
monotherapy compared with MTX monotherapy in patients with active RA whose disease had not failed prior
biologic agent or MTX therapy [9]. AMBITION was a
24-week, double-blind, double-dummy randomized trial
in which 673 patients with active RA were given
v35
Juan Gómez-Reino
FIG. 2 Effects of tocilizumab or MTX treatment on ACR20,
ACR50 and ACR70 responses in the AMBITION trial [9].
*P < 0.001; yP = 0.002; zP 4 0.005; §P = 0.01 vs MTX.
(A) Proportion of patients achieving ACR20, ACR50 and
ACR70 responses at week 24 (ITT population).
(B) Proportion of MTX-naive patients achieving ACR20,
ACR50 and ACR70 responses at week 24 (ITT population).
Reproduced from Jones G, Sebba A, Gu J et al.
Comparison of tocilizumab monotherapy vs MTX
monotherapy in patients with moderate to severe RA:
the AMBITION study. Ann Rheum Dis 2010;69:88–96. !
2010. With permission from BMJ Publishing Group Ltd.
tocilizumab 8 mg/kg every 4 weeks, MTX up to 20 mg/
week or placebo (for 8 weeks followed by tocilizumab
8 mg/kg; Table 1) [9]. Patients were required to have moderate to severe active RA for 53 months and were
excluded if they had been unsuccessfully treated with a
TNF inhibitor, had received MTX within 6 months of
random allocation or had discontinued prior MTX therapy
because of lack of efficacy or clinically important adverse
events. The mean disease duration was 6.3 years and
about two-thirds of patients were MTX naive. The mean
number of previous DMARDs or TNF inhibitors was 1.2
and just less than 50% of patients had previously used
oral CSs. The primary endpoint was the percentage of
patients achieving ACR20 response at week 24 [9].
Tocilizumab monotherapy was superior to MTX alone
for the primary endpoint (ACR20 response at week 24),
with values of 69.9 and 52.5%, respectively (P < 0.001),
when assessed in the intent-to-treat population (Fig. 2 and
v36
Table 2) [9]. Tocilizumab monotherapy also was superior
to MTX monotherapy for ACR50 (44.1% vs 33.5%;
P = 0.002) and ACR70 (28.0% vs 15.1%; P < 0.001) response at week 24. Similar results were observed when
the analysis was restricted to patients who were MTX
naive; tocilizumab demonstrated significant superiority
for ACR20, ACR50 and ACR70 responses at 24 weeks
compared with MTX (Fig. 2) [9]. Improvements in
DAS-28 at week 24 also were significantly greater in patients receiving tocilizumab, who were 5.8-fold more likely
to achieve DAS-28 remission. Tocilizumab was associated with a significantly greater reduction in disability
as evidenced by HAQ Disability Index scores (treatment
difference, 0.2; 95% CI 0.3, 0.1; Table 2) [9]. Further,
tocilizumab was superior to MTX in decreasing
acute-phase reactants (i.e. CRP and ESR), with CRP
levels normalized in >90% of patients receiving tocilizumab after 12–24 weeks [9].
Both treatments were well tolerated and demonstrated
similar incidence rates for overall adverse events, serious
events, infections, gastrointestinal events and events
leading to discontinuation or dose modification between
tocilizumab and MTX monotherapy [9]. Infusion-site reactions (5.6% vs 1.8%; P = 0.016), reversible grade 3 neutropenia (3.1% vs 0.4%) and serious infections (1.4% vs
0.7%) were more common with tocilizumab, but elevations more than three times the upper limit of normal for
alanine aminotransferase (1.7% vs 3.6%) and aspartate
aminotransferase (1.0% vs 1.5%) were more frequent for
patients in the MTX-treated group [9].
Overall, tocilizumab is the first biologic agent to demonstrate statistical superiority as monotherapy compared
with MTX in patients with early active RA with limited/no
exposure to MTX [9]. The superior efficacy of tocilizumab
and relative safety shown in this study provide evidence
that tocilizumab has a favourable risk/benefit profile in this
patient population.
Conclusions
MTX—either alone or in combination with biologic agents
or other conventional DMARDs—remains the anchor drug
for patients with RA [2, 4]. However, because patients may
not be able to tolerate conventional DMARDs or may have
contraindications to their use, patients require alternative
therapeutic options. The emergence of biologic agents
has revolutionized the treatment of RA by helping patients
achieve the goals of preventing structural damage and
restoring functional capacity through the achievement of
disease remission or a state of low disease activity [2]. In
addition, biologic agents can produce clinically meaningful improvements in health-related quality of life, including
physical function, fatigue and emotional and mental health
[13, 14]. To date, clinical trials evaluating monotherapy
with the TNF antagonists do not show any clear advantage compared with treatment with MTX [6–8]. These trials
suggest that TNF inhibitors may need to be given in conjunction with MTX in order to improve the clinical efficacy
of MTX monotherapy in patients who have not been
deemed as MTX non-responders. Furthermore, therapy
www.rheumatology.oxfordjournals.org
Biologic monotherapy in RA
with TNF inhibitors in combination with MTX is clearly
more effective than TNF inhibitor monotherapy [8–10].
Recent data with tocilizumab provide promising results
of a biologic agent as monotherapy. The results of the
AMBITION trial demonstrated that tocilizumab was superior to MTX in terms of clinical response, disease activity,
remission and functionality in patients who had not previously failed MTX or other biologic therapy [9]. Although it
is impossible to compare results across clinical trials, the
results with tocilizumab compare favourably with those
demonstrating the efficacy of TNF antagonists with MTX.
So far, tocilizumab is the only biologic agent to demonstrate clinical superiority compared with MTX monotherapy [9]. These data suggest that tocilizumab monotherapy
may be a favourable treatment when compared with MTX
monotherapy in certain patient populations with RA.
Rheumatology key messages
Biologic monotherapy has demonstrated efficacy in
RA patients never exposed to/never failed MTX.
. RA patients intolerant to traditional DMARDs may
benefit from biologic monotherapy.
.
Acknowledgements
The author thanks ApotheCom for writing and editorial
assistance, which was funded by F. Hoffmann-La Roche
Ltd.
Funding: This study was funded by Roche. Support for
third-party writing assistance for this supplement was provided by F. Hoffmann-La Roche Ltd.
Supplement: This article forms part of the supplement
‘Current Treatment Options and New Directions in the
Management of Rheumatoid Arthritis’. This supplement
was commissioned and funded by F. HoffmannLa Roche Ltd.
Disclosure statement. J.G.-R. is on the advisory boards of
Pfizer, MSD, Schering-Plough, Wyeth, Bristol Meyers
Squibb, Roche and UCB; has received lecture fees from
Abbott Laboratories, MSD, Wyeth, Roche, Bristol Meyers
Squibb and Schering-Plough and has received grants
from Schering-Plough and Roche.
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